Search

This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effectiveness of manual paper reminders in changing professional practice and improving patient outcomes To explore whether a number of potential effect modifiers influence the effectiveness of manual paper reminders

Hyperthermia is a type of cancer treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells. It was introduced into clinical oncology practice several decades ago. Positive clinical results, mostly obtained in single institutions, resulted in clinical implementation albeit in a limited number of cancer centres worldwide. Because large scale randomised clinical trials (RCTs) are lacking, firm conclusions cannot be drawn regarding its definitive role as an adjunct to radiotherapy in the treatment of locally advanced cervical carcinoma (LACC).To assess whether adding hyperthermia to standard radiotherapy for LACC has an impact on (1) local tumour control, (2) survival and (3) treatment related morbidity.The electronic databases of the Cochrane Central Register of Controlled Trials (CENTRAL), (Issue 1, 2009) and Cochrane Gynaecological Cancer Groups Specialised Register, MEDLINE, EMBASE, online databases for trial registration, handsearching of journals and conference abstracts, reviews, reference lists, and contacts with experts were used to identify potentially eligible trials, published and unpublished until January 2009.RCTs comparing radiotherapy alone (RT) versus combined hyperthermia and radiotherapy (RHT) in patients with LACC.Between 1987 and 2009 the results of six RCTs were published, these were used for the current analysis.74% of patients had FIGO stage IIIB LACC. Treatment outcome was significantly better for patients receiving the combined treatment (Figures 1 to 3). The pooled data analysis yielded a significantly higher complete response rate (relative risk (RR) 0.56; 95% confidence interval (CI) 0.39 to 0.79; p

BACKGROUND: Respiratory disease is the main cause of morbidity and mortality in cystic fibrosis (CF), and many different therapies are used by people with CF in the management of respiratory problems. Bronchodilator therapy is used to relieve symptoms of shortness of breath and to open the airways to allow clearance of mucus. Despite the widespread use of inhaled bronchodilators in CF, there is little objective evidence of their efficacy. A Cochrane Review looking at both short‐ and long‐acting inhaled bronchodilators for CF was withdrawn from the Cochrane Library in 2016. That review has been replaced by two separate Cochrane Reviews: one on long‐acting inhaled bronchodilators for CF, and this review on short‐acting inhaled bronchodilators for CF. For this review 'inhaled' includes the use of pressurised metered dose inhalers (MDIs), with or without a spacer, dry powder devices and nebulisers. OBJECTIVES: To evaluate short‐acting inhaled bronchodilators in children and adults with CF in terms of clinical outcomes and safety. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books on 28 March 2022 and searched trial registries for any new or ongoing trials on 12 April 2022. We also searched the reference lists of relevant articles and reviews. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) or quasi‐RCTs that looked at the effect of any short‐acting inhaled bronchodilator delivered by any device, at any dose, at any frequency and for any duration compared to either placebo or another short‐acting inhaled bronchodilator in people with CF. We screened references as per standard Cochrane methodology. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed risk of bias using the Cochrane RoB 1 tool. Where we were not able to enter data into our analyses we reported results directly from the papers. We assessed the certainty of evidence using GRADE. MAIN RESULTS: We included 11 trials from our systematic search, with 191 participants meeting our inclusion criteria; three of these trials had three treatment arms. Eight trials compared short‐acting inhaled beta‐2 agonists to placebo and four trials compared short‐acting inhaled muscarinic antagonists to placebo. Three trials compared short‐acting inhaled beta‐2 agonists to short‐acting inhaled muscarinic antagonists. All were cross‐over trials with only small numbers of participants. We were only able to enter data into the analysis from three trials comparing short‐acting inhaled beta‐2 agonists to placebo. Short‐acting inhaled beta‐2 agonists versus placebo All eight trials (six single‐dose trials and two longer‐term trials) reporting on this comparison reported on forced expiratory volume in 1 second (FEV(1)), either as per cent predicted (% predicted) or L. We were able to combine the data from two trials in a meta‐analysis which showed a greater per cent change from baseline in FEV(1) L after beta‐2 agonists compared to placebo (mean difference (MD) 6.95%, 95% confidence interval (CI) 1.88 to 12.02; 2 trials, 82 participants). Only one of the longer‐term trials reported on exacerbations, as measured by hospitalisations and courses of antibiotics. Only the second longer‐term trial presented results for participant‐reported outcomes. Three trials narratively reported adverse events, and these were all mild. Three single‐dose trials and the two longer trials reported on forced vital capacity (FVC), and five trials reported on peak expiratory flow, i.e. forced expiratory flow between 25% and 75% (FEF(25-75)). One trial reported on airway clearance in terms of sputum weight. We judged the certainty of evidence for each of these outcomes to be very low, meaning we are very uncertain about the effect of short‐acting inhaled beta‐2 agonists on any of the outcomes we assessed. Short‐acting inhaled muscarinic antagonists versus placebo All four trials reporting on this comparison looked at the effects of ipratropium bromide, but in different doses and via different delivery methods. One trial reported FEV(1) % predicted; three trials measured this in L. Two trials reported adverse events, but these were few and mild. One trial reported FVC and three trials reported FEF(25-75). None of the trials reported on quality of life, exacerbations or airway clearance. We judged the certainty of evidence for each of these outcomes to be very low, meaning we are very uncertain about the effect of short‐acting inhaled muscarinic antagonists on any of the outcomes we assessed. Short‐acting inhaled beta‐2 agonists versus short‐acting inhaled muscarinic antagonists None of the three single‐dose trials reporting on this comparison provided data we could analyse. The original papers from three trials report that both treatments lead to an improvement in FEV(1) L. Only one trial reported on adverse events; but none were experienced by any participant. No trial reported on any of our other outcomes. We judged the certainty of evidence to be very low, meaning we are very uncertain about the effect of short‐acting inhaled beta‐2 agonists compared to short‐acting inhaled muscarinic antagonists on any of the outcomes we assessed. AUTHORS' CONCLUSIONS: All included trials in this review are small and of a cross‐over design. Most trials looked at very short‐term effects of inhaled bronchodilators, and therefore did not measure longer‐term outcomes. The certainty of evidence across all outcomes was very low, and therefore we have been unable to describe any effects with certainty.

Background Many women experience perineal pain after childbirth, especially after having sustained perineal trauma. Perineal pain-management strategies are thus an important part of postnatal care. Non-steroidal anti-inflammatory drugs (NSAIDs) are a commonly used type of medication in the management of postpartum pain and their effectiveness and safety should be assessed. Objectives To determine the effectiveness of a single dose of an oral NSAID for relief of acute perineal pain in the early postpartum period. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2016), OpenSIGLE, ProQuest Dissertations and Theses, the ISRCTN Registry and ClinicalTrials.gov (31 March 2016). We also reviewed reference lists of retrieved papers and contacted experts in the field. Selection criteria Randomised controlled trials (RCTs) assessing a single dose of a NSAID versus a single dose of placebo, paracetamol or another NSAID for women with perineal pain in the early postpartum period. Quasi-RCTs and cross-over trials were excluded. Data collection and analysis Two review authors (FW and VS) independently assessed all identified papers for inclusion and risk of bias. Any discrepancies were resolved through discussion and consensus. Data extraction, including calculations of pain relief scores, was also conducted independently by two review authors and checked for accuracy. Main results We included 28 studies that examined 13 different NSAIDs and involved 4181 women (none of whom were breastfeeding). Studies were published between 1967 and 2013, with the majority published in the 1980s. Of the 4181 women involved in the studies, 2642 received a NSAID and 1539 received placebo or paracetamol. Risk of bias was generally unclear due to poor reporting, but in most studies the participants and personnel were blinded, outcome data were complete and the outcomes that were specified in the methods section were reported. None of the included studies reported on any of this review's secondary outcomes: prolonged hospitalisation or re-hospitalisation due to perineal pain; breastfeeding (fully or mixed) at discharge; breastfeeding (fully or mixed) at six weeks; perineal pain at six weeks; maternal views; postpartum depression; instrumental measures of disability due to perineal pain. NSAID versus placebo Compared to women who received a placebo, more women who received a single dose NSAID achieved adequate pain relief at four hours (risk ratio (RR) 1.91, 95% confidence interval (CI) 1.64 to 2.23, 10 studies, 1573 participants (low-quality evidence)) and adequate pain relief at six hours (RR 1.92, 95% CI 1.69 to 2.17, 17 studies, 2079 participants (very low-quality evidence)). Women who received a NSAID were also less likely to need additional analgesia compared to women who received placebo at four hours (RR 0.39, 95% CI 0.26 to 0.58, four studies, 486 participants (low-quality evidence)) and at six hours after initial administration (RR 0.32, 95% CI 0.26 to 0.40, 10 studies, 1012 participants (low-quality evidence)). Fourteen maternal adverse effects were reported in the NSAID group (drowsiness (5), abdominal discomfort (2), weakness (1), dizziness (2), headache (2), moderate epigastralgia (1), not specified (1)) and eight in the placebo group (drowsiness (2), light headed (1), nausea (1), backache (1), dizziness (1), epigastric pain (1), not specified (1)), although not all studies assessed adverse effects. There was no difference in overall maternal adverse effects between NSAIDs and placebo at six hours post-administration (RR 1.38, 95% CI 0.71 to 2.70, 13 studies, 1388 participants (very low-quality evidence)). One small study (with two treatment arms) assessed maternal adverse effects at four hours post-administration, but there were no maternal adverse effects observed (one study, 90 participants (low-quality evidence)). Neonatal adverse effects were not assessed in any of the included studies. NSAID versus paracetamol NSAIDs versus paracetamol were also more effective for adequate pain relief at four hours (RR 1.54, 95% CI 1.07 to 2.22, three studies, 342 participants) but not at six hours post-administration. There was no difference in the need for additional analgesia between the two groups at four hours (RR 0.55, 95% CI 0.27 to 1.13, one study, 73 participants), but women in the NSAID group were less likely to need any additional analgesia at six hours (RR 0.28, 95% CI 0.12 to 0.67, one study, 59 participants). No maternal adverse effects were reported four hours after drug administration (one study). Six hours post-administration, there was no difference between the groups in the number of maternal adverse effects (RR 0.74, 95% CI 0.27 to 2.08, three studies, 300 participants), with one case of pruritis in the NSAID group and one case of sleepiness in the paracetamol group. Neonatal adverse effects were not assessed in any of the included studies. Comparisons of different NSAIDs and different doses of the same NSAID did not demonstrate any differences in their effectiveness on any of the primary outcome measures; however, few data were available on some NSAIDs. Authors' conclusions In women who are not breastfeeding and who sustained perineal trauma, NSAIDs (compared to placebo) provide greater pain relief for acute postpartum perineal pain and fewer women need additional analgesia when treated with a NSAID. However, the risk of bias was unclear for many of the included studies, adverse effects were often not assessed and breastfeeding women were not included in the studies. The overall quality of the evidence (GRADE) was low with the evidence for all outcomes rated as low or very low. The main reasons for downgrading were inclusion of studies with high risk of bias and inconsistency of findings of individual studies. NSAIDs also appear to be more effective in providing relief for perineal pain than paracetamol, but few studies were included in this analysis. Future studies should examine NSAIDs' adverse effects profile including neonatal adverse effects and the compatibility of NSAIDs with breastfeeding, and assess other important secondary outcomes of this review. Moreover, studies mostly included women who had episiotomies. Future research should consider women with and without perineal trauma, including perineal tears. High-quality studies should be conducted to further assess the efficacy of NSAIDs versus paracetamol and the efficacy of multimodal treatments.

Background Health systems need timely and reliable access to essential medicines and health commodities, but problems with access are common in many settings. Mobile technologies offer potential low‐cost solutions to the challenge of drug distribution and commodity availability in primary healthcare settings. However, the evidence on the use of mobile devices to address commodity shortages is sparse, and offers no clear way forward. Objectives Primary objective To assess the effects of strategies for notifying stock levels and digital tracking of healthcare‐related commodities and inventory via mobile devices across the primary healthcare system Secondary objectives To describe what mobile device strategies are currently being used to improve reporting and digital tracking of health commodities To identify factors influencing the implementation of mobile device interventions targeted at reducing stockouts of health commodities Search methods We searched CENTRAL, MEDLINE Ovid, Embase Ovid, Global Index Medicus WHO, POPLINE K4Health, and two trials registries in August 2019. We also searched Epistemonikos for related systematic reviews and potentially eligible primary studies. We conducted a grey literature search using mHealthevidence.org, and issued a call for papers through popular digital health communities of practice. Finally, we conducted citation searches of included studies. We searched for studies published after 2000, in any language. Selection criteria For the primary objective, we included individual and cluster‐randomised trials, controlled before‐after studies, and interrupted time series studies. For the secondary objectives, we included any study design, which could be quantitative, qualitative, or descriptive, that aimed to describe current strategies for commodity tracking or stock notification via mobile devices; or aimed to explore factors that influenced the implementation of these strategies, including studies of acceptability or feasibility. We included studies of all cadres of healthcare providers, including lay health workers, and others involved in the distribution of health commodities (administrative staff, managerial and supervisory staff, dispensary staff); and all other individuals involved in stock notification, who may be based in a facility or a community setting, and involved with the delivery of primary healthcare services. We included interventions aimed at improving the availability of health commodities using mobile devices in primary healthcare settings. For the primary objective, we included studies that compared health commodity tracking or stock notification via mobile devices with standard practice. For the secondary objectives, we included studies of health commodity tracking and stock notification via mobile device, if we could extract data relevant to our secondary objectives. Data collection and analysis For the primary objective, two authors independently screened all records, extracted data from the included studies, and assessed the risk of bias. For the analyses of the primary objectives, we reported means and proportions where appropriate. We used the GRADE approach to assess the certainty of the evidence, and prepared a 'Summary of findings' table. For the secondary objective, two authors independently screened all records, extracted data from the included studies, and applied a thematic synthesis approach to synthesise the data. We assessed methodological limitation using the Ways of Evaluating Important and Relevant Data (WEIRD) tool. We used the GRADE‐CERQual approach to assess our confidence in the evidence, and prepared a 'Summary of qualitative findings' table. Main results Primary objective For the primary objective, we included one controlled before‐after study conducted in Malawi. We are uncertain of the effect of cStock plus enhanced management, or cStock plus effective product transport on the availability of commodities, quality and timeliness of stock management, and satisfaction and acceptability, because we assessed the evidence as very low‐certainty. The study did not report on resource use or unintended consequences. Secondary objective For the secondary objectives, we included 16 studies, using a range of study designs, which described a total of eleven interventions. All studies were conducted in African (Tanzania, Kenya, Malawi, Ghana, Ethiopia, Cameroon, Zambia, Liberia, Uganda, South Africa, and Rwanda) and Asian (Pakistan and India) countries. Most of the interventions aimed to make data about stock levels and potential stockouts visible to managers, who could then take corrective action to address them. We identified several factors that may influence the implementation of stock notification and tracking via mobile device. These include challenges tied to infrastructural issues, such as poor access to electricity or internet, and broader health systems issues, such as drug shortages at the national level which cannot be mitigated by interventions at the primary healthcare level (low confidence). Several factors were identified as important, including strong partnerships with local authorities, telecommunication companies, technical system providers, and non‐governmental organizations (very low confidence); availability of stock‐level data at all levels of the health system (low confidence); the role of supportive supervision and responsive management (moderate confidence); familiarity and training of health workers in the use of the digital devices (moderate confidence); availability of technical programming expertise for the initial development and ongoing maintenance of the digital systems (low confidence); incentives, such as phone credit for personal use, to support regular use of the system (low confidence); easy‐to‐use systems built with user participation (moderate confidence); use of basic or personal mobile phones to support easier adoption (low confidence); consideration for software features, such as two‐way communication (low confidence); and data availability in an easy‐to‐use format, such as an interactive dashboard (moderate confidence). Authors' conclusions We need more, well‐designed, controlled studies comparing stock notification and commodity management via mobile devices with paper‐based commodity management systems. Further studies are needed to understand the factors that may influence the implementation of such interventions, and how implementation considerations differ by variations in the intervention., Plain language summary Using mobile phones to keep track of medicines and notify superiors when more are needed What is the aim of this review? In this Cochrane Review, we aimed to assess if health workers would have better access to medicines and other supplies, if they used mobile phones or other mobile devices to keep track of the amount of supplies they had available, and to notify superiors when they needed more supplies. We also described how health workers are currently using these mobile systems, and what factors influence their use. Key messages We do not know if using mobile phones to keep track of medical supplies gives primary healthcare workers better access to these supplies. This is because the certainty of the available evidence was very low. However, the evidence does point to several factors that could influence the implementation of these systems. These include the sharing of data across all levels of the health system; reliable access to electricity and the internet; easy‐to‐use and functional phones and systems; good technical support; and sufficient training and supervision. Well‐functioning digital systems will only succeed if medical supplies are actually available. What was studied in the review? Healthcare workers need medicines, vaccines, syringes, and other supplies to do their jobs properly. But many healthcare settings, particularly in poor countries, often lack supplies because governments cannot afford to buy them, or because they do not have good systems for distributing them to the right places at the right time. To address some of these problems, managers and health workers can use mobile phones to keep track of supplies, decide how much more to order and when, and let people at higher levels of the system know when supplies are running low. The main aim of our review was to find out if health workers who use these mobile systems had better access to supplies than health workers using other systems, or no systems at all. We also looked at how these mobile systems are being used in primary healthcare settings, and the factors that influences their use. What are the main results of the review? We found one study from Malawi that measured the effect of mobile phone systems on access to medicines and supplies in health facilities. However, we do not know whether these systems improve access or not, because the certainty of this evidence was very low. We found 16 studies conducted in African and Asian countries, in which study authors identified several factors that could help to set up systems successfully. ‐ Study authors suggested that allowing healthcare officials at all levels of the healthcare system to see the data could help them to respond on time and avoid supply shortages (low confidence). ‐ Study authors highlighted how poor access to electricity and internet could make it difficult for health workers to charge phones and send data (moderate confidence). ‐ Study authors pointed to the importance of user‐friendly systems, built with user participation (moderate confidence); access to technical experts to develop and maintain the system (low confidence); proper support and supervision for health workers (moderate confidence); and training of health workers in how to use the mobile system itself (moderate confidence). ‐ One author suggested that adding phone credits to health workers’ mobile phones for their personal use, could motivate them, and improve their use of the system (low confidence). Study authors also suggested several mobile phone functions that could be helpful to health workers using these systems. These included phones that could take pictures and map geographic locations, systems that allowed toll‐free text messaging, two‐way communication, and easy sharing of information (low confidence). But study authors also suggested that health workers might find it easier to use basic phones and maintain their own personal phones (low confidence). ‐ Study authors emphasised that digital notification systems will only give health workers better access to supplies if the supplies are actually available at the district or national level (low confidence). How up‐to‐date is this review? We searched for studies that had been published up to August 2019.

BACKGROUND: Printed educational materials are widely used dissemination strategies to improve the quality of healthcare professionals' practice and patient health outcomes. Traditionally they are presented in paper formats such as monographs, publication in peer‐reviewed journals and clinical guidelines. This is the fourth update of the review. OBJECTIVES: To assess the effect of printed educational materials (PEMs) on the practice of healthcare professionals and patient health outcomes. To explore the influence of some of the characteristics of the printed educational materials (e.g. source, content, format) on their effect on healthcare professionals' practice and patient health outcomes. SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), HealthStar, CINAHL, ERIC, CAB Abstracts, Global Health, and EPOC Register from their inception to 6 February 2019. We checked the reference lists of all included studies and relevant systematic reviews. SELECTION CRITERIA: We included randomised trials (RTs), controlled before‐after studies (CBAs) and interrupted time series studies (ITSs) that evaluated the impact of PEMs on healthcare professionals' practice or patient health outcomes. We included three types of comparisons: (1) PEM versus no intervention, (2) PEM versus single intervention, (3) multifaceted intervention where PEM is included versus multifaceted intervention without PEM. Any objective measure of professional practice (e.g. prescriptions for a particular drug), or patient health outcomes (e.g. blood pressure) were included. DATA COLLECTION AND ANALYSIS: Two reviewers undertook data extraction independently. Disagreements were resolved by discussion. For analyses, we grouped the included studies according to study design, type of outcome and type of comparison. For controlled trials, we reported the median effect size for each outcome within each study, the median effect size across outcomes for each study and the median of these effect sizes across studies. Where data were available, we re‐analysed the ITS studies by converting all data to a monthly basis and estimating the effect size from the change in the slope of the regression line between before and after implementation of the PEM. We reported median changes in slope for each outcome, for each study, and then across studies. We standardised all changes in slopes by their standard error, allowing comparisons and combination of different outcomes. We categorised each PEM according to potential effects modifiers related to the source of the PEMs, the channel used for their delivery, their content, and their format. We assessed the risks of bias of all the included studies. MAIN RESULTS: We included 84 studies: 32 RTs, two CBAs and 50 ITS studies. Of the 32 RTs, 19 were cluster RTs that used various units of randomisation, such as practices, health centres, towns, or areas. The majority of the included studies (82/84) compared the effectiveness of PEMs to no intervention. Based on the RTs that provided moderate‐certainty evidence, we found that PEMs distributed to healthcare professionals probably improve their practice, as measured with dichotomous variables, compared to no intervention (median absolute risk difference (ARD): 0.04; interquartile range (IQR): 0.01 to 0.09; 3,963 healthcare professionals randomised within 3073 units). We could not confirm this finding using the evidence gathered from continuous variables (standardised mean difference (SMD): 0.11; IQR: ‐0.16 to 0.52; 1631 healthcare professionals randomised within 1373 units ), from the ITS studies (standardised median change in slope = 0.69; 35 studies), or from the CBA study because the certainty of this evidence was very low. We also found, based on RTs that provided moderate‐certainty evidence, that PEMs distributed to healthcare professionals probably make little or no difference to patient health as measured using dichotomous variables, compared to no intervention (ARD: 0.02; IQR: ‐0.005 to 0.09; 935,015 patients randomised within 959 units). The evidence gathered from continuous variables (SMD: 0.05; IQR: ‐0.12 to 0.09; 6,737 patients randomised within 594 units) or from ITS study results (standardised median change in slope = 1.12; 8 studies) do not strengthen these findings because the certainty of this evidence was very low. Two studies (a randomised trial and a CBA) compared a paper‐based version to a computerised version of the same PEM. From the RT that provided evidence of low certainty, we found that PEM in computerised versions may make little or no difference to professionals' practice compared to PEM in printed versions (ARD: ‐0.02; IQR: ‐0.03 to 0.00; 139 healthcare professionals randomised individually). This finding was not strengthened by the CBA study that provided very low certainty evidence (SMD: 0.44; 32 healthcare professionals). The data gathered did not allow us to conclude which PEM characteristics influenced their effectiveness. The methodological quality of the included studies was variable. Half of the included RTs were at risk of selection bias. Most of the ITS studies were conducted retrospectively, without prespecifying the expected effect of the intervention, or acknowledging the presence of a secular trend. AUTHORS' CONCLUSIONS: The results of this review suggest that, when used alone and compared to no intervention, PEMs may slightly improve healthcare professionals' practice outcomes and patient health outcomes. The effectiveness of PEMs compared to other interventions, or of PEMs as part of a multifaceted intervention, is uncertain.

Background Mobile health (mHealth), refers to healthcare practices supported by mobile devices, such as mobile phones and tablets. Within primary care, health workers often use mobile devices to register clients, track their health, and make decisions about care, as well as to communicate with clients and other health workers. An understanding of how health workers relate to, and experience mHealth, can help in its implementation. Objectives To synthesise qualitative research evidence on health workers' perceptions and experiences of using mHealth technologies to deliver primary healthcare services, and to develop hypotheses about why some technologies are more effective than others. Search methods We searched MEDLINE, Embase, CINAHL, Science Citation Index and Social Sciences Citation Index in January 2018. We searched Global Health in December 2015. We screened the reference lists of included studies and key references and searched seven sources for grey literature (16 February to 5 March 2018). We re‐ran the search strategies in February 2020. We screened these records and any studies that we identified as potentially relevant are awaiting classification. Selection criteria We included studies that used qualitative data collection and analysis methods. We included studies of mHealth programmes that were part of primary healthcare services. These services could be implemented in public or private primary healthcare facilities, community and workplace, or the homes of clients. We included all categories of health workers, as well as those persons who supported the delivery and management of the mHealth programmes. We excluded participants identified as technical staff who developed and maintained the mHealth technology, without otherwise being involved in the programme delivery. We included studies conducted in any country. Data collection and analysis We assessed abstracts, titles and full‐text papers according to the inclusion criteria. We found 53 studies that met the inclusion criteria and sampled 43 of these for our analysis. For the 43 sampled studies, we extracted information, such as country, health worker category, and the mHealth technology. We used a thematic analysis process. We used GRADE‐CERQual to assess our confidence in the findings. Main results Most of the 43 included sample studies were from low‐ or middle‐income countries. In many of the studies, the mobile devices had decision support software loaded onto them, which showed the steps the health workers had to follow when they provided health care. Other uses included in‐person and/or text message communication, and recording clients' health information. Almost half of the studies looked at health workers' use of mobile devices for mother, child, and newborn health. We have moderate or high confidence in the following findings. mHealth changed how health workers worked with each other: health workers appreciated being more connected to colleagues, and thought that this improved co‐ordination and quality of care. However, some described problems when senior colleagues did not respond or responded in anger. Some preferred face‐to‐face connection with colleagues. Some believed that mHealth improved their reporting, while others compared it to "big brother watching". mHealth changed how health workers delivered care: health workers appreciated how mHealth let them take on new tasks, work flexibly, and reach clients in difficult‐to‐reach areas. They appreciated mHealth when it improved feedback, speed and workflow, but not when it was slow or time consuming. Some health workers found decision support software useful; others thought it threatened their clinical skills. Most health workers saw mHealth as better than paper, but some preferred paper. Some health workers saw mHealth as creating more work. mHealth led to new forms of engagement and relationships with clients and communities: health workers felt that communicating with clients by mobile phone improved care and their relationships with clients, but felt that some clients needed face‐to‐face contact. Health workers were aware of the importance of protecting confidential client information when using mobile devices. Some health workers did not mind being contacted by clients outside working hours, while others wanted boundaries. Health workers described how some community members trusted health workers that used mHealth while others were sceptical. Health workers pointed to problems when clients needed to own their own phones. Health workers' use and perceptions of mHealth could be influenced by factors tied to costs, the health worker, the technology, the health system and society, poor network access, and poor access to electricity: some health workers did not mind covering extra costs. Others complained that phone credit was not delivered on time. Health workers who were accustomed to using mobile phones were sometimes more positive towards mHealth. Others with less experience, were sometimes embarrassed about making mistakes in front of clients or worried about job security. Health workers wanted training, technical support, user‐friendly devices, and systems that were integrated into existing electronic health systems. The main challenges health workers experienced were poor network connections, access to electricity, and the cost of recharging phones. Other problems included damaged phones. Factors outside the health system also influenced how health workers experienced mHealth, including language, gender, and poverty issues. Health workers felt that their commitment to clients helped them cope with these challenges. Authors' conclusions Our findings propose a nuanced view about mHealth programmes. The complexities of healthcare delivery and human interactions defy simplistic conclusions on how health workers will perceive and experience their use of mHealth. Perceptions reflect the interplay between the technology, contexts, and human attributes. Detailed descriptions of the programme, implementation processes and contexts, alongside effectiveness studies, will help to unravel this interplay to formulate hypotheses regarding the effectiveness of mHealth., Plain language summary Health workers' perceptions and experiences of using mHealth technologies to deliver primary healthcare services: a qualitative evidence synthesis What is the aim of this review? The aim of this Cochrane Review of qualitative research was to explore how health workers view and experience the use of mobile phones and tablets when delivering primary healthcare services. To answer this, we analysed 43 studies about health workers' views and experiences of mobile health (mHealth) programmes. Key messages Health workers welcomed the benefits of mHealth, and described how they used mobile phones to improve their work and relationships with each other and with clients. However, they also experienced challenges, including poor network coverage and access to electricity. People implementing mHealth programmes should try to address these challenges and build on health workers' positive experiences. What was studied in this review? Health workers often use mobile phones and tablets to provide services. It is important to understand what health workers think about these devices, as this can affect the quality of services. We looked for studies that explored health workers' views and experiences of using mobile devices in primary care. What are the main findings of this review? We sampled 43 of the 53 included studies in this review. Most were from low‐ or middle‐income countries, and included both lay health workers and health professionals. Many used mobile phones or tablets when delivering health care to mothers, children or newborns. Many of the mobile devices had software that helped health workers follow the correct steps when providing services. Health workers also used mobile phones to communicate with clients, and to record clients' health information. We have moderate or high confidence in the following findings. mHealth changed how health workers worked with each other: health workers appreciated being more connected to colleagues, and thought that this improved co‐ordination and quality of care. However, some described problems when senior colleagues did not respond or responded in anger. Some preferred face‐to‐face connection with colleagues. Some believed that mHealth improved their reporting, while others compared it to "big brother watching". mHealth changed how health workers delivered care: health workers appreciated how mHealth let them take on new tasks, work flexibly, and reach clients in difficult‐to‐reach areas. They appreciated mHealth when it improved feedback, speed and workflow, but not when it was slow or time consuming. Some health workers found decision support software useful; others thought it threatened their clinical skills. Most health workers saw mHealth as better than paper, but others saw mHealth as creating more work. mHealth led to new forms of engagement and relationships with clients and communities: health workers felt that communicating with clients by mobile phone improved care and their relationships with clients, but felt that some clients needed face‐to‐face contact. Health workers were aware of the importance of protecting confidential client information when using mobile devices. Some health workers did not mind being contacted by clients outside working hours, while others wanted boundaries. Health workers described how some community members trusted health workers that used mHealth while others were sceptical. Health workers pointed to problems when clients needed to own their own phones. Health workers' use and perceptions of mHealth could be influenced by factors tied to costs, the health worker, the technology, the health system and society, poor network access, and poor access to electricity: some health workers did not mind covering extra costs. Others complained that phone credit was not delivered on time. Health workers who were accustomed to using mobile phones were sometimes more positive towards mHealth. Others with less experience, were sometimes embarrassed about making mistakes in front of clients or worried about job security. Health workers wanted training, technical support, user‐friendly devices, and systems that were integrated into existing electronic health systems. The main challenges health workers experienced were poor network connections, access to electricity, and the cost of recharging phones. Other problems included damaged phones. Factors outside the health system also influenced how health workers experienced mHealth, including language, gender, and poverty issues. Health workers felt that their commitment to clients helped them cope with these challenges. How up‐to‐date is this review? We searched for studies published up to January 2018.

Background Vitamins and minerals are essential for growth and maintenance of a healthy body, and have a role in the functioning of almost every organ. Multiple interventions have been designed to improve micronutrient deficiency, and food fortification is one of them. Objectives To assess the impact of food fortification with multiple micronutrients on health outcomes in the general population, including men, women and children. Search methods We searched electronic databases up to 29 August 2018, including the Cochrane Central Register of Controlled Trial (CENTRAL), the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register and Cochrane Public Health Specialised Register; MEDLINE; Embase, and 20 other databases, including clinical trial registries. There were no date or language restrictions. We checked reference lists of included studies and relevant systematic reviews for additional papers to be considered for inclusion. Selection criteria We included randomised controlled trials (RCTs), cluster-RCTs, quasi-randomised trials, controlled before-after (CBA) studies and interrupted time series (ITS) studies that assessed the impact of food fortification with multiple micronutrients (MMNs). Primary outcomes included anaemia, micronutrient deficiencies, anthropometric measures, morbidity, all-cause mortality and cause-specific mortality. Secondary outcomes included potential adverse outcomes, serum concentration of specific micronutrients, serum haemoglobin levels and neurodevelopmental and cognitive outcomes. We included food fortification studies from both high-income and low- and middle-income countries (LMICs). Data collection and analysis Two review authors independently screened, extracted and quality-appraised the data from eligible studies. We carried out statistical analysis using Review Manager 5 software. We used random-effects meta-analysis for combining data, as the characteristics of study participants and interventions differed significantly. We set out the main findings of the review in 'Summary of findings' tables, using the GRADE approach. Main results We identified 127 studies as relevant through title/abstract screening, and included 43 studies (48 papers) with 19,585 participants (17,878 children) in the review. All the included studies except three compared MMN fortification with placebo/no intervention. Two studies compared MMN fortification versus iodised salt and one study compared MMN fortification versus calcium fortification alone. Thirty-six studies targeted children; 20 studies were conducted in LMICs. Food vehicles used included staple foods, such as rice and flour; dairy products, including milk and yogurt; non-dairy beverages; biscuits; spreads; and salt. Fourteen of the studies were fully commercially funded, 13 had partial-commercial funding, 14 had non-commercial funding and two studies did not specify the source of funding. We rated all the evidence as of low to very low quality due to study limitations, imprecision, high heterogeneity and small sample size. When compared with placebo/no intervention, MMN fortification may reduce anaemia by 32% (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.56 to 0.84; 11 studies, 3746 participants; low-quality evidence), iron deficiency anaemia by 72% (RR 0.28, 95% CI 0.19 to 0.39; 6 studies, 2189 participants; low-quality evidence), iron deficiency by 56% (RR 0.44, 95% CI 0.32 to 0.60; 11 studies, 3289 participants; low-quality evidence); vitamin A deficiency by 58% (RR 0.42, 95% CI 0.28 to 0.62; 6 studies, 1482 participants; low-quality evidence), vitamin B2 deficiency by 64% (RR 0.36, 95% CI 0.19 to 0.68; 1 study, 296 participants; low-quality evidence), vitamin B6 deficiency by 91% (RR 0.09, 95% CI 0.02 to 0.38; 2 studies, 301 participants; low-quality evidence), vitamin B12 deficiency by 58% (RR 0.42, 95% CI 0.25 to 0.71; 3 studies, 728 participants; low-quality evidence), weight-for-age z-scores (WAZ) (mean difference (MD) 0.1, 95% CI 0.02 to 0.17; 8 studies, 2889 participants; low-quality evidence) and weight-for-height/length z-score (WHZ/WLZ) (MD 0.1, 95% CI 0.02 to 0.18; 6 studies, 1758 participants; low-quality evidence). We are uncertain about the effect of MMN fortification on zinc deficiency (RR 0.84, 95% CI 0.65 to 1.08; 5 studies, 1490 participants; low-quality evidence) and height/length-for-age z-score (HAZ/LAZ) (MD 0.09, 95% CI 0.01 to 0.18; 8 studies, 2889 participants; low-quality evidence). Most of the studies in this comparison were conducted in children. Subgroup analyses of funding sources (commercial versus non-commercial) and duration of intervention did not demonstrate any difference in effects, although this was a relatively small number of studies and the possible association between commercial funding and increased effect estimates has been demonstrated in the wider health literature. We could not conduct subgroup analysis by food vehicle and funding; since there were too few studies in each subgroup to draw any meaningful conclusions. When we compared MMNs versus iodised salt, we are uncertain about the effect of MMN fortification on anaemia (R 0.86, 95% CI 0.37 to 2.01; 1 study, 88 participants; very low-quality evidence), iron deficiency anaemia (RR 0.40, 95% CI 0.09 to 1.83; 2 studies, 245 participants; very low-quality evidence), iron deficiency (RR 0.98, 95% CI 0.82 to 1.17; 1 study, 88 participants; very low-quality evidence) and vitamin A deficiency (RR 0.19, 95% CI 0.07 to 0.55; 2 studies, 363 participants; very low-quality evidence). Both of the studies were conducted in children. Only one study conducted in children compared MMN fortification versus calcium fortification. None of the primary outcomes were reported in the study. None of the included studies reported on morbidity, adverse events, all-cause or cause-specific mortality. Authors' conclusions The evidence from this review suggests that MMN fortification when compared to placebo/no intervention may reduce anaemia, iron deficiency anaemia and micronutrient deficiencies (iron, vitamin A, vitamin B2 and vitamin B6). We are uncertain of the effect of MMN fortification on anthropometric measures (HAZ/LAZ, WAZ and WHZ/WLZ). There are no data to suggest possible adverse effects of MMN fortification, and we could not draw reliable conclusions from various subgroup analyses due to a limited number of studies in each subgroup. We remain cautious about the level of commercial funding in this field, and the possibility that this may be associated with higher effect estimates, although subgroup analysis in this review did not demonstrate any impact of commercial funding. These findings are subject to study limitations, imprecision, high heterogeneity and small sample sizes, and we rated most of the evidence low to very low quality. and hence no concrete conclusions could be drawn from the findings of this review.

Adrenaline and vasopressin are widely used to treat people with cardiac arrest, but there is uncertainty about the safety, effectiveness and the optimal dose.To determine whether adrenaline or vasopressin, or both, administered during cardiac arrest, afford any survival benefit.We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase and DARE from their inception to 8 May 2018, and the International Liaison Committee on Resuscitation 2015 Advanced Life Support Consensus on Science and Treatment Recommendations. We also searched four trial registers on 5 September 2018 and checked the reference lists of the included studies and review papers to identify potential papers for review.Any randomised controlled trial comparing: standard-dose adrenaline versus placebo; standard-dose adrenaline versus high-dose adrenaline; and adrenaline versus vasopressin, in any setting, due to any cause of cardiac arrest, in adults and children. There were no language restrictions.Two review authors independently identified trials for review, assessed risks of bias and extracted data, resolving disagreements through re-examination of the trial reports and by discussion. We used risk ratios (RRs) with 95% confidence intervals (CIs) to compare dichotomous outcomes for clinical events. There were no continuous outcomes reported. We examined groups of trials for heterogeneity. We report the quality of evidence for each outcome, using the GRADE approach.We included 26 studies (21,704 participants).Moderate-quality evidence found that adrenaline increased survival to hospital discharge compared to placebo (RR 1.44, 95% CI 1.11 to 1.86; 2 studies, 8538 participants; an increase from 23 to 32 per 1000, 95% CI 25 to 42). We are uncertain about survival to hospital discharge for high-dose compared to standard-dose adrenaline (RR 1.10, 95% CI 0.75 to 1.62; participants = 6274; studies = 10); an increase from 33 to 36 per 1000, 95% CI 24 to 53); standard-dose adrenaline versus vasopressin (RR 1.25, 95% CI 0.84 to 1.85; 6 studies; 2511 participants; an increase from 72 to 90 per 1000, 95% CI 60 to 133); and standard-dose adrenaline versus vasopressin plus adrenaline (RR 0.76, 95% CI 0.47 to 1.22; 3 studies; 3242 participants; a possible decrease from 24 to 18 per 1000, 95% CI 11 to 29), due to very low-quality evidence.Moderate-quality evidence found that adrenaline compared with placebo increased survival to hospital admission (RR 2.51, 95% CI 1.67 to 3.76; 2 studies, 8489 participants; an increase from 83 to 209 per 1000, 95% CI 139 to 313). We are uncertain about survival to hospital admission when comparing standard-dose with high-dose adrenaline, due to very low-quality evidence. Vasopressin may improve survival to hospital admission when compared with standard-dose adrenaline (RR 1.27, 95% CI 1.04 to 1.54; 3 studies, 1953 participants; low-quality evidence; an increase from 260 to 330 per 1000, 95% CI 270 to 400), and may make little or no difference when compared to standard-dose adrenaline plus vasopressin (RR 0.95, 95% CI 0.83 to 1.08; 3 studies; 3249 participants; low-quality evidence; a decrease from 218 to 207 per 1000 (95% CI 181 to 236).There was no evidence that adrenaline (any dose) or vasopressin improved neurological outcomes.The rate of return of spontaneous circulation (ROSC) was higher for standard-dose adrenaline versus placebo (RR 2.86, 95% CI 2.21 to 3.71; participants = 8663; studies = 3); moderate-quality evidence; an increase from 115 to 329 per 1000, 95% CI 254 to 427). We are uncertain about the effect on ROSC for the comparison of standard-dose versus high-dose adrenaline and standard-does adrenaline compared to vasopressin, due to very low-quality evidence. Standard-dose adrenaline may make little or no difference to ROSC when compared to standard-dose adrenaline plus vasopressin (RR 0.97, 95% CI 0.87 to 1.08; 3 studies, 3249 participants; low-quality evidence; a possible decrease from 299 to 290 per 1000, 95% CI 260 to 323).The source of funding was not stated in 11 of the 26 studies. The study drugs were provided by the manufacturer in four of the 26 studies, but neither drug represents a profitable commercial option. The other 11 studies were funded by organisations such as research foundations and government funding bodies.This review provides moderate-quality evidence that standard-dose adrenaline compared to placebo improves return of spontaneous circulation, survival to hospital admission and survival to hospital discharge, but low-quality evidence that it did not affect survival with a favourable neurological outcome. Very low -quality evidence found that high-dose adrenaline compared to standard-dose adrenaline improved return of spontaneous circulation and survival to admission. Vasopressin compared to standard dose adrenaline improved survival to admission but not return of spontaneous circulation, whilst the combination of adrenaline and vasopressin compared with adrenaline alone had no effect on these outcomes. Neither standard dose adrenaline, high-dose adrenaline,vasopressin nor a combination of adrenaline and vasopressin improved survival with a favourable neurological outcome. Many of these studies were conducted more than 20 years ago. Treatment has changed in recent years, so the findings from older studies may not reflect current practice.

Background Needle syringe programmes and opioid substitution therapy for preventing hepatitis C transmission in people who inject drugs Needle syringe programmes (NSP) and opioid substitution therapy (OST) are the primary interventions to reduce hepatitis C (HCV) transmission in people who inject drugs. There is good evidence for the effectiveness of NSP and OST in reducing injecting risk behaviour and increasing evidence for the effectiveness of OST and NSP in reducing HIV acquisition risk, but the evidence on the effectiveness of NSP and OST for preventing HCV acquisition is weak. Objectives To assess the effects of needle syringe programmes and opioid substitution therapy, alone or in combination, for preventing acquisition of HCV in people who inject drugs. Search methods We searched the Cochrane Drug and Alcohol Register, CENTRAL, the Cochrane Database of Systematic Reviews (CDSR), the Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment Database (HTA), the NHS Economic Evaluation Database (NHSEED), MEDLINE, Embase, PsycINFO, Global Health, CINAHL, and the Web of Science up to 16 November 2015. We updated this search in March 2017, but we have not incorporated these results into the review yet. Where observational studies did not report any outcome measure, we asked authors to provide unpublished data. We searched publications of key international agencies and conference abstracts. We reviewed reference lists of all included articles and topic-related systematic reviews for eligible papers. Selection criteria We included prospective and retrospective cohort studies, cross-sectional surveys, case-control studies and randomised controlled trials that measured exposure to NSP and/or OST against no intervention or a reduced exposure and reported HCV incidence as an outcome in people who inject drugs. We defined interventions as current OST (within previous 6 months), lifetime use of OST and high NSP coverage (regular attendance at an NSP or all injections covered by a new needle/syringe) or low NSP coverage (irregular attendance at an NSP or less than 100% of injections covered by a new needle/syringe) compared with no intervention or reduced exposure. Data collection and analysis We followed the standard Cochrane methodological procedures incorporating new methods for classifying risk of bias for observational studies. We described study methods against the following 'Risk of bias' domains: confounding, selection bias, measurement of interventions, departures from intervention, missing data, measurement of outcomes, selection of reported results; and we assigned a judgment (low, moderate, serious, critical, unclear) for each criterion. Main results We identified 28 studies (21 published, 7 unpublished): 13 from North America, 5 from the UK, 4 from continental Europe, 5 from Australia and 1 from China, comprising 1817 incident HCV infections and 8806.95 person-years of follow-up. HCV incidence ranged from 0.09 cases to 42 cases per 100 person-years across the studies. We judged only two studies to be at moderate overall risk of bias, while 17 were at serious risk and 7 were at critical risk; for two unpublished datasets there was insufficient information to assess bias. As none of the intervention effects were generated from RCT evidence, we typically categorised quality as low. We found evidence that current OST reduces the risk of HCV acquisition by 50% (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.40 to 0.63, I2 = 0%, 12 studies across all regions, N = 6361), but the quality of the evidence was low. The intervention effect remained significant in sensitivity analyses that excluded unpublished datasets and papers judged to be at critical risk of bias. We found evidence of differential impact by proportion of female participants in the sample, but not geographical region of study, the main drug used, or history of homelessness or imprisonment among study samples. Overall, we found very low-quality evidence that high NSP coverage did not reduce risk of HCV acquisition (RR 0.79, 95% CI 0.39 to 1.61) with high heterogeneity (I2 = 77%) based on five studies from North America and Europe involving 3530 participants. After stratification by region, high NSP coverage in Europe was associated with a 76% reduction in HCV acquisition risk (RR 0.24, 95% CI 0.09 to 0.62) with less heterogeneity (I2 =0%). We found low-quality evidence of the impact of combined high coverage of NSP and OST, from three studies involving 3241 participants, resulting in a 74% reduction in the risk of HCV acquisition (RR 0.26 95% CI 0.07 to 0.89). Authors' conclusions OST is associated with a reduction in the risk of HCV acquisition, which is strengthened in studies that assess the combination of OST and NSP. There was greater heterogeneity between studies and weaker evidence for the impact of NSP on HCV acquisition. High NSP coverage was associated with a reduction in the risk of HCV acquisition in studies in Europe. Interventions for reducing hepatitis C infection in people who inject drugs Review question We examine research on the effect of needle syringe programmes (NSP) and opioid substitution treatment (OST) in reducing the risk of becoming infected with the hepatitis C virus. Background There are around 114.9 million people living with hepatitis C and 3 to 4 million people newly infected each year. The main risk for becoming infected is sharing used needles/syringes. Almost half the people who inject drugs have hepatitis C. The provision of sterile injecting equipment through NSPs reduces the need for sharing equipment when preparing and injecting drugs. OST is taken orally and reduces frequency of injection and unsafe injecting practices. We examined whether NSP and OST, provided alone or together, are effective in reducing the chances of becoming infected with hepatitis C in people who inject drugs. Search date The evidence is current to November 2015. Study characteristics We identified 28 research studies across Europe, Australia, North America and China. On average across the studies, the rate of new hepatitis C infections per year was 19.0 for every 100 people. Data from 11,070 people who inject drugs who were not infected with hepatitis C at the start of the study were combined in the analysis. Of the sample, 32% were female, 50% injected opioids, 51% injected daily, and 40% had been homeless. Our study was funded by the National Institute of Health Research's (NIHR) Public Health Research Programme, the Health Protection Research Unit in Evaluation of Interventions, and the European Commission Drug Prevention and Information Programme (DIPP), Treatment as Prevention in Europe: Model Projections. Key results Current use of OST (defined as use at the time of survey or within the previous six months) may reduce risk of acquiring hepatitis C by 50%. We are uncertain whether high coverage NSP (defined as regular attendance at an NSP or all injections being covered by a new needle/syringe) reduces the risk of becoming infected with hepatitis C across all studies globally, but there was some evidence from studies in Europe that high NSP coverage may reduce the risk of hepatitis C infection by 76%. The combined use of high coverage NSP with OST may reduce risk of hepatitis C infection by 74%. Quality of the evidence Quality of evidence ranged from moderate to very low because none of the studies used the gold standard design of randomised controlled trials.

Background Hyperbilirubinaemia occurs in approximately two-thirds of all newborns during the first days of life and is frequently treated with phototherapy. Although generally seen as safe, there is rising concern regarding phototherapy and its potentially damaging effects on DNA and increased side effects particularly for preterm infants. Other methods, such as enteral feeding supplementation with prebiotics, may have an effective use in the management of hyperbilirubinaemia in neonates. Objectives To determine whether administration of prebiotics reduces the incidence of hyperbilirubinaemia among term and preterm infants compared with enteral supplementation of milk with distilled water/placebo or no supplementation. Search methods We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 14 June 2018), Embase (1980 to 14 June 2018), and CINAHL (1982 to 14 June 2018). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. Selection criteria We considered all RCTs that studied neonates comparing enteral feeding supplementation with prebiotics versus distilled water/placebo or no supplementation. Data collection and analysis Two reviewers screened papers and extracted data from selected papers. We used a fixed-effect method in combining the effects of studies that were sufficiently similar. We then used the GRADE approach to assess the quality of the evidence. Main results Three small studies evaluating 154 infants were included in this review. One study reported a significant reduction in the risk of hyperbilirubinaemia and rate of treatment with phototherapy associated with enteral supplementation with prebiotics (risk ratio (RR) 0.75, 95% confidence interval (95% CI) 0.58 to 0.97; one study, 50 infants; low-quality evidence). Meta-analyses of two studies showed no significant difference in maximum plasma unconjugated bilirubin levels in infants with prebiotic supplementation (mean difference (MD) 0.14 mg/dL, 95% CI -0.91 to 1.20, I² = 81%, P = 0.79; two studies, 78 infants; low-quality evidence). There was no evidence of a significant difference in duration of phototherapy between the prebiotic and control groups, which was only reported by one study (MD 0.10 days, 95% CI -2.00 to 2.20; one study, 50 infants; low-quality evidence). The meta-analyses of two studies demonstrated a significant reduction in the length of hospital stay (MD -10.57 days, 95% CI -17.81 to -3.33; 2 studies, 78 infants; I² = 0%, P = 0.004; low-quality evidence). Meta-analysis of the three studies showed a significant increase in stool frequency in the prebiotic groups (MD 1.18, 95% CI 0.90 to 1.46, I² = 90%; 3 studies, 154 infants; high-quality evidence). No significant difference in mortality during hospital stay after enteral supplementation with prebiotics was reported (typical RR 0.94, 95% CI 0.14 to 6.19; I² = 6%, P = 0.95; 2 studies; 78 infants; low-quality evidence). There were no reports of the need for exchange transfusion and incidence of acute bilirubin encephalopathy, chronic bilirubin encephalopathy, and major neurodevelopmental disability in the included studies. None of the included studies reported any side effects. Authors' conclusions Current studies are unable to provide reliable evidence about the effectiveness of prebiotics on hyperbilirubinaemia. Additional large, well-designed RCTs should be undertaken in neonates that compare effects of enteral supplementation with prebiotics on neonatal hyperbilirubinaemia with supplementation of milk with any other placebo (particularly distilled water) or no supplementation.

Background: This is an update of a Cochrane Review first published in 2004 (Issue 1) and previously updated in 2012 (Issue 10). Anxiety is common in palliative care patients. It can be a natural response to the complex uncertainty of having a life-limiting illness or impending death, but it may represent a clinically significant issue in its own right. Objectives: To assess the effectiveness of drug therapy for treating symptoms of anxiety in adults with a progressive life-limiting illness who are thought to be in their last year of life. Search methods: We ran the searches for this update to May 2016. We searched the CENTRAL, MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCO), PsychLIT (Silver Platter) and PsycINFO (Ovid). We searched seven trials registers and seven pharmaceutical industry trials registers. We handsearched the conference abstracts of the European Association of Palliative Care. Selection criteria: Randomised controlled trials which examined the effect of drug therapy for the treatment of symptoms of anxiety in adult palliative care patients, that is, people with a known progressive life-limiting illness that is no longer responsive to curative treatment, including advanced heart, respiratory and neurological diseases (including dementia). Comparator treatments included placebo; another drug therapy or different dose schedule; or a non-drug intervention such as counselling, cognitive behaviour therapies or relaxation therapies. Data collection and analysis: Two review authors independently screened titles and abstracts to identify potentially relevant papers for inclusion in the review. We sought full-text reports for all papers retained at this stage and two reviews authors independently assessed these for inclusion in the review. We planned to assess risk of bias and extract data including information on adverse events. We planned to assess the evidence using GRADE and to create a 'Summary of findings' table. Main results: In this update, we identified 707 potentially relevant papers and of these we sought the full-text reports of 10 papers. On examination of these full-text reports, we excluded eight and two are awaiting classification as we have insufficient information to make a decision. Thus, in this update, we found no studies which met our inclusion criteria. For the original review, we identified, and then excluded, the full-text reports of six potentially relevant studies. For the 2012 update, we sought, and excluded, two full-text reports. Thus, we found no studies that assessed the effectiveness of drugs to treat symptoms of anxiety in palliative care patients. Authors' conclusions: There is a lack of evidence to draw a conclusion about the effectiveness of drug therapy for symptoms of anxiety in adult palliative care patients. To date, we have found no studies that meet the inclusion criteria for this review. We are awaiting further information for two studies which may be included in a future update. Randomised controlled trials which assess management of anxiety as a primary endpoint are required to establish the benefits and harms of drug therapy for the treatment of anxiety in palliative care.

Background: \ud The Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE) is a structured interview based on informant responses that is used to assess for possible dementia. IQCODE has been used for retrospective or contemporaneous assessment of cognitive decline. There is considerable interest in tests that may identify those at future risk of developing dementia. Assessing a population free of dementia for the prospective development of dementia is an approach often used in studies of dementia biomarkers. In theory, questionnaire-based assessments, such as IQCODE, could be used in a similar way, assessing for dementia that is diagnosed on a later (delayed) assessment.\ud \ud Objectives: \ud To determine the diagnostic accuracy of IQCODE in a population free from dementia for the delayed diagnosis of dementia (test accuracy with delayed verification study design).\ud \ud Search methods: \ud We searched these sources on 16 January 2016: ALOIS (Cochrane Dementia and Cognitive Improvement Group), MEDLINE Ovid SP, Embase Ovid SP, PsycINFO Ovid SP, BIOSIS Previews on Thomson Reuters Web of Science, Web of Science Core Collection (includes Conference Proceedings Citation Index) on Thomson Reuters Web of Science, CINAHL EBSCOhost, and LILACS BIREME. We also searched sources specific to diagnostic test accuracy: MEDION (Universities of Maastricht and Leuven); DARE (Database of Abstracts of Reviews of Effects, in the Cochrane Library); HTA Database (Health Technology Assessment Database, in the Cochrane Library), and ARIF (Birmingham University). We checked reference lists of included studies and reviews, used searches of included studies in PubMed to track related articles, and contacted research groups conducting work on IQCODE for dementia diagnosis to try to find additional studies. We developed a sensitive search strategy; search terms were designed to cover key concepts using several different approaches run in parallel, and included terms relating to cognitive tests, cognitive screening, and dementia. We used standardised database subject headings, such as MeSH terms (in MEDLINE) and other standardised headings (controlled vocabulary) in other databases, as appropriate.\ud \ud Selection criteria: \ud We selected studies that included a population free from dementia at baseline, who were assessed with the IQCODE and subsequently assessed for the development of dementia over time. The implication was that at the time of testing, the individual had a cognitive problem sufficient to result in an abnormal IQCODE score (defined by the study authors), but not yet meeting dementia diagnostic criteria.\ud \ud Data collection and analysis: \ud We screened all titles generated by the electronic database searches, and reviewed abstracts of all potentially relevant studies. Two assessors independently checked the full papers for eligibility and extracted data. We determined quality assessment (risk of bias and applicability) using the QUADAS-2 tool, and reported quality using the STARDdem tool.\ud \ud Main results: \ud From 85 papers describing IQCODE, we included three papers, representing data from 626 individuals. Of this total, 22% (N = 135/626) were excluded because of prevalent dementia. There was substantial attrition; 47% (N = 295) of the study population received reference standard assessment at first follow-up (three to six months) and 28% (N = 174) received reference standard assessment at final follow-up (one to three years). Prevalence of dementia ranged from 12% to 26% at first follow-up and 16% to 35% at final follow-up.\ud \ud The three studies were considered to be too heterogenous to combine, so we did not perform meta-analyses to describe summary estimates of interest. Included patients were poststroke (two papers) and hip fracture (one paper). The IQCODE was used at three thresholds of positivity (higher than 3.0, higher than 3.12 and higher than 3.3) to predict those at risk of a future diagnosis of dementia. Using a cut-off of 3.0, IQCODE had a sensitivity of 0.75 (95%CI 0.51 to 0.91) and a specificity of 0.46 (95%CI 0.34 to 0.59) at one year following stroke. Using a cut-off of 3.12, the IQCODE had a sensitivity of 0.80 (95%CI 0.44 to 0.97) and specificity of 0.53 (95C%CI 0.41 to 0.65) for the clinical diagnosis of dementia at six months after hip fracture. Using a cut-off of 3.3, the IQCODE had a sensitivity of 0.84 (95%CI 0.68 to 0.94) and a specificity of 0.87 (95%CI 0.76 to 0.94) for the clinical diagnosis of dementia at one year after stroke.\ud \ud In generaI, the IQCODE was sensitive for identification of those who would develop dementia, but lacked specificity. Methods for both excluding prevalent dementia at baseline and assessing for the development of dementia were varied, and had the potential to introduce bias.\ud \ud Authors' conclusions: \ud Included studies were heterogenous, recruited from specialist settings, and had potential biases. The studies identified did not allow us to make specific recommendations on the use of the IQCODE for the future diagnosis of dementia in clinical practice. The included studies highlighted the challenges of delayed verification dementia research, with issues around prevalent dementia assessment, loss to follow-up over time, and test non-completion potentially limiting the studies. Future research should recognise these issues and have explicit protocols for dealing with them.

In a review and meta-analysis conducted in 1993, psychological preparation was found to be beneficial for a range of outcome variables including pain, behavioural recovery, length of stay and negative affect. Since this review, more detailed bibliographic searching has become possible, additional studies testing psychological preparation for surgery have been completed and hospital procedures have changed. The present review examines whether psychological preparation (procedural information, sensory information, cognitive intervention, relaxation, hypnosis and emotion-focused intervention) has impact on the outcomes of postoperative pain, behavioural recovery, length of stay and negative affect. \ud Objectives\ud To review the effects of psychological preparation on postoperative outcomes in adults undergoing elective surgery under general\ud anaesthetic.\ud Search methods\ud We searched the Cochrane Register of Controlled Trials (CENTRAL 2014, Issue 5), MEDLINE (OVID SP) (1950 to May 2014),\ud EMBASE (OVID SP) (1982 to May 2014), PsycINFO (OVID SP) (1982 to May 2014), CINAHL (EBESCOhost) (1980 to May 2014), Dissertation Abstracts (to May 2014) and Web of Science (1946 to May 2014). We searched reference lists of relevant studies\ud and contacted authors to identify unpublished studies. We reran the searches in July 2015 and placed the 38 studies of interest in the ‘awaiting classification’ section of this review.\ud Psychological preparation and postoperative outcomes for adults undergoing surgery under general anaesthesia (Review) 1\ud Copyright © 2016 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.\ud Selection criteria\ud We included randomized controlled trials of adult participants (aged 16 or older) undergoing elective surgery under general anaesthesia.\ud We excluded studies focusing on patient groups with clinically diagnosed psychological morbidity. We did not limit the search by\ud language or publication status.We included studies testing a preoperative psychological intervention that included at least one of these seven techniques: procedural information; sensory information; behavioural instruction; cognitive intervention; relaxation techniques; hypnosis; emotion-focused intervention. We included studies that examined any one of our postoperative outcome measures (pain, behavioural recovery, length of stay, negative affect) within one month post-surgery. \ud Data collection and analysis\ud One author checked titles and abstracts to exclude obviously irrelevant studies. We obtained full reports of apparently relevant studies; two authors fully screened these. Two authors independently extracted data and resolved discrepancies by discussion. Where possible we used random-effects meta-analyses to combine the results from individual studies. For length of stay we pooled mean differences. For pain and negative affect we used a standardized effect size (the standardized mean difference (SMD), or Hedges’ g) to combine data from different outcome measures. If data were not available in a form suitable for meta-analysis we performed a narrative review.\ud Main results\ud Searches identified 5116 unique papers; we retrieved 827 for full screening. In this review, we included 105 studies from 115 papers, in which 10,302 participants were randomized.Mainly as a result of updating the search in July 2015, 38 papers are awaiting classification. Sixty-one of the 105 studies measured the outcome pain, 14 behavioural recovery, 58 length of stay and 49 negative affect. Participants underwent a wide range of surgical procedures, and a range of psychological components were used in interventions, frequently in combination. In the 105 studies, appropriate datawere provided for themeta-analysis of 38 studiesmeasuring the outcome postoperative pain (2713 participants), 36 for length of stay (3313 participants) and 31 for negative affect (2496 participants). We narratively reviewed the remaining studies (including the 14 studies with 1441 participants addressing behavioural recovery). When pooling the results for all types of intervention there was low quality evidence that psychological preparation techniques were associated with lower\ud postoperative pain (SMD -0.20, 95% confidence interval (CI) -0.35 to -0.06), length of stay (mean difference -0.52 days, 95% CI -\ud 0.82 to -0.22) and negative affect (SMD -0.35, 95% CI -0.54 to -0.16) compared with controls. Results tended to be similar for all\ud categories of intervention, although there was no evidence that behavioural instruction reduced the outcome pain. However, caution\ud must be exercised when interpreting the results because of heterogeneity in the types of surgery, interventions and outcomes. Narratively reviewed evidence for the outcome behavioural recovery provided very low quality evidence that psychological preparation, in particular behavioural instruction, may have potential to improve behavioural recovery outcomes, but no clear conclusions could be reached.\ud Generally, the evidence suffered from poor reporting, meaning that few studies could be classified as having low risk of bias. Overall,we\ud rated the quality of evidence for each outcome as ‘low’ because of the high level of heterogeneity in meta-analysed studies and the\ud unclear risk of bias. In addition, for the outcome behavioural recovery, too few studies used robust measures and reported suitable data for meta-analysis, so we rated the quality of evidence as ‘very low’.\ud Conclusions\ud The evidence suggested that psychological preparation may be beneficial for the outcomes postoperative pain, behavioural recovery, negative affect and length of stay, and is unlikely to be harmful. However, at present, the strength of evidence is insufficient to reach firm conclusions on the role of psychological preparation for surgery. Further analyses are needed to explore the heterogeneity in the data, to identify more specifically when intervention techniques are of benefit.

Background Drugs used to treat psychotic illnesses may take weeks to be effective. In the interim, additional 'as required' doses of medication can be used to calm patients in psychiatric wards. The practice is widespread, with 20% to 50% of people on acute psychiatric wards receiving at least one 'as required' dose of psychotropic medication during their admission. Objectives To compare the effects of 'as required' medication regimens with regular patterns of medication for the treatment of psychotic symptoms or behavioural disturbance, thought to be secondary to psychotic illness. These regimens may be given alone or in addition to any regular psychotropic medication for the long-term treatment of schizophrenia or schizophrenia-like illnesses. Search methods We searched the Cochrane Schizophrenia Group's Trials Register, which is based on regular searches of MEDLINE, EMBASE, PubMed, CINAHL, BIOSIS, AMED, PsycINFO and registries of clinical trials, in November 2001, March 2006, July 2012 andOctober 2013. Selection criteria We aimed to include all relevant randomised controlled trials involving hospital inpatients with schizophrenia or schizophrenia-like illnesses, comparing any regimen of medication administered for the short-term relief of behavioural disturbance, or psychotic symptoms, to be given at the discretion of ward staff ('as required', 'prn') with fixed non-discretionary patterns of drug administration of the same drug(s). This was in addition to regular psychotropic medication for the long-term treatment of schizophrenia or schizophrenia-like illnesses where prescribed. Data collection and analysis We independently inspected abstracts and papers for inclusion. If trials had been found, we would have extracted data from the papers and quality assessed the data. For dichotomous data we would have calculated the risk ratios (RR), with the 95% confidence intervals (CI). We would have conducted analyses on an intention-to-treat basis. If data were available we would have completed a 'Summary of findings' table using GRADE. Main results We have not been able to identify any randomised trials comparing 'as required' medication regimens to regular regimens of the same drug. Our main outcomes of interest were important changes in (i) mental state, (ii) behaviour, (iii) dose of medication used, (iv) adverse events, (v) satisfaction with care and (iv) cost of care. Authors' conclusions There is currently no evidence from within randomised trials to support this common practice. Current practice is based on clinical experience and habit rather than high quality evidence.

There are a limited number of treatment options for patients with ulcerative colitis (UC). An increased risk of thrombosis in UC coupled with an observation that UC patients being treated with anticoagulant therapy for thrombotic events had an improvement in their bowel symptoms led to trials examining the use of unfractionated heparin (UFH) and low molecular weight heparins (LMWH) in patients with active UC.To review randomized trials examining the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis.We searched MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD/FBD group specialized trials register up to June 2014. We also searched review papers on ulcerative colitis and references from identified papers in an effort to identify additional randomized trials studying UFH or LMWH use in patients with ulcerative colitis. We searched abstracts from major gastroenterological meetings to identify research published in abstract form.Randomized controlled trials comparing UFH or LMWH to placebo or a control therapy for induction of remission in ulcerative colitis were included. Studies published in abstract form only were included if the authors could be contacted for further information.A data extraction form was developed and used to extract data from included studies. Two authors independently extracted data. Any disagreements were resolved by consensus. The Cochrane Risk of Bias tool was used to assess study quality. Data were analyzed on an intention-to-treat basis. The primary outcome was induction of remission, as defined by the studies. Secondary outcomes measures included: endoscopic remission as defined by the authors; clinical, histological or endoscopic improvement as defined by the authors; the occurrence of adverse events; the occurrence of bleeding; and improvements in quality of life as measured by a validated instrument. We calculated the risk ratio (RR) and corresponding 95% confidence interval for dichotomous outcomes. Data were combined for analysis if they assessed the same treatments (UFH or LMWH versus placebo or other therapy). The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria.Five studies were eligible for inclusion (329 patients). Three studies (270 patients) compared low molecular weight heparin to placebo, one study (34 patients) compared LMWH in addition to standard therapy, and one study (25 patients) compared UFH to corticosteroids. The study comparing UFH to corticosteroids was rated at high risk of bias due to a single-blind design. The study that compared the addition of LMWH to standard therapy to standard therapy alone was rated at high risk of bias due to open-label design. The other three studies were rated as low risk of bias. LMWH administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission (very low quality of evidence), and clinical, endoscopic, or histological improvement. High dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (RR 1.39; 95% CI 1.09 to 1.77 ; P = 0.008; very low quality of evidence), clinical improvement (RR 1.28; 95% CI 1.06 to 1.55; P = 0.01; very low quality of evidence), and endoscopic improvement (RR 1.21; 95% CI 1.00 to 1.47 ; P = 0.05) but not endoscopic remission or histologic improvement. LMWH was not beneficial when added to standard therapy for clinical remission, clinical improvement, endoscopic remission or endoscopic improvement. LMWH was well-tolerated but provided no significant benefit for quality of life. One study examining UFH versus corticosteroids for the treatment of severe UC demonstrated the inferiority of UFH for clinical improvement. More patients assigned to UFH had rectal hemorrhage as an adverse event.There is evidence to suggest that LMWH may be effective for the treatment of active UC. When administered by extended colon-release tablets, LMWH was more effective than placebo for treating outpatients with mild to moderate disease. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC. A further trial of UFH in patients with mild disease may also be justified. Any benefit found would need to be weighed against a possible increased risk of rectal bleeding in patients with active UC.Es limitado el número de opciones terapéuticas para los pacientes con colitis ulcerosa (CU). Un mayor riesgo de trombosis en la CU, junto con una observación de que los pacientes con CU tratados con tratamiento anticoagulante para los eventos trombóticos presentaron una mejoría en sus síntomas intestinales, generó ensayos que examinaron el uso de la heparina no fraccionada (HNF) y las heparinas de bajo peso molecular (HBPM) en los pacientes con CU activa.Examinar los ensayos aleatorizados sobre la eficacia de la heparina no fraccionada (HNF) o las heparinas de bajo peso molecular (HBPM) para la inducción de la remisión en los pacientes con colitis ulcerosa. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en MEDLINE, EMBASE, CENTRAL y en el registro de ensayos especializados del Grupo Cochrane de EII/TFI hasta junio de 2014. También se realizaron búsquedas en los documentos de revisión sobre la colitis ulcerosa y en las referencias de los documentos identificados, con el fin de identificar ensayos aleatorizados adicionales que estudiaran el uso de HNF o HBPM en pacientes con colitis ulcerosa. Se realizaron búsquedas en los resúmenes de los principales encuentros de gastroenterología para identificar las investigaciones publicadas en forma de resumen. CRITERIOS DE SELECCIÓN: Se incluyeron ensayos controlados aleatorizados que comparaban la HNF o la HBPM con el placebo o un tratamiento de control para la inducción de la remisión en la colitis ulcerosa. Los estudios publicados sólo como resúmenes se incluyeron cuando se pudo establecer contacto con los autores para obtener información adicional. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se desarrolló y utilizó un formulario de extracción de datos de los estudios incluidos. Dos autores de la revisión de forma independiente extrajeron los datos. Los desacuerdos se resolvieron por consenso. Se utilizó la herramienta Cochrane de Riesgo de Sesgo para evaluar la calidad de los estudios. Los datos se analizaron por intención de tratar. El resultado principal fue la inducción de la remisión, según la definición de los estudios. Las medidas de resultados secundarios incluían: remisión endoscópica según la definición de los autores; mejoría clínica, histológica o endoscópica según la definición de los autores; aparición de eventos adversos; aparición de hemorragias; y mejoras en la calidad de vida según la medición de un instrumento validado. Se calculó el riesgo relativo (RR) y el intervalo de confianza (IC) del 95% correspondiente para los resultados dicotómicos. Los datos se combinaron para el análisis si evaluaban los mismos tratamientos (HNF o HBPM versus placebo u otro tratamiento). La calidad general de la evidencia que apoya los resultados se evaluó mediante los criterios GRADE.Cinco estudios fueron elegibles para su inclusión (329 pacientes). Tres estudios (270 pacientes) compararon la heparina de bajo peso molecular con el placebo, un estudio (34 pacientes) comparó la HBPM además del tratamiento estándar, y un estudio (25 pacientes) comparó la HNF con los corticosteroides. El estudio que comparaba la HNF con los corticosteroides fue calificado como de alto riesgo de sesgo debido a un diseño de cegamiento simple. El estudio que comparó la adición de HBPM a la terapia estándar con la terapia estándar sola se calificó con un alto riesgo de sesgo debido al diseño de etiqueta abierta. Los otros tres estudios fueron calificados como de bajo riesgo de sesgo. Las HBPM administradas por vía subcutánea no mostraron ningún beneficio sobre el placebo para ningún resultado, incluyendo la remisión clínica (muy baja calidad de la evidencia), y la mejoría clínica, endoscópica o histológica. Las HBPM en dosis altas administradas mediante un comprimido de liberación prolongada del colon demostraron beneficios sobre el placebo para la remisión clínica (RR 1,39; IC del 95%: 1,09 a 1,77; P = 0,008; muy baja calidad de la evidencia), la mejoría clínica (RR 1.28; IC del 95%: 1,06 a 1,55; p = 0,01; muy baja calidad de la evidencia), y la mejoría endoscópica (RR 1,21; IC del 95%: 1,00 a 1,47; p = 0,05), pero no la remisión endoscópica o la mejoría histológica. La HBPM no fue beneficiosa cuando se agregó al tratamiento estándar para la remisión clínica, la mejoría clínica, la remisión endoscópica ni la mejoría endoscópica. La HBPM se toleró bien pero no proporcionó un beneficio significativo para la calidad de vida. Un estudio que examinó HNF versus corticosteroides en el tratamiento de la CU grave demostró la inferioridad de la HNF para la mejoría clínica. Una mayor cantidad de pacientes asignados a la HNF presentó hemorragia rectal como un evento adverso.La evidencia indica que la HBPM puede ser efectiva para el tratamiento de la CU activa. Cuando se administró mediante comprimidos de liberación prolongada en el colon, la HBPM fue más efectiva que placebo para tratar a los pacientes ambulatorios con enfermedad leve a moderada. Este beneficio se debe confirmar en estudios controlados aleatorizados. Los mismos beneficios no se observaron cuando la HBPM se administró por vía subcutánea a dosis inferiores. No hay evidencia que apoye el uso de HNF para el tratamiento de la CU activa. Un ensayo adicional de HNF en pacientes con enfermedad leve también puede estar justificado. Todo beneficio hallado deberá compararse contra un posible riesgo mayor de hemorragia rectal en los pacientes con CU activa.

Background: Self-administered survey questionnaires are an important data collection tool in clinical practice, public health research and epidemiology. They are ideal for achieving a wide geographic coverage of the target population, dealing with sensitive topics and are less resource intensive than other data collection methods. These survey questionnaires can be delivered electronically, which can maximise the scalability and speed of data collection while reducing cost. In recent years, the use of apps running on consumer smart devices (i.e., smartphones and tablets) for this purpose has received considerable attention. However, variation in the mode of delivering a survey questionnaire could affect the quality of the responses collected. Objectives: To assess the impact that smartphone and tablet apps as a delivery mode have on the quality of survey questionnaire responses compared to any other alternative delivery mode: paper, laptop computer, tablet computer (manufactured before 2007), short message service (SMS) and plastic objects. Search methods: We searched MEDLINE, EMBASE, PsycINFO, IEEEXplore, Web of Science, CABI: CAB Abstracts, Current Contents Connect, ACM Digital, ERIC, Sociological Abstracts, Health Management Information Consortium, the Campbell Library and CENTRAL. We also searched registers of current and ongoing clinical trials such as ClinicalTrials.gov and the World Health Organization (WHO)International Clinical Trials Registry Platform. We also searched the grey literature in OpenGrey, Mobile Active and ProQuest Dissertation & Theses. Lastly, we searched Google Scholar and the reference lists of included studies and relevant systematic reviews. We performed all searches up to 12 and 13 April 2015. Selection criteria: We included parallel randomised controlled trials (RCTs), crossover trials and paired repeated measures studies that compared the electronic delivery of self-administered survey questionnaires via a smartphone or tablet app with any other delivery mode. We included data obtained from participants completing health-related self-administered survey questionnaire, both validated and non-validated. We also included data offered by both healthy volunteers and by those with any clinical diagnosis. We included studies that reported any of the following outcomes: data equivalence; data accuracy; data completeness; response rates; differences in the time taken to complete a survey questionnaire; differences in respondent’s adherence to the original sampling protocol; and acceptability to respondents of the delivery mode. We included studies that were published in 2007 or after, as devices that became available during this time are compatible with the mobile operating system (OS) framework that focuses on apps. Data collection and analysis: Two review authors independently extracted data from the included studies using a standardised form created for this systematic review in REDCap. They then compared their forms to reach consensus. Through an initial systematic mapping on the included studies, we identified two settings in which survey completion took place: controlled and uncontrolled. These settings differed in terms of (i) the location where surveys were completed, (ii) the frequency and intensity of sampling protocols, and (iii) the level of control over potential confounders (e.g., type of technology, level of help offered to respondents).We conducted a narrative synthesis of the evidence because a meta-analysis was not appropriate due to high levels of clinical and methodological diversity. We reported our findings for each outcome according to the setting in which the studies were conducted. Main results: We included 14 studies (15 records) with a total of 2275 participants; although we included only 2272 participants in the final analyses as there were missing data for three participants from one included study. Regarding data equivalence, in both controlled and uncontrolled settings, the included studies found no significant differences in the mean overall scores between apps and other delivery modes, and that all correlation coefficients exceeded the recommended thresholds for data equivalence. Concerning the time taken to complete a survey questionnaire in a controlled setting, one study found that an app was faster than paper, whereas the other study did not find a significant difference between the two delivery modes. In an uncontrolled setting, one study found that an app was faster than SMS. Data completeness and adherence to sampling protocols were only reported in uncontrolled settings. Regarding the former, an app was found to result in more complete records than paper, and in significantly more data entries than an SMS-based survey questionnaire. Regarding adherence to the sampling protocol, apps may be better than paper but no different from SMS. We identified multiple definitions of acceptability to respondents, with inconclusive results: preference; ease of use; willingness to use a delivery mode; satisfaction; effectiveness of the system informativeness; perceived time taken to complete the survey questionnaire; perceived benefit of a delivery mode; perceived usefulness of a delivery mode; perceived ability to complete a survey questionnaire; maximum length of time that participants would be willing to use a delivery mode; and reactivity to the delivery mode and its successful integration into respondents’ daily routine. Finally, regardless of the study setting, none of the included studies reported data accuracy or response rates. Authors’ conclusions: Our results, based on a narrative synthesis of the evidence, suggest that apps might not affect data equivalence as long as the intended clinical application of the survey questionnaire, its intended frequency of administration and the setting in which it was validated remain unchanged. There were no data on data accuracy or response rates, and findings on the time taken to complete a self-administered survey questionnaire were contradictory. Furthermore, although apps might improve data completeness, there is not enough evidence to assess their impact on adherence to sampling protocols. None of the included studies assessed how elements of user interaction design, survey questionnaire design and intervention design might influence mode effects. Those conducting research in public health and epidemiology should not assume that mode effects relevant to other delivery modes apply to apps running on consumer smart devices. Those conducting methodological research might wish to explore the issues highlighted by this systematic review.

BACKGROUND Corticosteroids continue to play a central role in induction of remission in active Crohn's disease. However, their use comes at a price of significant adverse effects when used repeatedly or for extended periods. Newer corticosteroid agents with limited systemic bioavailability offer a tantalizing option, if they can be shown to be efficacious and safer than conventional corticosteroids. Budesonide is the main alternative corticosteroid currently available in an enteric formulation. OBJECTIVES To evaluate the effectiveness of oral budesonide for the treatment of acute flares of Crohn's disease. A secondary but important endpoint was to evaluate the adverse effect profile. SEARCH STRATEGY The following sources were used to search the literature for potentially relevant papers and trials. 1. A computer-assisted search of the on-line bibliographic database MEDLINE from 1986 onwards. 2. Hand searching the reference lists of trials and review articles identified by means of the computer- assisted search. 3. Proceedings from major gastrointestinal meetings were manually searched from 1990 onwards. 4. Contact with the relevant pharmaceutical companies that have been involved in the development of budesonide. SELECTION CRITERIA Potentially relevant articles were reviewed in an independent unblinded fashion by two authors to determine if they met the criteria specified below: 1) STUDY POPULATION: Patients of any age with acutely active Crohn's disease, as defined by a CDAI > 150. 2) METHODOLOGY: Randomized double blind controlled trials comparing budesonide to a control treatment. Patients in the control arm may have received placebo, conventional corticosteroids, 5-aminosalicylic acid or sulfasalazine. 3) OUTCOME MEASURES: Clinical remission was the outcome measure of interest. The definition of remission was usually a CDAI < 150 by 8 to 16 weeks of therapy. DATA COLLECTION AND ANALYSIS Eligible articles were reviewed in duplicate and the results of the primary research trials were abstracted onto specially designed data extraction forms. The proportion of patients achieving remission in the active treatment and control groups of each study were derived from the data provided in the original research papers. Where possible, data were broken down based on site of disease or other strata used by the individual trials. STATISTICAL ANALYSIS Data extracted from the original research articles were converted, where necessary, into individual 2 x 2 tables (remission versus no remission x budesonide versus control) for each of the individual studies. Where available, individual 2 x 2 tables for strata within studies were also used. The presence of significant heterogeneity among studies was tested for using the chi-square test. Because this is a relatively insensitive test for the presence of heterogeneity, a p-value of 0.10 was regarded as statistically significant. Where p < 0.10 the data from the individual studies were still combined but the pooled results were interpreted with caution. The 2 x 2 tables were synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel. A fixed effects model was used for the pooling of data. The analysis was performed initially by combining data from all trials to estimate the response rate to budesonide therapy. The analysis was also performed by combining only studies with comparable control groups. MAIN RESULTS Eight studies were deemed eligible for review. EFFICACY Budesonide was superior to placebo for induction of remission with a pooled odds ratio for the two placebo-controlled trials of 2.85 (95% CI 1.67 - 4.87). A single trial comparing budesonide with mesalamine demonstrated an odds ratio of 2.80 (95% CI 1.50 - 5.20) in favour of budesonide over mesalamine for induction of remission in active Crohn's disease. However, budesonide was inferior to conventional corticosteroids (prednisone or prednisolone) for induction of remission with a pooled odds ratio for the five trials of 0.69 (95% CI 0.51 - 0.95). SAFETY The two trials comparing budesonide versus placebo (Greenberg 1994; Tremaine 2002) showed no difference between study groups for proportion of reported corticosteroid-related adverse effects with the pooled odds ratio for both trials of 0.98 (95% CI 0.58 - 1.67). Five trials comparing budesonide versus prednisone showed the budesonide study group had fewer reported corticosteroid-related adverse effects than the prednisone study group (pooled odds ratio was 0.38 (95% CI 0.28 - 0.53). AUTHORS' CONCLUSIONS With disease in the ileum or ascending colon, budesonide offers an effective therapy which is somewhat less efficacious but with fewer adverse effects than conventional corticosteroids (e.g. prednisone, prednisolone, or 6-methylprednisolone).

Background Growing expenditures on prescription medicines represent a major challenge to many health systems. Cap and co-payment policies are intended as an incentive to deter unnecessary or marginal utilisation, and to reduce third-party payer expenditures by shifting parts of the financial burden from insurers to patients, thus increasing their financial responsibility for prescription medicines. Direct patient payment policies include caps (maximum numbers of prescriptions or medicines that are reimbursed), fixed co-payments (patients pay a fixed amount per prescription or medicine), co-insurance (patients pay a percentage of the price), ceilings (patients pay the full price or part of the cost up to a ceiling, after which medicines are free or are available at reduced cost) and tier co-payments (differential co-payments usually assigned to generic and brand medicines). This is the first update of the original review. Objectives To determine the effects of cap and co-payment (cost-sharing) policies on use of medicines, healthcare utilisation, health outcomes and costs (expenditures). Search methods For this update, we searched the following databases and websites: The Cochrane Central Register of Controlled Trials (CENTRAL) (including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register, Cochrane Library; MEDLINE, Ovid; EMBASE, Ovid; IPSA, EBSCO; EconLit, ProQuest; Worldwide Political Science Abstracts, ProQuest; PAIS International, ProQuest; INRUD Bibliography; WHOLIS, WHO; LILACS), VHL; Global Health Library WHO; PubMed, NHL; SCOPUS; SciELO, BIREME; OpenGrey; JOLIS Library Network; OECD Library; World Bank e-Library; World Health Organization, WHO; World Bank Documents & Reports; International Clinical Trials Registry Platform (ICTRP), WHO; ClinicalTrials.gov, NIH. We searched all databases during January and February 2013, apart from SciELO, which we searched in January 2012, and ICTRP and ClinicalTrials.gov, which we searched in March 2014. Selection criteria We defined policies in this review as laws, rules or financial or administrative orders made by governments, non-government organisations or private insurers. We included randomised controlled trials, non-randomised controlled trials, interrupted time series studies, repeated measures studies and controlled before-after studies of cap or co-payment policies for a large jurisdiction or system of care. To be included, a study had to include an objective measure of at least one of the following outcomes: medicine use, healthcare utilisation, health outcomes or costs (expenditures). Data collection and analysis Two review authors independently extracted data and assessed study limitations. We reanalysed time series data for studies with sufficient data, if appropriate analyses were not reported. Main results We included 32 full-text articles (17 new) reporting evaluations of 39 different interventions (one study - Newhouse 1993 - comprises five papers). We excluded from this update eight controlled before-after studies included in the previous version of this review, because they included only one site in their intervention or control groups. Five papers evaluated caps, and six evaluated a cap with co-insurance and a ceiling. Six evaluated fixed co-payment, two evaluated tiered fixed co-payment, 10 evaluated a ceiling with fixed co-payment and 10 evaluated a ceiling with co-insurance. Only one evaluation was a randomised trial. The certainty of the evidence was found to be generally low to very low. Increasing the amount of money that people pay for medicines may reduce insurers’ medicine expenditures and may reduce patients’ medicine use. This may include reductions in the use of life-sustaining medicines as well as medicines that are important in treating chronic conditions and medicines for asymptomatic conditions. These types of interventions may lead to small decreases in or uncertain effects on healthcare utilisation. We found no studies that reliably reported the effects of these types of interventions on health outcomes. Authors' conclusions The diversity of interventions and outcomes addressed across studies and differences in settings, populations and comparisons made it difficult to summarise results across studies. Cap and co-payment polices may reduce the use of medicines and reduce medicine expenditures for health insurers. However, they may also reduce the use of life-sustaining medicines or medicines that are important in treating chronic, including symptomatic, conditions and, consequently, could increase the use of healthcare services. Fixed co-payment with a ceiling and tiered fixed co-payment may be less likely to reduce the use of essential medicines or to increase the use of healthcare services.

BACKGROUND Frey's syndrome is a rare disorder, the symptoms of which include sweating, flushing and warming over the preauricular and temporal areas following a gustatory stimulus. It often occurs in patients who have undergone parotidectomy, submandibular gland surgery, radical neck dissection, infection and traumatic injury in the parotid region, and is caused by the aberrant regrowth of facial autonomic nerve fibres. Currently there are several options used to treat patients with Frey's syndrome; for example, the topical application of anticholinergics and antiperspirants, and the intradermal injection of botulinum toxin. It is uncertain which treatment is most effective and safe. OBJECTIVES To assess the efficacy and safety of different interventions for the treatment of Frey's syndrome. SEARCH METHODS We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; ICTRP and additional sources for published and unpublished trials. The date of the search was 28 April 2014. SELECTION CRITERIA We included randomised or quasi-randomised controlled trials (RCTs) in participants diagnosed with Frey's syndrome using a clinical standard such as Minor's starch-iodine test. We planned to include trials in which participants received any intervention versus no treatment (observation) or an alternative intervention, with or without a second active treatment. Our primary outcome measures were success rate (as assessed clinically by Minor's starch-iodine test, the iodine-sublimated paper histogram method, blotting paper technique or another method) and adverse events. Our secondary outcome measure was success rate as assessed by patients (disappearance or improvement of symptoms). DATA COLLECTION AND ANALYSIS We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS We identified no RCTs or quasi-RCTs that fulfilled the inclusion criteria. Our searches retrieved eight potentially relevant studies, but after assessment of the full-text reports we excluded all of them due to the absence of randomisation or because the patients did not have Frey's syndrome. We excluded one randomised controlled trial that compared two different doses of botulinum toxin in patients with Frey's syndrome because the comparator was not an alternative treatment. AUTHORS' CONCLUSIONS We are unable to establish the efficacy and safety of the different methods used for the treatment of Frey's syndrome.RCTs are urgently needed to assess the effectiveness of interventions for the treatment of Frey's syndrome. Future RCTs should include patients with Frey's syndrome of different ranges of severity and report these patients separately. Studies should investigate all possibly effective treatments (such as anticholinergics, antiperspirants and botulinum toxin) compared to control groups using different treatments or placebo. Subjective assessment of Frey's syndrome should be considered as one of the outcome measures.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 10, 2010, on droperidol for the treatment of nausea and vomiting in palliative care patients. Nausea and vomiting are common symptoms in patients with terminal illness and can be very unpleasant and distressing. There are several different types of antiemetic treatments that can be used to control these symptoms. Droperidol is an antipsychotic drug and has been used and studied as an antiemetic in the management of postoperative and chemotherapy nausea and vomiting. OBJECTIVES: To evaluate the efficacy and adverse events (both minor and serious) associated with the use of droperidol for the treatment of nausea and vomiting in palliative care patients. SEARCH METHODS: We searched electronic databases including CENTRAL, MEDLINE (1950‐), EMBASE (1980‐), CINAHL (1981‐) and AMED (1985‐), using relevant search terms and synonyms. The basic search strategy was ("droperidol" OR "butyrophenone") AND ("nausea" OR "vomiting"), modified for each database. We updated the search on 2 December 2009. We performed updated searches of MEDLINE, EMBASE, CENTRAL and AMED 2009 to 2013 on 19 November 2013 and of CINAHL on 20 November 2013. We also searched trial registers (metaRegister of controlled trials (www.controlled‐trials.com/mrct), clinicaltrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/)) on 22 November 2013, using the keyword "droperidol". SELECTION CRITERIA: Randomised controlled trials (RCTs) of droperidol for the treatment of nausea or vomiting, or both, in adults receiving palliative care or suffering from an incurable progressive medical condition. DATA COLLECTION AND ANALYSIS: We judged the potential relevance of studies based on their titles and abstracts, and obtained studies that we anticipated might meet the inclusion criteria. Two review authors independently reviewed the abstracts for the initial review and four review authors reviewed the abstracts for the update to assess suitability for inclusion. We discussed discrepancies to achieve consensus. MAIN RESULTS: The 2010 search strategy identified 1664 abstracts (and 827 duplicates) of which we obtained 23 studies in full as potentially meeting the inclusion criteria. On review of the full papers, we identified no studies that met the inclusion criteria. The updated searches carried out in November 2013 identified 304 abstracts (261 excluding duplicates) of which we obtained 18 references in full as potentially meeting the inclusion criteria. On review of the full papers, we identified no studies that met the inclusion criteria, therefore there were no included studies in this review. We found no registered trials of droperidol for the management of nausea or vomiting in palliative care. AUTHORS' CONCLUSIONS: Since first publication of this review, no new studies were found. There is insufficient evidence to advise on the use of droperidol for the management of nausea and vomiting in palliative care. Studies of antiemetics in palliative care settings are needed to identify which agents are most effective, with minimum side effects.

Background The IQCODE (Informant Questionnaire for Cognitive Decline in the Elderly) is a commonly used questionnaire based tool that uses collateral information to assess for cognitive decline and dementia. Brief tools that can be used for dementia "screening" or "triage" may have particular utility in primary care / general practice healthcare settings but only if they have suitable test accuracy. A synthesis of the available data regarding IQCODE accuracy in a primary care setting should help inform cognitive assessment strategies for clinical practice; research and policy. Objectives We sought to describe the accuracy of IQCODE (the index test) against a clinical diagnosis of dementia (the reference standard). In this review we focus on those studies conducted in a primary care (general practice) setting. Search methods A search was performed in the following sources on the 28th of January 2013: ALOIS (Cochrane Dementia and Cognitive Improvement Group), MEDLINE (Ovid SP), EMBASE (Ovid SP), PsycINFO (Ovid SP), BIOSIS (Ovid SP), ISI Web of Science and Conference Proceedings (ISI Web of Knowledge), CINHAL (EBSCOhost) and LILACs (BIREME). We also searched sources specific to diagnostic test accuracy: MEDION (Universities of Maastricht and Leuven); DARE (York University); HTA Database (Health Technology Assessments Database via The Cochrane Library) and ARIF (Birmingham University). We developed a sensitive search strategy; search terms were designed to cover key concepts using several different approaches run in parallel and included terms relating to cognitive tests, cognitive screening and dementia. We used standardized database subject headings such as MeSH terms (in MEDLINE) and other standardized headings (controlled vocabulary) in other databases, as appropriate. Selection criteria We selected those studies performed in primary care settings, which included (not necessarily exclusively) IQCODE to assess for the presence of dementia and where dementia diagnosis was confirmed with clinical assessment. For the "primary care" setting, we included those healthcare settings where unselected patients, present for initial, non-specialist assessment of memory or non-memory related symptoms; often with a view to onward referral for more definitive assessment. Data collection and analysis We screened all titles generated by electronic database searches and abstracts of all potentially relevant studies were reviewed. Full papers were assessed for eligibility and data extracted by two independent assessors. Quality assessment (risk of bias and applicability) was determined using the QUADAS-2 tool. Reporting quality was determined using the STARDdem extension to the STARD tool. Main results From 71 papers describing IQCODE test accuracy, we included 1 paper, representing data from 230 individuals (n=16 [7%] with dementia). The paper described those patients consulting a primary care service who self-identified as Japanese-American. Dementia diagnosis was made using Benson & Cummings criteria and the IQCODE was recorded as part of a longer interview with the informant. IQCODE accuracy was assessed at various test thresholds, with a "trade-off" between sensitivity and specificity across these cutpoints. At an IQCODE threshold of 3.2 sensitivity: 100%, specificity: 76%; for IQCODE 3.7 sensitivity: 75%, specificity: 98%. Applying the QUADAS-2 assessments, the study was at high risk of bias in all categories. In particular degree of blinding was unclear and not all participants were included in the final analysis. Authors' conclusions It is not possible to give definitive guidance on the test accuracy of IQCODE for the diagnosis of dementia in a primary care setting based on the single study identified. We are surprised by the lack of research using the IQCODE in primary care as this is, arguably, the most appropriate setting for targeted case finding of those with undiagnosed dementia in order to maximise opportunities to intervene and provide support for the individual and their carers.

Background\ud \ud Various tools exist for initial assessment of possible dementia with no consensus on the optimal assessment method. Instruments that use collateral sources to assess change in cognitive function over time may have particular utility. The most commonly used informant dementia assessment is the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE).\ud \ud A synthesis of the available data regarding IQCODE accuracy will help inform cognitive assessment strategies for clinical practice, research and policy.\ud \ud Objectives\ud \ud Our primary objective was to determine the diagnostic accuracy of the informant based questionnaire IQCODE, for detection of all cause (undifferentiated) dementia in community-dwelling adults with no previous cognitive assessment. We sought to describe the accuracy of IQCODE (the index test) against a clinical diagnosis of dementia (the reference standard).\ud \ud Our secondary objective was to describe the effect of heterogeneity on the summary estimates. We were particularly interested in the traditional 26-item scale versus the 16-item short form; and language of administration. We explored the effect of varying the threshold IQCODE score used to define 'test positivity'.\ud \ud Search methods\ud \ud We searched the following sources on 28 January 2013: ALOIS (Cochrane Dementia and Cognitive Improvement Group), MEDLINE (OvidSP), EMBASE (OvidSP), PsycINFO (OvidSP), BIOSIS Previews (ISI Web of Knowledge), Web of Science with Conference Proceedings (ISI Web of Knowledge), LILACS (BIREME). We also searched sources relevant or specific to diagnostic test accuracy: MEDION (Universities of Maastrict and Leuven); DARE (York University); ARIF (Birmingham University). We used sensitive search terms based on MeSH terms and other controlled vocabulary.\ud \ud Selection criteria\ud \ud We selected those studies performed in community settings that used (not necessarily exclusively) the IQCODE to assess for presence of dementia and, where dementia diagnosis was confirmed, with clinical assessment. Our intention with limiting the search to a 'community' setting was to include those studies closest to population level assessment. Within our predefined community inclusion criteria, there were relevant papers that fulfilled our definition of community dwelling but represented a selected population, for example stroke survivors. We included these studies but performed sensitivity analyses to assess the effects of these less representative populations on the summary results.\ud \ud Data collection and analysis\ud \ud We screened all titles generated by the electronic database searches and abstracts of all potentially relevant studies were reviewed. Full papers were assessed for eligibility and data extracted by two independent assessors. For quality assessment (risk of bias and applicability) we used the QUADAS 2 tool. We included test accuracy data on the IQCODE used at predefined diagnostic thresholds. Where data allowed, we performed meta-analyses to calculate summary values of sensitivity and specificity with corresponding 95% confidence intervals (CIs). We pre-specified analyses to describe the effect of IQCODE format (traditional or short form) and language of administration for the IQCODE.\ud \ud Main results\ud \ud From 16,144 citations, 71 papers described IQCODE test accuracy. We included 10 papers (11 independent datasets) representing data from 2644 individuals (n = 379 (14%) with dementia). Using IQCODE cut-offs commonly employed in clinical practice (3.3, 3.4, 3.5, 3.6) the sensitivity and specificity of IQCODE for diagnosis of dementia across the studies were generally above 75%.\ud \ud Taking an IQCODE threshold of 3.3 (or closest available) the sensitivity was 0.80 (95% CI 0.75 to 0.85); specificity was 0.84 (95% CI 0.78 to 0.90); positive likelihood ratio was 5.2 (95% CI 3.7 to 7.5) and the negative likelihood ratio was 0.23 (95% CI 0.19 to 0.29).\ud \ud Comparative analysis suggested no significant difference in the test accuracy of the 16 and 26-item IQCODE tests and no significant difference in test accuracy by language of administration. There was little difference in sensitivity across our predefined diagnostic cut-points.\ud \ud There was substantial heterogeneity in the included studies. Sensitivity analyses removing potentially unrepresentative populations in these studies made little difference to the pooled data estimates.\ud \ud The majority of included papers had potential for bias, particularly around participant selection and sampling. The quality of reporting was suboptimal particularly regarding timing of assessments and descriptors of reproducibility and inter-observer variability.\ud \ud Authors' conclusions\ud \ud Published data suggest that if using the IQCODE for community dwelling older adults, the 16 item IQCODE may be preferable to the traditional scale due to lesser test burden and no obvious difference in accuracy. Although IQCODE test accuracy is in a range that many would consider 'reasonable', in the context of community or population settings the use of the IQCODE alone would result in substantial misdiagnosis and false reassurance. Across the included studies there were issues with heterogeneity, several potential biases and suboptimal reporting quality.

Background Chlorpromazine, formulated in the 1950s, remains a benchmark treatment for people with schizophrenia. Objectives To evaluate the effects of chlorpromazine for schizophrenia in comparison with placebo. Search strategy We updated previous searches of the Cochrane Schizophrenia Group Register (October 1999), Biological Abstracts (1982-1995), the Cochrane Library (1999, Issue 2), EMBASE (1980-1995), MEDLINE (1966-1995) and PsycLIT (1974-1995), by searching Cochrane Schizophrenia Group Register (June 2002). References of all identified studies were searched for further trial citations. Pharmaceutical companies and authors of trials were contacted. Selection criteria All randomised controlled trials (RCTs) comparing chlorpromazine with placebo relevant to people with schizophrenia, and non-affective serious/chronic mental illness irrespective of mode of diagnosis. Primary outcomes of interest were death, violent behaviours, overall improvement, relapse and satisfaction with care. Data collection and analysis Citations and, where possible, abstracts were inspected independently by reviewers, papers ordered, re-inspected and quality assessed. Data were extracted by BT and JR. CA and GA independently checked a 10% sample for reliability. Dichotomous data were analysed using random effects relative risk (RR) and the 95% confidence interval (CI) around this was estimated. Where possible the number needed to treat (NNT) or number needed to harm statistics (NNH) were calculated. Continuous data were excluded if more than 50% of people were lost to follow up, but, where possible, weighted mean difference (WMD) was calculated. Main results Over 1000 electronic records were inspected. The review currently mentions 302 papers in its Excluded Studies table and 50 studies in its Included Studies table. Four papers are awaiting translation. Chlorpromazine reduces relapse over six months to two years (n=512, 3 RCTs, RR 0.65 CI 0.5 to 0.9, NNT 3 CI 2.5 to 4) and promotes a global improvement in a person's symptoms and functioning (n=1121, 13 RCTs, RR no change/not improved 0.76 CI 0.7 to 0.9, NNT 7 CI 5 to 10) although the placebo response is also considerable. Fewer people allocated to chlorpromazine leave trials early (n=1755, 25 RCTs, RR 0.77 CI 0.6 to 1.1) but the difference is not statistically significant. There are many adverse effects. Chlorpromazine is clearly sedating (n=1404, 19 RCTs, RR 2.65 CI 1.9 to 3.7, NNH 5 CI 4 to 6), it increases a person's chances of experiencing acute movement disorders (n=942, 5 RCTs, RR 3.38 CI 1.4 to 8.0, NNH 22 CI 15 to 46), parkinsonism (n=1265, 12 RCTs, RR 2.56 CI 1.2 to 5.4, NNH 10 CI 8 to 16) and, perhaps, fits (n=695, 3 RCTs, RR 2.41 CI 0.4 to 16). Amongst other things it clearly causes a lowering of blood pressure with accompanying dizziness (n=1394, 16 RCTs, RR 2.10 CI 1.5 to 2.8, NNH 10 CI 8 to 15) and considerable increases in weight (n=165, 5 RCTs, RR 4.44 CI 2.1 to 9, NNH 3 CI 2 to 5). Authors' conclusions This review will confirm much that clinicians and recipients of care already know, but provides quantification to support clinical impression. Chlorpromazine's global position as a 'benchmark' treatment for psychoses is not threatened by this review. Chlorpromazine, in common use for half a century, is a well established but imperfect treatment. Judicious use of this best available evidence should lead to improved evidence-based decision making by clinicians, carers and patients.

Background Across the developed world, an estimated 150,000 to 300,000 people are treated annually with pelvic radiotherapy and 80% will develop gastrointestinal (GI) symptoms during treatment. Acute GI symptoms are associated with a greater risk of chronic, often debilitating, GI symptoms. Up to one-third of patients are malnourished before pelvic radiotherapy and up to four-fifths of patients lose weight during treatment. Malnutrition is linked to a higher risk of GI toxicity, which can lead to breaks in radiotherapy and early cessation of chemotherapy, thus compromising the efficacy of the primary cancer treatment. Objectives To assess the effects of nutritional interventions for reducing GI toxicity in adults undergoing radical pelvic radiotherapy. Search methods We searched the Cochrane Gynaecological Cancer Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 4, 2012, MEDLINE and EMBASE to May 2012. We handsearched the citation lists of included studies and previous systematic reviews identified to identify further relevant trials. Selection criteria We included studies if they were randomised controlled trials (RCTs) or non-randomised studies with concurrent comparison groups including quasi-randomised trials, cluster RCTs, non-randomised trials, prospective and retrospective cohort studies, and case series of 30 or more patients. We only included studies if they assessed the effect of a nutritional intervention in adults aged 18 years or over undergoing radical pelvic radiotherapy as part of anticancer treatment for a primary pelvic malignancy. We excluded patients with stomas and a previous history of inflammatory bowel disease. Nutritional support interventions could be provided at any stage before or during pelvic radiotherapy and included dietary counselling; dietary modification of fibre, lactose or fat; supplementary foods or drinks or fortified foods; standard oral nutrition supplements including polymeric-, peptide- or amino acid-based supplements and those where novel substrates have been added; enteral tube feeds; or parenteral nutrition (partial or total). We excluded probiotics, prebiotics and synbiotics. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We contacted study authors to obtain missing data. We assessed bias for each of the included studies using the bias assessment tables in the Cochrane software Review Manager5. We performed meta-analysis, when indicated, using the Mantel-Haenszel fixed-effect method or inverse variance fixed-effect method displayed with heterogeneity. We undertook meta-analyses on trials evaluating dietary modification against standard treatment for diarrhoea at the end of radiotherapy and for change in weight from baseline to end of radiotherapy. Main results The searches identified 7558 titles, and we excluded 7513 during title and abstract searches. We reviewed 45 papers in full, and excluded 39. We identified four studies on handsearching of the references, which, along with the six eligible papers from the database search, led to 10 studies being included. Four studies, three of which were RCTs and one prospective study, investigated the effect of elemental diet on GI symptoms; one RCT investigated the effect of dietary modification and elemental diet; and five RCTs investigated dietary modification. Studies were varied in terms of risk of bias. Data were dichotomised for presence and absence of diarrhoea at the end of radiotherapy for four trials evaluating dietary modification comprising modified fat, lactose, fibre or combinations of these dietary changes. A reduction in diarrhoea was demonstrated with nutritional intervention (risk ratio (RR) 0.66; 95% confidence interval (CI) 0.51 to 0.87, four studies, 413 participants, moderate quality of evidence) with low heterogeneity (Chi2 = 3.50, I2 = 14%). Two trials evaluating dietary modification on weight change (comparing baseline and end of radiotherapy) showed no difference between intervention or control (mean difference (MD) -0.57 kg; 95% CI -1.22 to 0.09) with low heterogeneity (Chi2 = 1.41, I2 = 29%). Generally adverse effects were poorly reported in included studies. Elemental diet in particular was poorly tolerated. GI symptoms or toxicity > 6 months after radiotherapy was not reported in included studies Authors' conclusions There have been benefits demonstrated with dietary modification during pelvic radiotherapy to reduce diarrhoea. Those diets included single interventions or combinations of modified fat, lactose-restriction, fat-restriction and fibre supplementation. We were unable to meta-analyse elemental diet, as data were not available. We considered some of the studies to be at high risk of bias. There have been recent advances in novel, more targeted radiotherapy techniques, such that the findings of older studies need to be interpreted with caution. In addition, there were problems with compliance and palatability with some of the interventions, particularly elemental diet, which limits its usefulness in clinical practice.

Background Adult and adolescent congenital heart disease is increasing in prevalence as better medical care means more children are surviving to adulthood. People with chronic disease often also experience depression. There are several non-pharmacological treatments that might be effective in treating depression and improving quality of life for adults and young adults with congenital heart disease. The aim of this review was to assess the effects of treatments such as psychotherapy, cognitive behavioural therapies and talking therapies for treating depression in this population. Objectives To update the previous review on the effects (both harms and benefits) of psychological interventions for treating depression in young adults and adults with congenital heart disease. Psychological interventions include cognitive behavioural therapy, psychotherapy, or 'talking/counselling' therapy for depression. Search methods We updated the searches of the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 1, 2013), MEDLINE (OVID, 1946 to January week 4 2013), EMBASE (OVID, 1980 to 2013 week 05), PsycINFO (OVID, 1806 to January week 5 2013), the Database of Abstracts of Reviews of Effectiveness (DARE) on The Cochrane Library (Issue 1, 2013), BIOSIS (Thomson Reuters, 1969 to 21 February 2013), and CINAHL (January 1980 to February 2013) on 5 February 2013. We did not search abstracts from national and international cardiology and psychology conferences and dissertation abstracts for this update. No language restrictions were applied. Selection criteria Randomised controlled trials comparing psychological interventions with no intervention for people over 15 years with depression who have congenital heart disease. Data collection and analysis Two review authors independently screened titles and abstracts of studies that were potentially relevant to the review. We rejected studies that were clearly ineligible. Two review authors independently assessed the abstracts or full papers for inclusion criteria. We sought further information from the authors where papers contained insufficient information to make a decision about eligibility. Main results We did not identify any randomised controlled trials that met the inclusion criteria. Authors' conclusions Depression is common in people with congenital heart disease and can exacerbate the physical consequences of the illness. There are effective pharmacological and non-pharmacological treatments for depression, but we have not been able to identify any trials showing the effectiveness of non-pharmacological treatments. A well-designed randomised controlled trial is needed to assess the effects of psychological interventions for depression in congenital heart disease.

Dysfunctional breathing/hyperventilation syndrome (DB/HVS) is a respiratory disorder, psychologically or physiologically based, involving breathing too deeply and/or too rapidly (hyperventilation) or erratic breathing interspersed with breath-holding or sighing (DB). DB/HVS can result in significant patient morbidity and an array of symptoms including breathlessness, chest tightness, dizziness, tremor and paraesthesia. DB/HVS has an estimated prevalence of 9.5% in the general adult population, however, there is little consensus regarding the most effective management of this patient group.(1) To determine whether breathing exercises in patients with DB/HVS have beneficial effects as measured by quality of life indices (2) To determine whether there are any adverse effects of breathing exercises in patients with DB/HVS SEARCH METHODS: We identified trials for consideration using both electronic and manual search strategies. We searched CENTRAL, MEDLINE, EMBASE, and four other databases. The latest search was in February 2013.We planned to include randomised, quasi-randomised or cluster randomised controlled trials (RCTs) in which breathing exercises, or a combined intervention including breathing exercises as a key component, were compared with either no treatment or another therapy that did not include breathing exercises in patients with DB/HVS. Observational studies, case studies and studies utilising a cross-over design were not eligible for inclusion.We considered any type of breathing exercise for inclusion in this review, such as breathing control, diaphragmatic breathing, yoga breathing, Buteyko breathing, biofeedback-guided breathing modification, yawn/sigh suppression. Programs where exercises were either supervised or unsupervised were eligible as were relaxation techniques and acute-episode management, as long as it was clear that breathing exercises were a key component of the intervention.We excluded any intervention without breathing exercises or where breathing exercises were not key to the intervention.Two review authors independently checked search results for eligible studies, assessed all studies that appeared to meet the selection criteria and extracted data. We used standard procedures recommended by The Cochrane Collaboration.We included a single RCT assessed at unclear risk of bias, which compared relaxation therapy (n = 15) versus relaxation therapy and breathing exercises (n = 15) and a no therapy control group (n = 15).Quality of life was not an outcome measure in this RCT, and no numerical data or statistical analysis were presented in this paper. A significant reduction in the frequency and severity of hyperventilation attacks in the breathing exercise group compared with the control group was reported. In addition, a significant difference in frequency and severity of hyperventilation attacks between the breathing and relaxation group was reported. However, no information could be extracted from the paper regarding the size of the treatment effects.The results of this systematic review are unable to inform clinical practice, based on the inclusion of only one small, poorly reported RCT. There is no credible evidence regarding the effectiveness of breathing exercises for the clinical symptoms of DB/HVS. It is currently unknown whether these interventions offer any added value in this patient group or whether specific types of breathing exercise demonstrate superiority over others. Given that breathing exercises are frequently used to treat DB/HVS, there is an urgent need for further well designed clinical trials in this area. Future trials should conform to the CONSORT statement for standards of reporting and use appropriate, validated outcome measures. Trial reports should also ensure full disclosure of data for all important clinical outcomes.

Background Attention deficit hyperactivity disorder (ADHD) is a major problem in children and adolescents, characterised by age-inappropriate levels of inattention, hyperactivity and impulsivity, and is associated with long-term social, academic and mental health problems. The stimulant medications methylphenidate and amphetamine are the most frequently used treatments for ADHD, but these are not always effective and can be associated with side effects. Clinical and biochemical evidence suggests that deficiencies of polyunsaturated fatty acids (PUFA) could be related to ADHD. Children and adolescents with ADHD have been shown to have significantly lower plasma and blood concentrations of PUFA and, in particular, lower levels of omega-3 PUFA. These findings suggest that PUFA supplementation may reduce the attention and behaviour problems associated with ADHD. Objectives To compare the efficacy of PUFA to other forms of treatment or placebo in treating the symptoms of ADHD in children and adolescents. Search methods We searched the following databases in August 2011: CENTRAL (The Cochrane Library 2011, Issue 2), MEDLINE (1948 to July Week 3, 2011), EMBASE (1980 to 2011 Week 29), PsycINFO (1806 to current), CINAHL (1937 to current), BIOSIS (1969 to 30 July 2011), Science Citation Index (1970 to 30 July 2011), Social Science Citation Index (1970 to 30 July 2011), Conference Proceedings Citation Index - Science (1990 to 30 July 2011), Conference Proceedings Citation Index - Social Science and Humanities (1990 to 30 July 2011), Cochrane Database of Systematic Reviews (2011, Issue 7), DARE (2011 Issue 2), Dissertation Abstracts (via Dissertation Express) and the metaRegister of Controlled Trials (mRCT). In addition, we searched the following repositories for theses on 2 August 2011: DART, NTLTD and TROVE. We also checked reference lists of relevant studies and reviews for additional references. Selection criteria Two review authors independently assessed the results of the database searches. We resolved any disagreements regarding the selection of studies through consensus or, if necessary, by consultation with a third member of the review team. Data collection and analysis Two members of the review team independently extracted details of participants and setting, interventions, methodology and outcome data. If differences were identified, we resolved them by consensus or referral to a third member of the team. We made all reasonable attempts to contact the authors where further clarification or missing data were needed. Main results We included 13 trials with 1011 participants in the review. After screening 366 references, we considered 23 relevant and obtained the full text for consideration. We excluded five papers and included 18 papers describing the 13 trials. Eight of the included trials had a parallel design: five compared an omega-3 PUFA supplement to placebo; two compared a combined omega-3 and omega-6 supplement to placebo, and one compared an omega-3 PUFA to a dietary supplement. Five of the included trials had a cross-over design: two compared combined omega-3/6 PUFA to placebo; two compared omega-6 PUFA with placebo; one compared omega-3 to omega-6 PUFA, and one compared omega-6 PUFA to dexamphetamine. Supplements were given for a period of between four and 16 weeks. There was a significantly higher likelihood of improvement in the group receiving omega-3/6 PUFA compared to placebo (two trials, 97 participants; risk ratio (RR) 2.19, 95% confidence interval (CI) 1.04 to 4.62). However, there were no statistically significant differences in parent-rated ADHD symptoms (five trials, 413 participants; standardised mean difference (SMD) -0.17, 95% CI -0.38 to 0.03); inattention (six trials, 469 participants; SMD -0.04, 95% CI -0.29 to 0.21) or hyperactivity/impulsivity (five trials, 416 participants; SMD -0.04, 95% CI -0.25 to 0.16) when all participants receiving PUFA supplements were compared to those receiving placebo. There were no statistically significant differences in teacher ratings of overall ADHD symptoms (four trials, 324 participants; SMD 0.05, 95% CI -0.18 to 0.27); inattention (three trials, 260 participants; SMD 0.26, 95% CI -0.22 to 0.74) or hyperactivity/impulsivity (three trials, 259 participants; SMD 0.10, 95% CI -0.16 to 0.35). There were also no differences between groups in behaviour, side effects or loss to follow-up. Overall, there were no other differences between groups for any other comparison. Authors' conclusions Overall, there is little evidence that PUFA supplementation provides any benefit for the symptoms of ADHD in children and adolescents. The majority of data showed no benefit of PUFA supplementation, although there were some limited data that did show an improvement with combined omega-3 and omega-6 supplementation. It is important that future research addresses current weaknesses in this area, which include small sample sizes, variability of selection criteria, variability of the type and dosage of supplementation, short follow-up times and other methodological weaknesses.

Background Endoscopic retrograde cholangiopancreatography (ERCP) is an uncomfortable therapeutic procedure that cannot be performed without adequate sedation or general anaesthesia. A considerable number of ERCPs are performed annually in the UK (at least 48,000) and many more worldwide. Objectives The primary objective of our review was to evaluate and compare the efficacy and safety of sedative or anaesthetic techniques used to facilitate the procedure of ERCP in adult (age > 18 years) patients. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 8); MEDLINE (1950 to September 2011); EMBASE (1950 to September 2011); CINAHL, Web of Science and LILACS (all to September 2011). We searched for additional studies drawn from reference lists of retrieved trial materials and review articles and conference proceedings. Selection criteria We considered all randomized or quasi-randomized controlled studies where the main procedures performed were ERCPs. The three interventions we searched for were (1) conscious sedation (using midazolam plus opioid) versus deep sedation (using propofol); (2) conscious sedation versus general anaesthesia; and (3) deep sedation versus general anaesthesia. We considered all studies regardless of which healthcare professional administered the sedation. Data collection and analysis We reviewed 124 papers and identified four randomized trials (with a total of 510 participants) that compared the use of conscious sedation using midazolam and meperidine with deep sedation using propofol in patients undergoing ERCP procedures. All sedation was administered by non-anaesthetic personnel. Due to the clinical heterogeneity of the studies we decided to review the papers from a narrative perspective as opposed to a full meta-analysis. Our primary outcome measures included mortality, major complications and inability to complete the procedure due to sedation-related problems. Secondary outcomes encompassed sedation efficacy and recovery. Main results No immediate mortality was reported. There was no significant difference in serious cardio-respiratory complications suffered by patients in either sedation group. Failure to complete the procedure due to sedation-related problems was reported in one study. Three studies found faster and better recovery in patients receiving propofol for their ERCP procedures. Study protocols regarding use of supplemental oxygen, intravenous fluid administration and capnography monitoring varied considerably. The studies showed either moderate or high risk of bias. Authors' conclusions Results from individual studies suggested that patients have a better recovery profile after propofol sedation for ERCP procedures than after midazolam and meperidine sedation. As there was no difference between the two sedation techniques as regards safety, propofol sedation is probably preferred for patients undergoing ERCP procedures. However, in all of the studies that were identified only non-anaesthesia personnel were involved in administering the sedation. It would be helpful if further research was conducted where anaesthesia personnel were involved in the administration of sedation for ERCP procedures. This would clarify the extent to which anaesthesia personnel should be involved in the administration of propofol sedation.

Background Hypertrophic cardiomyopathy (HCM) is a genetic disease with an autosomal-dominant inheritance for which negative inotropes are the most widely used initial therapies. Observational studies and small randomised trials have suggested symptomatic and functional benefits using pacing and several theories have been put forward to explain why. Pacing, although not the primary treatment for HCM, could be beneficial to patients with relative or absolute contraindications to surgery or alcohol ablation. Several randomised controlled trials comparing pacing to other therapeutic modalities have been conducted but no Cochrane-style systematic review has been done. Objectives To assess the effects of pacing in drug-refractory or drug-intolerant hypertrophic cardiomyopathy patients. Search methods We searched the following on the 14/4/2010: CENTRAL (The Cochrane Library 2010, Issue 1), MEDLINE OVID (from 1950 onwards ), EMBASE OVID (from1980 onwards ), Web of Science with Conference Proceedings (from 1970 onwards). No language restrictions were applied. Selection criteria Randomised controlled trials of either parallel or crossover design that assess the beneficial and harmful effects of pacing for hypertrophic cardiomyopathy were included. When crossover studies were identified, we considered data only from the first phase. Data collection and analysis Data from included studies were extracted onto a pre-formed data extraction paper by two authors independently. Data was then entered into Review Manager 5.1 for analysis. Risk of bias was assessed using the guidance provided in the Cochrane Handbook. For dichotomous data, relative risk was calculated; and for continuous data, the mean differences were calculated. Where appropriate data were available, meta-analysis was performed. Where meta-analysis was not possible, a narrative synthesis was written. A QUROUM flow chart was provided to show the flow of papers. Main results Five studies (reported in 10 papers) were identified. However, three of the five studies provided un-usable data. Thus the data from only two studies (reported in seven papers) with 105 participants were included for this review. There was insufficient data to compare results on all-cause mortality, cost effectiveness, exercise capacity, Quality of life and Peak O2 consumption. When comparing active pacing versus placebo pacing on exercise capacity, one study showed that exercise time decreased from (13.1 ± 4.4) minutes to (12.6 ± 4.3) minutes in the placebo group and increased from (12.1 ± 5.6) minutes to (12.9 ± 4.2) minutes in the treatment group (MD 0.30; 95% CI -1.54 to 2.14). Statistically significant data from the same study showed that left ventricular outflow tract obstruction decreased from (71 ± 32) mm Hg to (52 ± 34) mm Hg in the placebo group and from (70 ± 24) mm Hg to (33 ± 27) mm Hg in the active pacing group (MD -19.00; 95% CI -32.29 to -5.71). This study was also able to show that New York Heart Association (NYHA) functional class decreased from (2.5 ± 0.5) to (2.2 ± 0.6) in the inactive pacing group and decreased from (2.6 ± 0.5) to (1.7 ± 0.7) in the placebo group (MD -0.50; 95% CI -0.78 to -0.22). When comparing active pacing versus trancoronary ablation of septal hypertrophy (TASH), data from one study showed that NYHA functional class decreased from (3.2 ± 0.7) to (1.5 ± 0.5) in the TASH group and decreased from (3.0 ± 0.1) to (1.9 ± 0.6) in the pacemaker group. This study also showed that LV wall thickness remained unchanged in the active pacing group compared to reduction from (22 ± 4) mm to (17 ± 3) mm in the TASH group (MD 0.60; 95% CI -5.65 to 6.85) and that LV outflow tract obstruction decreased from (80 ± 35.5) mm Hg in the TASH group to (49.3 ± 37.7) mm Hg in the pacemaker group. Authors' conclusions Trials published to date lack information on clinically relevant end-points. Existing data is derived from small trials at high risk of bias, which concentrate on physiological measures. Their results are inconclusive. Further large and high quality trials with more appropriate outcomes are warranted.

BACKGROUND: Lichen sclerosus is a chronic, inflammatory skin condition that most commonly occurs in adult women, although it may also be seen in men and children. It primarily affects the genital area and around the anus, where it causes persistent itching and soreness. Scarring after inflammation may lead to severe damage by fusion of the vulval lips (labia); narrowing of the vaginal opening; and burying of the clitoris in women and girls, as well as tightening of the foreskin in men and boys, if treatments are not started early. Affected people have an increased risk of genital cancers. OBJECTIVES: To assess the effects of topical interventions for genital lichen sclerosus and adverse effects reported in included trials. SEARCH METHODS: We searched the following databases up to 16 September 2011: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2007), LILACS (from 1982), CINAHL (from 1981), British Nursing Index and Archive (from 1985), Science Citation Index Expanded (from 1945), BIOSIS Previews (from 1926), Conference Papers Index (from 1982), and Conference Proceedings Citation Index ‐ Science (from 1990). We also searched ongoing trial registries and scanned the bibliographies of included studies, published reviews, and papers that had cited the included studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of topical interventions in genital lichen sclerosus. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, extracted data, and assessed the risk of bias. A third author was available for resolving differences of opinion. MAIN RESULTS: We included 7 RCTs, with a total of 249 participants, covering 6 treatments. Six of these RCTs tested the efficacy of one active intervention against placebo or another active intervention, while the other trial tested three active interventions against placebo. When compared to placebo in one trial, clobetasol propionate 0.05% was effective in treating genital lichen sclerosus in relation to the following outcomes: 'participant‐rated improvement or remission of symptoms' (risk ratio (RR) 2.85, 95% confidence interval (CI) 1.45 to 5.61) and 'investigator‐rated global degree of improvement' (standardised mean difference (SMD) 5.74, 95% CI 4.26 to 7.23). When mometasone furoate 0.05% was compared to placebo in another trial, there was a significant improvement in the 'investigator‐rated change in clinical grade of phimosis' (SMD ‐1.04, 95% CI ‐1.77 to ‐0.31). Both trials found no significant differences in reported adverse drug reactions between the corticosteroid and placebo groups. The data from four trials found no significant benefit for topical testosterone, dihydrotestosterone, and progesterone. When used as maintenance therapy after an initial treatment with topical clobetasol propionate in another trial, topical testosterone worsened the symptoms (P < 0.05), but the placebo did not. One trial found no differences between pimecrolimus and clobetasol propionate in relieving symptoms through change in pruritus (itching) (SMD ‐0.33, 95% CI ‐0.99 to 0.33) and burning/pain (SMD 0.03, 95% CI ‐0.62 to 0.69). However, pimecrolimus was less effective than clobetasol propionate with regard to the 'investigator‐rated global degree of improvement' (SMD ‐1.64, 95% CI ‐2.40 to ‐0.87). This trial found no significant differences in reported adverse drug reactions between the pimecrolimus and placebo groups. AUTHORS' CONCLUSIONS: The current limited evidence demonstrates the efficacy of clobetasol propionate, mometasone furoate, and pimecrolimus in treating genital lichen sclerosus. Further RCTs are needed to determine the optimal potency and regimen of topical corticosteroids, examine other topical interventions, assess the duration of remission or prevention of flares, evaluate the reduction in the risk of genital squamous cell carcinoma or genital intraepithelial neoplasia, and examine the efficacy in improving the quality of the sex lives of people with this condition.

BACKGROUND Hodgkin's Disease is one of the most curable cancers in children, particularly at the early stages. The debate rests now more with retention of high cures and eliminating treatment sequelae. OBJECTIVES To assess relapse free survival and overall survival rates in children with Stage l-llA Hodgkin's Disease treated with radiotherapy, chemotherapy or a combination of the two treatments. SEARCH STRATEGY MEDLINE, EMBASE, CINAHL, Cancer-CD and the Cochrane Library were searched for randomised controlled trials. Key words included 'Hodgkin's Disease', 'Reed-Sternberg cells' and variations of 'child'. SELECTION CRITERIA Treatments with a combination of the following therapies; involved field radiotherapy, extended field radiotherapy, anthracycline based chemotherapy regimens, or alkylating chemotherapy agents. Patients included children to 19 years of age. DATA COLLECTION AND ANALYSIS Seven papers were identified as meeting the selection criteria. Of these four were usable, though one only covered a small section of the paper. It was not possible to combine the outcomes as they covered different treatment regimens and the numbers in one study were inaccurate. MAIN RESULTS The results comparing IF with EF radiotherapy for children are based on one large multi-centred trial. Although the study is substantial and methodologically rigorous, the evidence for efficacy rests simply on this one trial. The results from the other three studies are not generalizable. The outcomes could not be combined as the studies assessed different treatment regimens. In addition there is little evidence to suggest that the methodological quality, particularly in terms of randomisation and simple arithmetic, is of a sufficiently robust nature in two of the studies. REVIEWER'S CONCLUSIONS The treatment of Hodgkin's Disease Stage l -llA for children has undergone considerable evolution and development in the previous three decades with the introduction and refinement of combined modality treatments. There is now overall consensus that the prognosis for these patients following a short course of chemotherapy and low dose local radiotherapy is very good with a large percentage achieving long-term survival or relapse free survival. The main issues and problems facing practitioners in the field is the reduction and management of late effects and sequelae of treatment. The evidence for this overall agreement is based on a mass of cohort studies that have influenced changes in practice and significantly improved outcomes. However, apart from the collaborative study looking at radiotherapy alone, there is little evidence from randomised controlled trials to support this consensus.

Background Scientific findings must withstand critical review if they are to be accepted as valid, and editorial peer review (critique, effort to disprove) is an essential element of the scientific process. We review the evidence of the editorial peer-review process of original research studies submitted for paper or electronic publication in biomedical journals. Objectives To estimate the effect of processes in editorial peer review. Search methods The following databases were searched to June 2004: CINAHL, Ovid, Cochrane Methodology Register, Dissertation abstracts, EMBASE, Evidence Based Medicine Reviews: ACP Journal Club, MEDLINE, PsycINFO, PubMed. Selection criteria We included prospective or retrospective comparative studies with two or more comparison groups, generated by random or other appropriate methods, and reporting original research, regardless of publication status. We hoped to find studies identifying good submissions on the basis of: importance of the topic dealt with, relevance of the topic to the journal, usefulness of the topic, soundness of methods, soundness of ethics, completeness and accuracy of reporting. Data collection and analysis Because of the diversity of study questions, viewpoints, methods, and outcomes, we carried out a descriptive review of included studies grouping them by broad study question. Main results We included 28 studies. We found no clear-cut evidence of effect of the well-researched practice of reviewer and/or author concealment on the outcome of the quality assessment process (9 studies). Checklists and other standardisation media have some evidence to support their use (2 studies). There is no evidence that referees' training has any effect on the quality of the outcome (1 study). Different methods of communicating with reviewers and means of dissemination do not appear to have an effect on quality (3 studies). On the basis of one study, little can be said about the ability of the peer-review process to detect bias against unconventional drugs. Validity of peer review was tested by only one small study in a specialist area. Editorial peer review appears to make papers more readable and improve the general quality of reporting (2 studies), but the evidence for this has very limited generalisability. Authors' conclusions At present, little empirical evidence is available to support the use of editorial peer review as a mechanism to ensure quality of biomedical research. However, the methodological problems in studying peer review are many and complex. At present, the absence of evidence on efficacy and effectiveness cannot be interpreted as evidence of their absence. A large, well-funded programme of research on the effects of editorial peer review should be urgently launched.

Communication about end of life (EoL) and EoL care is critically important for providing quality care as people approach death. Such communication is often complex and involves many people (patients, family members, carers, health professionals). How best to communicate with people in the period approaching death is not known, but is an important question for quality of care at EoL worldwide. This review fills a gap in the evidence on interpersonal communication (between people and health professionals) in the last year of life, focusing on interventions to improve interpersonal communication and patient, family member and carer outcomes.To assess the effects of interventions designed to improve verbal interpersonal communication about EoL care between health practitioners and people affected by EoL.We searched CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL from inception to July 2018, without language or date restrictions. We contacted authors of included studies and experts and searched reference lists to identify relevant papers. We searched grey literature sources, conference proceedings, and clinical trials registries in September 2019. Database searches were re-run in June 2021 and potentially relevant studies listed as awaiting classification or ongoing.This review assessed the effects of interventions, evaluated in randomised and quasi-randomised trials, intended to enhance interpersonal communication about EoL care between patients expected to die within 12 months, their family members and carers, and health practitioners involved in their care. Patients of any age from birth, in any setting or care context (e.g. acute catastrophic injury, chronic illness), and all health professionals involved in their care were eligible. All communication interventions were eligible, as long as they included interpersonal interaction(s) between patients and family members or carers and health professionals. Interventions could be simple or complex, with one or more communication aims (e.g. to inform, skill, engage, support). Effects were sought on outcomes for patients, family and carers, health professionals and health systems, including adverse (unintended) effects. To ensure this review's focus was maintained on interpersonal communication in the last 12 months of life, we excluded studies that addressed specific decisions, shared or otherwise, and the tools involved in such decision-making. We also excluded studies focused on advance care planning (ACP) reporting ACP uptake or completion as the primary outcome. Finally, we excluded studies of communication skills training for health professionals unless patient outcomes were reported as primary outcomes.Standard Cochrane methods were used, including dual review author study selection, data extraction and quality assessment of the included studies.Eight trials were included. All assessed intervention effects compared with usual care. Certainty of the evidence was low or very low. All outcomes were downgraded for indirectness based on the review's purpose, and many were downgraded for imprecision and/or inconsistency. Certainty was not commonly downgraded for methodological limitations. A summary of the review's findings is as follows. Knowledge and understanding (four studies, low-certainty evidence; one study without usable data): interventions to improve communication (e.g. question prompt list, with or without patient and physician training) may have little or no effect on knowledge of illness and prognosis, or information needs and preferences, although studies were small and measures used varied across trials. Evaluation of the communication (six studies measuring several constructs (communication quality, patient-centredness, involvement preferences, doctor-patient relationship, satisfaction with consultation), most low-certainty evidence): across constructs there may be minimal or no effects of interventions to improve EoL communication, and there is uncertainty about effects of interventions such as a patient-specific feedback sheet on quality of communication. Discussions of EoL or EoL care (six studies measuring selected outcomes, low- or very low-certainty evidence): a family conference intervention may increase duration of EoL discussions in an intensive care unit (ICU) setting, while use of a structured serious illness conversation guide may lead to earlier discussions of EoL and EoL care (each assessed by one study). We are uncertain about effects on occurrence of discussions and question asking in consultations, and there may be little or no effect on content of communication in consultations. Adverse outcomes or unintended effects (limited evidence): there is insufficient evidence to determine whether there are adverse outcomes associated with communication interventions (e.g. question prompt list, family conference, structured discussions) for EoL and EoL care. Patient and/or carer anxiety was reported by three studies, but judged as confounded. No other unintended consequences, or worsening of desired outcomes, were reported. Patient/carer quality of life (four studies, low-certainty evidence; two without useable data): interventions to improve communication may have little or no effect on quality of life. Health practitioner outcomes (three studies, low-certainty evidence; two without usable data): interventions to improve communication may have little or no effect on health practitioner outcomes (satisfaction with communication during consultation; one study); effects on other outcomes (knowledge, preparedness to communicate) are unknown. Health systems impacts: communication interventions (e.g. structured EoL conversations) may have little or no effect on carer or clinician ratings of quality of EoL care (satisfaction with care, symptom management, comfort assessment, quality of care) (three studies, low-certainty evidence), or on patients' self-rated care and illness, or numbers of care goals met (one study, low-certainty evidence). Communication interventions (e.g. question prompt list alone or with nurse-led communication skills training) may slightly increase mean consultation length (two studies), but other health service impacts (e.g. hospital admissions) are unclear.Findings of this review are inconclusive for practice. Future research might contribute meaningfully by seeking to fill gaps for populations not yet studied in trials; and to develop responsive outcome measures with which to better assess the effects of communication on the range of people involved in EoL communication episodes. Mixed methods and/or qualitative research may contribute usefully to better understand the complex interplay between different parties involved in communication, and to inform development of more effective interventions and appropriate outcome measures. Co-design of such interventions and outcomes, involving the full range of people affected by EoL communication and care, should be a key underpinning principle for future research in this area.

BACKGROUND: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative condition that may cause dysphagia, as well as limb weakness, dysarthria, emotional lability, and respiratory failure. Since normal salivary production is 0.5 L to 1.5 L daily, loss of salivary clearance due to dysphagia leads to salivary pooling and sialorrhea, often resulting in distress and inconvenience to people with MND. This is an update of a review first published in 2011. OBJECTIVES: To assess the effects of treatments for sialorrhea in MND, including medications, radiotherapy and surgery. SEARCH METHODS: On 27 August 2021, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, AMED, CINAHL, ClinicalTrials.gov and the WHO ICTRP. We checked the bibliographies of the identified randomized trials and contacted trial authors as needed. We contacted known experts in the field to identify further published and unpublished papers. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi‐RCTs, including cross‐over trials, on any intervention for sialorrhea and related symptoms, compared with each other, placebo or no intervention, in people with ALS/MND. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified four RCTs involving 110 participants with MND who were described as having intractable sialorrhea or bulbar dysfunction. A well‐designed study of botulinum toxin B compared to placebo injected into the parotid and submandibular glands of 20 participants showed that botulinum toxin B may produce participant‐reported improvement in sialorrhea, but the confidence interval (CI) was also consistent with no effect. Six of nine participants in the botulinum group and two of nine participants in the placebo group reported improvement (risk ratio (RR) 3.00, 95% CI 0.81 to 11.08; 1 RCT; 18 participants; low‐certainty evidence). An objective measure indicated that botulinum toxin B probably reduced saliva production (in mL/5 min) at eight weeks compared to placebo (MD −0.50, 95% CI −1.07 to 0.07; 18 participants, moderate‐certainty evidence). Botulinum toxin B may have little to no effect on quality of life, measured on the Schedule for Evaluation of Individual Quality of Life direct weighting scale (SEIQoL‐DW; 0‐100, higher values indicate better quality of life) (MD −2.50, 95% CI −17.34 to 12.34; 1 RCT; 17 participants; low‐certainty evidence). The rate of adverse events may be similar with botulinum toxin B and placebo (20 participants; low‐certainty evidence). Trialists did not consider any serious events to be related to treatment. A randomized pilot study of botulinum toxin A or radiotherapy in 20 participants, which was at high risk of bias, provided very low‐certainty evidence on the primary outcome of the Drool Rating Scale (DRS; range 8 to 39 points, higher scores indicate worse drooling) at 12 weeks (effect size −4.8, 95% CI −10.59 to 0.92; P = 0.09; 1 RCT; 16 participants). Quality of life was not measured. Evidence for adverse events, measured immediately after treatment (RR 7.00, 95% CI 1.04 to 46.95; 20 participants), and after four weeks (when two people in each group had viscous saliva) was also very uncertain. A phase 2, randomized, placebo‐controlled cross‐over study of 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (DMQ) found that DMQ may produce a participant‐reported improvement in sialorrhea, indicated by a slight improvement (decrease) in mean scores for the primary outcome, the Center for Neurologic Study Bulbar Function Scale (CNS‐BFS). Mean total CNS‐BFS (range 21 (no symptoms) to 112 (maximum symptoms)) was 53.45 (standard error (SE) 1.07) for the DMQ treatment period and 59.31 (SE 1.10) for the placebo period (mean difference) MD −5.85, 95% CI ‐8.77 to ‐2.93) with a slight decrease in the CNS‐BFS sialorrhea subscale score (range 7 (no symptoms) to 35 (maximum symptoms)) compared to placebo (MD –1.52, 95% CI ‐2.52 to ‐0.52) (1 RCT; 60 participants; moderate‐certainty evidence). The trial did not report an objective measure of saliva production or measure quality of life. The study was at an unclear risk of bias. Adverse events were similar to other trials of DMQ, and may occur at a similar rate as placebo (moderate‐certainty evidence, 60 participants), with the most common side effects being constipation, diarrhea, nausea, and dizziness. Nausea and diarrhea on DMQ treatment resulted in one withdrawal. A randomized, double‐blind, placebo‐controlled cross‐over study of scopolamine (hyoscine), administered using a skin patch, involved 10 randomized participants, of whom eight provided efficacy data. The participants were unrepresentative of clinic cohorts under routine clinical care as they had feeding tubes and tracheostomy ventilation, and the study was at high risk of bias. The trial provided very low‐certainty evidence on sialorrhea in the short term (7 days' treatment, measured on the Amyotrophic Lateral Scelerosis Functional Rating Scale‐Revised (ALSFRS‐R) saliva item (P = 0.572)), and the amount of saliva production in the short term, as indicated by the weight of a cotton roll (P = 0.674), or daily oral suction volume (P = 0.69). Quality of life was not measured. Adverse events evidence was also very uncertain. One person treated with scopolamine had a dry mouth and one died of aspiration pneumonia considered unrelated to treatment. AUTHORS' CONCLUSIONS: There is some low‐certainty or moderate‐certainty evidence for the use of botulinum toxin B injections to salivary glands and moderate‐certainty evidence for the use of oral dextromethorphan with quinidine (DMQ) for the treatment of sialorrhea in MND. Evidence on radiotherapy versus botulinum toxin A injections, and scopolamine patches is too uncertain for any conclusions to be drawn. Further research is required on treatments for sialorrhea. Data are needed on the problem of sialorrhea in MND and its measurement, both by participant self‐report measures and objective tests. These will allow the development of better RCTs.

BACKGROUND: Drug insurance schemes are systems that provide access to medicines on a prepaid basis and could potentially improve access to essential medicines and reduce out‐of‐pocket payments for vulnerable populations. OBJECTIVES: To assess the effects on drug use, drug expenditure, healthcare utilisation and healthcare outcomes of alternative policies for regulating drug insurance schemes. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, nine other databases, and two trials registers between November 2014 and September 2020, including a citation search for included studies on 15 September 2021 using Web of Science. We screened reference lists of all the relevant reports that we retrieved and reports from the Background section. Authors of relevant papers, relevant organisations, and discussion lists were contacted to identify additional studies, including unpublished and ongoing studies. SELECTION CRITERIA: We planned to include randomised trials, non‐randomised trials, interrupted time‐series studies (including controlled ITS [CITS] and repeated measures [RM] studies), and controlled before‐after (CBA) studies. Two review authors independently assessed the search results and reference lists of relevant reports, retrieved the full text of potentially relevant references and independently applied the inclusion criteria to those studies. We resolved disagreements by discussion, and when necessary by including a third review author. We excluded studies of the following pharmaceutical policies covered in other Cochrane Reviews: those that determined how decisions were made about which conditions or drugs were covered; those that placed restrictions on reimbursement for drugs that were covered; and those that regulated out‐of‐pocket payments for drugs. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included studies and assessed risk of bias for each study, with disagreements being resolved by consensus. We used the criteria suggested by Cochrane Effective Practice and Organisation of Care (EPOC) to assess the risk of bias of included studies. For randomised trials, non‐randomised trials and controlled before‐after studies, we planned to report relative effects. For dichotomous outcomes, we reported the risk ratio (RR) when possible and adjusted for baseline differences in the outcome measures. For interrupted time series and controlled interrupted time‐series studies, we computed changes along two dimensions: change in level; and change in slope. We undertook a structured synthesis following the EPOC guidance on this topic, describing the range of effects found in the studies for each category of outcomes. MAIN RESULTS: We identified 58 studies that met the inclusion criteria (25 interrupted time‐series studies and 33 controlled before‐after studies). Most of the studies (54) assessed a single policy implemented in the United States (US) healthcare system: Medicare Part D. The other four assessed other drug insurance schemes from Canada and the US, but only one of them provided analysable data for inclusion in the quantitative synthesis. The introduction of drug insurance schemes may increase prescription drug use (low‐certainty evidence). On the other hand, Medicare Part D may decrease drug expenditure measured as both out‐of‐pocket spending and total drug spending (low‐certainty evidence). Regarding healthcare utilisation, drug insurance policies (such as Medicare Part D) may lead to a small increase in visits to the emergency department. However, it is uncertain whether this type of policy increases or decreases hospital admissions or outpatient visits by beneficiaries of the scheme because the certainty of the evidence was very low. Likewise, it is uncertain if the policy increases or reduces health outcomes such as mortality because the certainty of the evidence was very low. AUTHORS' CONCLUSIONS: The introduction of drug insurance schemes such as Medicare Part D in the US health system may increase prescription drug use and may decrease out‐of‐pocket payments by the beneficiaries of the scheme and total drug expenditures. It may also lead to a small increase in visits to the emergency department by the beneficiaries of the policy. Its effects on other healthcare utilisation outcomes and on health outcomes are uncertain because of the very low certainty of the evidence. The applicability of this evidence to settings outside US healthcare is limited.

BACKGROUND: Late onset neonatal sepsis (systemic infection after 48 hours of age) continues to be a significant cause of morbidity and mortality. Early treatment with antibiotics is essential as infants can deteriorate rapidly. It is not clear which antibiotic regimen is most suitable for initial treatment of suspected late onset sepsis. This review has been superseded by a new Cochrane Review (Korang 2021). OBJECTIVES: To compare the effectiveness and adverse effects of different antibiotic regimens for treatment of suspected late onset sepsis in newborn infants. SEARCH METHODS: The standard search strategy of the Cochrane Neonatal Review Group was used. This includes electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2004), MEDLINE (1966 ‐ Dec 2004), EMBASE (1980 ‐ Dec 2004) and CINAHL (1982 ‐ Dec 2004), electronic abstracts of Pediatric Academic Society meetings (1996 ‐ Dec 2004) and previous reviews including cross references (all articles referenced). SELECTION CRITERIA: Randomised and quasi randomised controlled trials comparing different initial antibiotic regimens in neonates with suspected late onset sepsis were evaluated. DATA COLLECTION AND ANALYSIS: Both reviewer authors screened abstracts and papers against the inclusion criteria, appraised the quality of and extracted data from papers. For dichotomous outcomes, treatment effect was expressed as relative risk and risk difference with 95% confidence intervals. NNT was calculated for outcomes for which there was a statistically significant reduction in risk difference. MAIN RESULTS: Thirteen studies were identified as possibly eligible for inclusion. The majority of studies were excluded as they did not separate data for early and late onset infection. Two studies are still awaiting assessment. Only one small study, in 24 neonates, was included in this review. It compared beta‐lactam therapy with a combination of beta lactam plus aminoglycoside. The study did not meet our prespecified criteria for good methodological quality. In babies with suspected infection there was no significant difference in mortality (RR 0.17, 95% CI 0.01 to 3.23) or treatment failure (RR 0.17, 95% CI 0.01 to 3.23). Antibiotic resistance was assessed and there were no cases in either group. AUTHORS' CONCLUSIONS: There is inadequate evidence from randomised trials in favour of any particular antibiotic regimen for the treatment of suspected late onset neonatal sepsis. The available evidence is not of high quality. Although suspected sepsis and antibiotic use is common, quality research is required to specifically address both narrow and broad spectrum antibiotic use for late onset neonatal sepsis. Future research also needs to assess cost effectiveness and the impact of antibiotics in different settings such as developed or developing countries and lower gestational age groups.

BACKGROUND: Unit‐dose packaging of antimalarial drugs may improve the success of malaria treatments by making it easier for patients to take them correctly. OBJECTIVES: To summarize the effects of unit‐dose packaged treatment on treatment failure and treatment adherence in people with uncomplicated malaria. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register (February 2009); CENTRAL (The Cochrane Library Issue 1, 2009); MEDLINE (1966 to February 2009); EMBASE (1980 to February 2009); LILACS (February 2009); conference proceedings, and reference lists of articles. We also contacted pharmaceutical companies, organizations, and researchers in the field. SELECTION CRITERIA: Randomized controlled trials (RCTs), cluster‐RCTs and quasi‐RCTs of unit‐dose packaged drugs for treating uncomplicated malaria. DATA COLLECTION AND ANALYSIS: We independently assessed trial eligibility and risk of bias, and extracted data for an intention‐to‐treat analysis, where possible. We combined binary data using risk ratio (RR) and the fixed‐effect model, and presented them with 95% confidence intervals (CI). We attempted to contact trial authors for additional information. MAIN RESULTS: One RCT (203 participants), three quasi‐RCTs (895 participants), and one cluster‐RCT (six health facilities) met the inclusion criteria. Trials were generally of poor methodological quality, and none adequately assessed treatment failure. Unit‐dose packaged drugs (in conjunction with prescriber training and patient information) appeared to be associated with higher participant‐reported treatment adherence in all trials. A meta‐analysis of two trials (596 participants) showed that participant‐reported treatment adherence was slightly higher with blister‐packed tablets compared with tablets in paper envelopes (RR 1.18, 95% CI 1.12 to 1.25). Two trials using tablets in sectioned polythene bags as the intervention also noted an increase in participant‐reported treatment adherence: the cluster‐RCT (six clusters) compared it with tablets in paper envelopes, and the other trial compared it with syrup in bottles (RR 2.15, 95% CI 1.76 to 2.61; 299 participants). AUTHORS' CONCLUSIONS: There is insufficient evidence to know if the effects of unit‐dose packaged antimalarial drugs reduce treatment failure. Unit‐dose packaging, supported by prescriber training and patient information, appears to improve participant‐reported treatment adherence, but these data come from trials with methodological limitations.

BACKGROUND Cyclosporine was first found to be an effective and well-tolerated immunosuppressive agent in organ transplant recipients, and subsequently in several autoimmune diseases. It was reported in open studies that cyclosporine is effective for induction of remission in Crohn's disease. Four randomized controlled trials have been performed to determine whether the results observed in these open studies were valid. This systematic review summarizes the evidence on the use of oral cyclosporine for the induction of remission in Crohn's disease. OBJECTIVES To evaluate the effectiveness of oral cyclosporine for induction of remission in patients with active Crohn's disease in the presence and absence of concomitant steroid therapy. Secondary objectives were to evaluate clinical response rates and adverse events associated with cyclosporine. SEARCH STRATEGY Computer-assisted searches of the on-line bibliographic databases MEDLINE and EMBASE were performed to identify potentially relevant publications between 1980 and July 2004. The MeSH terms "Crohn Disease" or "Inflammatory Bowel disease" and "Cyclosporin" (exploded) were used to perform key word searches of the databases. Manual searches of reference lists from potentially relevant papers were performed in order to identify additional studies that may have been missed. Abstracts from major gastroenterological meetings, The Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were also searched for relevant studies. Appropriate officials at Sandoz Corporation were contacted to seek information on any unpublished trials. SELECTION CRITERIA Prospective, randomized, double-blinded, placebo-controlled trials of parallel design with treatment duration of a minimum 12 weeks comparing oral cyclosporine therapy with placebo for treatment of patients with active Crohn's disease were eligible for inclusion. DATA COLLECTION AND ANALYSIS All data were analyzed on an intention-to-treat basis. Data were extracted from the original research articles and converted into 2x2 tables (cyclosporine vs. placebo). Where available, individual 2x2 tables for strata within studies were also used. Heterogeneity was assessed using the chi-square test (p < 0.10 was regarded as statistically significant). For non-pooled data, p-values were derived using the chi-square test. For pooled data, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. A fixed effects model was used for pooling of data. For continuous data, summary test statistics were derived using the weighted mean difference and 95% confidence intervals. The definitions of treatment success, remission and clinical improvement were set by the authors of each paper, and the data were combined for analysis only if these definitions were sufficiently similar. MAIN RESULTS Brynskov 1989a found that patients receiving high dose cyclosporine (median 7.6 mg/kg/day) had statistically significant clinical improvement at 12 weeks compared to placebo patients. None of the other studies found any statistically significant benefit for clinical improvement or induction of remission for low dose cyclosporine treatment (5 mg/kg/day) used by itself or in combination with corticosteroids compared to placebo. Cyclosporine was associated with a significantly higher proportion of adverse events and withdrawals due to adverse events relative to placebo. AUTHORS' CONCLUSIONS Brynskov 1989a enrolled a small number of patients and the modified clinical grading scale used in the study has not been validated in other studies. Furthermore, statistically significant clinical improvement does not imply induction of clinical remission. Indeed, Brynskov 1989a found no statistically significant differences in the mean Crohn's Disease Activity Index score at 12 weeks indicating that cyclosporine was no more effective than placebo for induction of remission in Crohn's disease. The results of this review demonstrate that low dose (5 mg/kg/day) oral cyclosporine is not effective for the induction of remission in Crohn's disease. Patients treated with low dose oral cyclosporine are more likely than placebo treated patients to experience adverse events including renal dysfunction. The use of low dose oral cyclosporine for the treatment of chronic active Crohn's disease does not appear to be justified. Oral dosing at higher levels or parenteral administration of cyclosporine have not been adequately evaluated in controlled clinical trials. Higher doses of cyclosporine are not likely to be useful for the long-term management of Crohn's disease because of the risk of nephrotoxicity and the availability of other proven interventions.

Background Ulcerative colitis is largely a disease of nonsmokers. Intermittent smokers often experience improvement in their symptoms while smoking. Nonsmokers with ulcerative colitis who begin smoking may go into remission. Randomized controlled trials were developed to test the efficacy of transdermal nicotine for the induction of remission in ulcerative colitis. Objectives (1) To determine the efficacy of transdermal nicotine for induction of remission in ulcerative colitis. (2) To assess adverse events associated with transdermal nicotine therapy for ulcerative colitis Search strategy The MEDLINE (via PubMed) and EMBASE databases were searched using the search criteria "ulcerative colitis" and "transdermal nicotine" or "nicotine" to identify relevant papers published between 1970 and December 2003. Manual searches of reference lists from potentially relevant papers were performed to identify additional studies. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. The Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were also searched. Selection criteria We included only randomized controlled trials in which patients with active mild to moderate ulcerative colitis were randomly allocated to receive transdermal nicotine (15 to 25 mg/day) or a placebo or another treatment (corticosteroids or mesalamine). Data collection and analysis Data extraction and assessment of the methodological quality of each trial were independently performed by each author. Any disagreement among reviewers was resolved by consensus. The primary outcome measure was the number of patients achieving clinical or sigmoidoscopic remission as defined by the primary studies (e.g. no symptoms of ulcerative colitis), and expressed as a percentage of the patients randomized (intention to treat analysis). Secondary outcomes included clinical response, adverse events and withdrawal because of adverse events. Main results Seven studies were identified, five of which met the inclusion criteria. A meta-analysis of two trials in which 71 patients were randomized to nicotine and 70 to placebo showed a statistically significant benefit for nicotine treatment. After four to six weeks of treatment 19 of 71 patients treated with transdermal nicotine were in clinical remission compared to 9 of 70 treated with placebo (OR=2.56, 95% CI 1.02-6.45). In the same group of patients improvement or remission was noted in 29 of the 71 patients assigned to nicotine compared to 14 of 70 patients assigned to placebo (OR=2.72, 95% CI 1.28 - 5.81). For patients with left sided colitis the odds ratio was 2.31 (95% CI 1.05-5.10). When transdermal nicotine was compared to standard medical therapy no significant benefit for nicotine was observed. After four to six weeks of standard therapy (oral prednisone or mesalamine), 34 of 63 patients were in clinical or sigmoidoscopic remission compared to 33 of 66 patients treated with transdermal nicotine (OR=0.77, 95% CI 0.37-1.60). A meta-analysis of all five studies which included 137 patients treated with transdermal nicotine and 133 patients treated with a placebo or standard therapy demonstrated no statistically significant benefit of nicotine therapy (OR=1.23; 95% CI 0.71-2.14). Patients treated with transdermal nicotine were significantly more likely to withdrawal due to adverse events than patients treated with placebo or standard medical therapy (OR=5.82, 95% CI, 1.66 - 20.47) and were significantly more likely to suffer from an adverse event than patients treated with placebo or standard medical therapy (OR=3.54, 95% CI, 2.07 - 6.08). Reviewers' conclusions The results of this review provide evidence that transdermal nicotine is superior to placebo for the induction of remission in patient's with ulcerative colitis. The review did not identify any significant advantage for transdermal nicotine therapy compared to standard medical therapy. Adverse events associated with transdermal nicotine are significant and limit its use in some patients.

BACKGROUND: Hypertension is a major public health problem that increases the risk of cardiovascular and kidney diseases. Several studies have shown an inverse association between calcium intake and blood pressure, as small reductions in blood pressure have been shown to produce rapid reductions in vascular disease risk even in individuals with normal blood pressure ranges. This is the first update of the review to evaluate the effect of calcium supplementation in normotensive individuals as a preventive health measure. OBJECTIVES: To assess the efficacy and safety of calcium supplementation versus placebo or control for reducing blood pressure in normotensive people and for the prevention of primary hypertension. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to September 2020: the Cochrane Hypertension Specialised Register, CENTRAL (2020, Issue 9), Ovid MEDLINE, Ovid Embase, the WHO International Clinical Trials Registry Platform, and the US National Institutes of Health Ongoing Trials Register, ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: We selected trials that randomised normotensive people to dietary calcium interventions such as supplementation or food fortification versus placebo or control. We excluded quasi‐random designs. The primary outcomes were hypertension (defined as blood pressure ≥ 140/90 mmHg) and blood pressure measures. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, abstracted the data and assessed the risks of bias. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: The 2020 updated search identified four new trials. We included a total of 20 trials with 3512 participants, however we only included 18 for the meta‐analysis with 3140 participants. None of the studies reported hypertension as a dichotomous outcome. The effect on systolic and diastolic blood pressure was: mean difference (MD) ‐1.37 mmHg, 95% confidence interval (CI) ‐2.08, ‐0.66; 3140 participants; 18 studies; I(2) = 0%, high‐certainty evidence; and MD ‐1.45, 95% CI ‐2.23, ‐0.67; 3039 participants; 17 studies; I(2) = 45%, high‐certainty evidence, respectively. The effect on systolic and diastolic blood pressure for those younger than 35 years was: MD ‐1.86, 95% CI ‐3.45, ‐0.27; 452 participants; eight studies; I(2) = 19%, moderate‐certainty evidence; MD ‐2.50, 95% CI ‐4.22, ‐0.79; 351 participants; seven studies ; I(2) = 54%, moderate‐certainty evidence, respectively. The effect on systolic and diastolic blood pressure for those 35 years or older was: MD ‐0.97, 95% CI ‐1.83, ‐0.10; 2688 participants; 10 studies; I(2) = 0%, high‐certainty evidence; MD ‐0.59, 95% CI ‐1.13, ‐0.06; 2688 participants; 10 studies; I(2) = 0%, high‐certainty evidence, respectively. The effect on systolic and diastolic blood pressure for women was: MD ‐1.25, 95% CI ‐2.53, 0.03; 1915 participants; eight studies; I(2) = 0%, high‐certainty evidence; MD ‐1.04, 95% CI ‐1.86, ‐0.22; 1915 participants; eight studies; I(2) = 4%, high‐certainty evidence, respectively. The effect on systolic and diastolic blood pressure for men was MD ‐2.14, 95% CI ‐3.71, ‐0.59; 507 participants; five studies; I(2) = 8%, moderate‐certainty evidence; MD ‐1.99, 95% CI ‐3.25, ‐0.74; 507 participants; five studies; I(2) = 41%, moderate‐certainty evidence, respectively. The effect was consistent in both genders regardless of baseline calcium intake. The effect on systolic blood pressure was: MD ‐0.02, 95% CI ‐2.23, 2.20; 302 participants; 3 studies; I(2) = 0%, moderate‐certainty evidence with doses less than 1000 mg; MD ‐1.05, 95% CI ‐1.91, ‐0.19; 2488 participants; 9 studies; I(2) = 0%, high‐certainty evidence with doses 1000 to 1500 mg; and MD ‐2.79, 95% CI ‐4.71, 0.86; 350 participants; 7 studies = 8; I(2) = 0%, moderate‐certainty evidence with doses more than 1500 mg. The effect on diastolic blood pressure was: MD ‐0.41, 95% CI ‐2.07, 1.25; 201 participants; 2 studies; I(2) = 0, moderate‐certainty evidence; MD ‐2.03, 95% CI ‐3.44, ‐0.62 ; 1017 participants; 8 studies; and MD ‐1.35, 95% CI ‐2.75, ‐0.05; 1821 participants; 8 studies; I(2) = 51%, high‐certainty evidence, respectively. None of the studies reported adverse events. AUTHORS' CONCLUSIONS: An increase in calcium intake slightly reduces both systolic and diastolic blood pressure in normotensive people, particularly in young people, suggesting a role in the prevention of hypertension. The effect across multiple prespecified subgroups and a possible dose response effect reinforce this conclusion. Even small reductions in blood pressure could have important health implications for reducing vascular disease. A 2 mmHg lower systolic blood pressure is predicted to produce about 10% lower stroke mortality and about 7% lower mortality from ischaemic heart disease. There is a great need for adequately‐powered clinical trials randomising young people. Subgroup analysis should involve basal calcium intake, age, sex, basal blood pressure, and body mass index. We also require assessment of side effects, optimal doses and the best strategy to improve calcium intake.

BACKGROUND: Hepatocellular carcinoma is the sixth most common cancer worldwide. Hepatic resection is regarded as the curative therapy for hepatocellular carcinoma. However, only about 20% of people with hepatocellular carcinoma are candidates for resection, which highlights the importance of effective nonsurgical therapies. Until now, transcatheter arterial chemoembolisation (TACE) is the most common palliative therapy for hepatocellular carcinoma, but its clinical benefits remain unsatisfactory. During recent years, some studies have reported that the combination of TACE plus thermal ablation can confer a more favourable prognosis than TACE alone. However, clear and compelling evidence to prove the beneficial or harmful effects of the combination of TACE and thermal ablation therapy is lacking. OBJECTIVES: To assess the beneficial and harmful effects of the combination of thermal ablation with TACE versus TACE alone in people with hepatocellular carcinoma. SEARCH METHODS: We performed searches in the Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in the Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index‐Science. We endeavoured to identify relevant randomised clinical trials also in the China National Knowledge Infrastructure (CNKI) and Wanfang databases. We searched trial registration websites for ongoing studies. We also handsearched grey literature sources. The date of last search was 22 December 2020. SELECTION CRITERIA: We planned to include all randomised clinical trials comparing the combination of TACE plus thermal ablation versus TACE alone for hepatocellular carcinoma, no matter the language, year of publication, publication status, and reported outcomes. DATA COLLECTION AND ANALYSIS: We planned to use standard methodological procedures expected by Cochrane. We planned to calculate risk ratios (RRs) with the corresponding 95% confidence intervals (CIs). For time‐to‐event variables, we planned to use the methods of survival analysis and express the intervention effect as a hazard ratio (HR) with 95% Cl. If the log HR and the variance were not directly reported in reports, we planned to calculate them indirectly, following methods for incorporating summary time‐to‐event data into meta‐analysis. We planned to assess the risk of bias of the included studies using the RoB 2 tool. We planned to assess the certainty of evidence with GRADE and present the evidence in a summary of findings table. MAIN RESULTS: Out of 2224 records retrieved with the searches, we considered 135 records eligible for full‐text screening. We excluded 21 of these records because the interventions used were outside the scope of our review or the studies were not randomised clinical trials. We listed the remaining 114 records, reporting on 114 studies, under studies awaiting classification because we could not be sure that these were randomised clinical trials from the information in the study paper. We could not obtain information on the registration of the study protocol for any of the 114 studies. We could not obtain information on study approval by regional research ethics committees, either from the study authors or through our own searches of trial registries. Corresponding authors did not respond to our enquiries about the design and conduct of the studies, except for one from whom we did not receive a satisfactory response. We also raised awareness of our concerns to editors of the journals that published the 114 studies, and we did not hear back with useful information. Moreover, there seemed to be inappropriate inclusion of trial participants, based on cancer stage and severity of liver disease, who should have obtained other interventions according to guidelines from learned societies. Accordingly, we found no confirmed randomised clinical trials evaluating the combination of TACE plus thermal ablation versus TACE alone for people with hepatocellular carcinoma for inclusion in our review. We identified five ongoing trials, by handsearching in clinical trial websites. AUTHORS' CONCLUSIONS: We could not find for inclusion any confirmed randomised clinical trials assessing the beneficial or harmful effects of the combination of TACE plus thermal ablation versus TACE alone in people with hepatocellular carcinoma. Therefore, our results did not show or reject the efficiency of the combination of TACE plus thermal ablation versus TACE alone for people with hepatocellular carcinoma. We need trials that compare the beneficial and harmful effects of the combination of TACE plus thermal ablation versus TACE alone in people with hepatocellular carcinoma, not eligible for treatments with curative intent (liver transplantation, ablation surgical resection) and who have sufficient liver reserve, as assessed by the Child Pugh score, and who do not have extrahepatic metastases. Therefore, future trial participants must be classified at Barcelona Clinic Liver Cancer Stage B (intermediate stage) (BCLC‐B) or an equivalent, with other staging systems.

BACKGROUND: Cystic fibrosis (CF) is the most common, life‐limiting, genetically inherited disease. It affects multiple organs, particularly the respiratory system. However, gastrointestinal problems such as constipation and distal intestinal obstruction syndrome (DIOS) are also important and well‐recognised complications in CF. They share similar symptoms e.g. bloating, abdominal pain, but are distinct conditions. Constipation occurs when there is gradual faecal impaction of the colon, but DIOS occurs when there is an accumulation of faeces and sticky mucus, forming a mass in the distal part of the small intestine. The mass may partially block the intestine (incomplete DIOS) or completely block the intestine (complete DIOS). Symptoms of DIOS can affect quality of life and other aspects of CF health, such as airway clearance, exercise, sleep and nutritional status. Treatment of constipation and prevention of complete bowel obstruction are required for gastrointestinal management in CF. However, many different strategies are used in clinical practice and there is a lack of consensus. The importance of this topic was highlighted in a recent research priority setting exercise by the James Lind Alliance. OBJECTIVES: To evaluate the effectiveness and safety of laxative agents of differing types for preventing DIOS (complete and incomplete) in children and adults with CF. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of search: 09 September 2021. We also searched online trial registries. Date of last search: 12 October 2021. SELECTION CRITERIA: Randomised and quasi‐randomised controlled parallel trials comparing laxative therapy for preventing DIOS (including osmotic agents, stimulants, mucolytics and substances with more than one action) at any dose to placebo, no treatment or an alternative laxative therapy, in people of any age with pancreatic sufficient or insufficient CF and any stage of lung disease. Randomised cross‐over trials were judged on an individual basis. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion, extracted outcome data and performed a risk of bias assessment for the included data. We judged the certainty of the evidence using GRADE criteria. MAIN RESULTS: We included one cross‐over trial (17 participants) with a duration of 12 months, in which participants were randomly allocated to either cisapride (a gastro‐prokinetic agent) or placebo for six months each. The trial had an unclear risk of bias for most domains but had a high risk of reporting bias. Radiograph scores revealed no difference in occurrence of DIOS between cisapride and placebo (narrative report, no data provided). There were no adverse effects. Symptom scores were the only secondary outcome within the review that were reported. Total gastrointestinal symptom scores favoured cisapride with a statistically significant mean difference (MD) of ‐7.60 (95% confidence interval (CI) ‐14.73 to ‐0.47). There was no significant difference at six months between cisapride and placebo for abdominal distension, MD ‐0.90 (95% CI ‐2.39 to 0.59) or abdominal pain, MD ‐0.4 (95% CI ‐2.05 to 1.25). The global symptom scores (whether individuals felt better or worse) were reported in the paper to favour cisapride and be statistically significant (P < 0.05). We assessed the available data to be very low certainty. There was a great deal of missing data from the included trial and the investigators failed to report numerical data for many outcomes. The overall risk of bias of the trial was unclear and it had a high risk for reporting bias. There was also indirectness; the trial drug (cisapride) has since been removed from the market in several countries due to adverse effects, thus it has no current applicability for preventing DIOS. The included trial also had very few participants, which downgraded the certainty a further level for precision. AUTHORS' CONCLUSIONS: There is an absence of evidence for interventions for the prevention of DIOS. As there was only one included trial, we could not perform a meta‐analysis of the data. Furthermore, the included trial compared a prokinetic agent (cisapride) that is no longer licensed for use in a number of countries due to the risk of serious cardiac events, a finding that came to light after the trial was conducted. Therefore, the limited findings from the trial are not applicable in current clinical practice. Overall, a great deal more research needs to be undertaken on gastrointestinal complications in CF, as this is a very poorly studied area compared to respiratory complications in CF.

BACKGROUND: The Revised Cardiac Risk Index (RCRI) is a widely acknowledged prognostic model to estimate preoperatively the probability of developing in‐hospital major adverse cardiac events (MACE) in patients undergoing noncardiac surgery. However, the RCRI does not always make accurate predictions, so various studies have investigated whether biomarkers added to or compared with the RCRI could improve this. OBJECTIVES: Primary: To investigate the added predictive value of biomarkers to the RCRI to preoperatively predict in‐hospital MACE and other adverse outcomes in patients undergoing noncardiac surgery. Secondary: To investigate the prognostic value of biomarkers compared to the RCRI to preoperatively predict in‐hospital MACE and other adverse outcomes in patients undergoing noncardiac surgery. Tertiary: To investigate the prognostic value of other prediction models compared to the RCRI to preoperatively predict in‐hospital MACE and other adverse outcomes in patients undergoing noncardiac surgery. SEARCH METHODS: We searched MEDLINE and Embase from 1 January 1999 (the year that the RCRI was published) until 25 June 2020. We also searched ISI Web of Science and SCOPUS for articles referring to the original RCRI development study in that period. SELECTION CRITERIA: We included studies among adults who underwent noncardiac surgery, reporting on (external) validation of the RCRI and: ‐ the addition of biomarker(s) to the RCRI; or ‐ the comparison of the predictive accuracy of biomarker(s) to the RCRI; or ‐ the comparison of the predictive accuracy of the RCRI to other models. Besides MACE, all other adverse outcomes were considered for inclusion. DATA COLLECTION AND ANALYSIS: We developed a data extraction form based on the CHARMS checklist. Independent pairs of authors screened references, extracted data and assessed risk of bias and concerns regarding applicability according to PROBAST. For biomarkers and prediction models that were added or compared to the RCRI in ≥ 3 different articles, we described study characteristics and findings in further detail. We did not apply GRADE as no guidance is available for prognostic model reviews. MAIN RESULTS: We screened 3960 records and included 107 articles. Over all objectives we rated risk of bias as high in ≥ 1 domain in 90% of included studies, particularly in the analysis domain. Statistical pooling or meta‐analysis of reported results was impossible due to heterogeneity in various aspects: outcomes used, scale by which the biomarker was added/compared to the RCRI, prediction horizons and studied populations. Added predictive value of biomarkers to the RCRI Fifty‐one studies reported on the added value of biomarkers to the RCRI. Sixty‐nine different predictors were identified derived from blood (29%), imaging (33%) or other sources (38%). Addition of NT‐proBNP, troponin or their combination improved the RCRI for predicting MACE (median delta c‐statistics: 0.08, 0.14 and 0.12 for NT‐proBNP, troponin and their combination, respectively). The median total net reclassification index (NRI) was 0.16 and 0.74 after addition of troponin and NT‐proBNP to the RCRI, respectively. Calibration was not reported. To predict myocardial infarction, the median delta c‐statistic when NT‐proBNP was added to the RCRI was 0.09, and 0.06 for prediction of all‐cause mortality and MACE combined. For BNP and copeptin, data were not sufficient to provide results on their added predictive performance, for any of the outcomes. Comparison of the predictive value of biomarkers to the RCRI Fifty‐one studies assessed the predictive performance of biomarkers alone compared to the RCRI. We identified 60 unique predictors derived from blood (38%), imaging (30%) or other sources, such as the American Society of Anesthesiologists (ASA) classification (32%). Predictions were similar between the ASA classification and the RCRI for all studied outcomes. In studies different from those identified in objective 1, the median delta c‐statistic was 0.15 and 0.12 in favour of BNP and NT‐proBNP alone, respectively, when compared to the RCRI, for the prediction of MACE. For C‐reactive protein, the predictive performance was similar to the RCRI. For other biomarkers and outcomes, data were insufficient to provide summary results. One study reported on calibration and none on reclassification. Comparison of the predictive value of other prognostic models to the RCRI Fifty‐two articles compared the predictive ability of the RCRI to other prognostic models. Of these, 42% developed a new prediction model, 22% updated the RCRI, or another prediction model, and 37% validated an existing prediction model. None of the other prediction models showed better performance in predicting MACE than the RCRI. To predict myocardial infarction and cardiac arrest, ACS‐NSQIP‐MICA had a higher median delta c‐statistic of 0.11 compared to the RCRI. To predict all‐cause mortality, the median delta c‐statistic was 0.15 higher in favour of ACS‐NSQIP‐SRS compared to the RCRI. Predictive performance was not better for CHADS(2), CHA(2)DS(2)‐VASc, R(2)CHADS(2), Goldman index, Detsky index or VSG‐CRI compared to the RCRI for any of the outcomes. Calibration and reclassification were reported in only one and three studies, respectively. AUTHORS' CONCLUSIONS: Studies included in this review suggest that the predictive performance of the RCRI in predicting MACE is improved when NT‐proBNP, troponin or their combination are added. Other studies indicate that BNP and NT‐proBNP, when used in isolation, may even have a higher discriminative performance than the RCRI. There was insufficient evidence of a difference between the predictive accuracy of the RCRI and other prediction models in predicting MACE. However, ACS‐NSQIP‐MICA and ACS‐NSQIP‐SRS outperformed the RCRI in predicting myocardial infarction and cardiac arrest combined, and all‐cause mortality, respectively. Nevertheless, the results cannot be interpreted as conclusive due to high risks of bias in a majority of papers, and pooling was impossible due to heterogeneity in outcomes, prediction horizons, biomarkers and studied populations. Future research on the added prognostic value of biomarkers to existing prediction models should focus on biomarkers with good predictive accuracy in other settings (e.g. diagnosis of myocardial infarction) and identification of biomarkers from omics data. They should be compared to novel biomarkers with so far insufficient evidence compared to established ones, including NT‐proBNP or troponins. Adherence to recent guidance for prediction model studies (e.g. TRIPOD; PROBAST) and use of standardised outcome definitions in primary studies is highly recommended to facilitate systematic review and meta‐analyses in the future.

BACKGROUND: Depression occurs frequently in individuals with coronary artery disease (CAD) and is associated with a poor prognosis. OBJECTIVES: To determine the effects of psychological and pharmacological interventions for depression in CAD patients with comorbid depression. SEARCH METHODS: We searched the CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL databases up to August 2020. We also searched three clinical trials registers in September 2021. We examined reference lists of included randomised controlled trials (RCTs) and contacted primary authors. We applied no language restrictions. SELECTION CRITERIA: We included RCTs investigating psychological and pharmacological interventions for depression in adults with CAD and comorbid depression. Our primary outcomes included depression, mortality, and cardiac events. Secondary outcomes were healthcare costs and utilisation, health‐related quality of life, cardiovascular vital signs, biomarkers of platelet activation, electrocardiogram wave parameters, non‐cardiac adverse events, and pharmacological side effects. DATA COLLECTION AND ANALYSIS: Two review authors independently examined the identified papers for inclusion and extracted data from the included studies. We performed random‐effects model meta‐analyses to compute overall estimates of treatment outcomes. MAIN RESULTS: Thirty‐seven trials fulfilled our inclusion criteria. Psychological interventions may result in a reduction in end‐of‐treatment depression symptoms compared to controls (standardised mean difference (SMD) −0.55, 95% confidence interval (CI) −0.92 to −0.19, I(2) = 88%; low certainty evidence; 10 trials; n = 1226). No effect was evident on medium‐term depression symptoms one to six months after the end of treatment (SMD −0.20, 95% CI −0.42 to 0.01, I(2) = 69%; 7 trials; n = 2654). The evidence for long‐term depression symptoms and depression response was sparse for this comparison. There is low certainty evidence that psychological interventions may result in little to no difference in end‐of‐treatment depression remission (odds ratio (OR) 2.02, 95% CI 0.78 to 5.19, I(2) = 87%; low certainty evidence; 3 trials; n = 862). Based on one to two trials per outcome, no beneficial effects on mortality and cardiac events of psychological interventions versus control were consistently found. The evidence was very uncertain for end‐of‐treatment effects on all‐cause mortality, and data were not reported for end‐of‐treatment cardiovascular mortality and occurrence of myocardial infarction for this comparison. In the trials examining a head‐to‐head comparison of varying psychological interventions or clinical management, the evidence regarding the effect on end‐of‐treatment depression symptoms is very uncertain for: cognitive behavioural therapy compared to supportive stress management; behaviour therapy compared to person‐centred therapy; cognitive behavioural therapy and well‐being therapy compared to clinical management. There is low certainty evidence from one trial that cognitive behavioural therapy may result in little to no difference in end‐of‐treatment depression remission compared to supportive stress management (OR 1.81, 95% CI 0.73 to 4.50; low certainty evidence; n = 83). Based on one to two trials per outcome, no beneficial effects on depression remission, depression response, mortality rates, and cardiac events were consistently found in head‐to‐head comparisons between psychological interventions or clinical management. The review suggests that pharmacological intervention may have a large effect on end‐of‐treatment depression symptoms (SMD −0.83, 95% CI −1.33 to −0.32, I(2) = 90%; low certainty evidence; 8 trials; n = 750). Pharmacological interventions probably result in a moderate to large increase in depression remission (OR 2.06, 95% CI 1.47 to 2.89, I(2) = 0%; moderate certainty evidence; 4 trials; n = 646). We found an effect favouring pharmacological intervention versus placebo on depression response at the end of treatment, though strength of evidence was not rated (OR 2.73, 95% CI 1.65 to 4.54, I(2) = 62%; 5 trials; n = 891). Based on one to four trials per outcome, no beneficial effects regarding mortality and cardiac events were consistently found for pharmacological versus placebo trials, and the evidence was very uncertain for end‐of‐treatment effects on all‐cause mortality and myocardial infarction. In the trials examining a head‐to‐head comparison of varying pharmacological agents, the evidence was very uncertain for end‐of‐treatment effects on depression symptoms. The evidence regarding the effects of different pharmacological agents on depression symptoms at end of treatment is very uncertain for: simvastatin versus atorvastatin; paroxetine versus fluoxetine; and escitalopram versus Bu Xin Qi. No trials were eligible for the comparison of a psychological intervention with a pharmacological intervention. AUTHORS' CONCLUSIONS: In individuals with CAD and depression, there is low certainty evidence that psychological intervention may result in a reduction in depression symptoms at the end of treatment. There was also low certainty evidence that pharmacological interventions may result in a large reduction of depression symptoms at the end of treatment. Moderate certainty evidence suggests that pharmacological intervention probably results in a moderate to large increase in depression remission at the end of treatment. Evidence on maintenance effects and the durability of these short‐term findings is still missing. The evidence for our primary and secondary outcomes, apart from depression symptoms at end of treatment, is still sparse due to the low number of trials per outcome and the heterogeneity of examined populations and interventions. As psychological and pharmacological interventions can seemingly have a large to only a small or no effect on depression, there is a need for research focusing on extracting those approaches able to substantially improve depression in individuals with CAD and depression.