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The randomized controlled trial (RCT) is the gold standard for evaluating the causal effects of medications. Limitations of RCTs have led to increasing interest in using real‐world evidence (RWE) to augment RCT evidence and inform decision making on medications. Although RWE can be either randomized or nonrandomized, nonrandomized RWE can capitalize on the recent proliferation of large healthcare databases and can often answer questions that cannot be answered in randomized studies due to resource constraints. However, the results of nonrandomized studies are much more likely to be impacted by confounding bias, and the existence of unmeasured confounders can never be completely ruled out. Furthermore, nonrandomized studies require more complex design considerations which can sometimes result in design‐related biases. We discuss questions that can help investigators or evidence consumers evaluate the potential impact of confounding or other biases on their findings: Does the design emulate a hypothetical randomized trial design? Is the comparator or control condition appropriate? Does the primary analysis adjust for measured confounders? Do sensitivity analyses quantify the potential impact of residual confounding? Are methods open to inspection and (if possible) replication? Designing a high‐quality nonrandomized study of medications remains challenging and requires broad expertise across a range of disciplines, including relevant clinical areas, epidemiology, and biostatistics. The questions posed in this paper provide a guiding framework for assessing the credibility of nonrandomized RWE and could be applied across many clinical questions. [ABSTRACT FROM AUTHOR]

Background: Many people with aphasia have word‐finding difficulties, with some showing particular difficulties with verbs. Picture‐naming therapy is often used to improve naming, but gains are usually limited to therapy items and do not transfer to conversation. Therapy where words are produced in sentences and in real‐life activities may be more effective. Aims: The current pilot study investigated whether an activity‐oriented therapy approach would be accepted and viable if implemented in a community setting, and whether communicating whilst cooking was more beneficial than using paper‐based activities. If successful, it would be expected that verb production would improve in structured and unstructured tasks in both naming and narrative tasks. Methods & Procedures: The study employed a case‐series repeated‐measures design, with testing of treated and control items. Seven adults with anomia participated, although only five completed the full programme. Participants were divided into two groups and each group completed both treatments, but in different orders. Each treatment was employed for six 2‐h sessions over a 3‐week period. Outcomes & Results: Naming of both treated and untreated verbs showed a statistically significant improvement following both treatments and this continued into the maintenance phase. There was a numerical but not statistically significant gain in the variety of verbs used in spoken narratives. Participants predominantly chose positive terms to describe their experience of the programme, but did not prefer one therapy over the other. Conclusions & Implications: Preliminary findings suggest that an activity‐oriented therapy approach, whether it involves carrying out tasks or paper‐based activities, can result in clinically meaningful improvements for people with chronic aphasia. Further research using a randomized control trial is required to determine whether cooking therapy alone is effective. [ABSTRACT FROM AUTHOR]

The review focuses on the last decade of research regarding the use of various oral appliances ( OAs) in the management of sleep bruxism ( SB) in adults. Sixteen ( n = 16) papers of 641 identified citations involving 398 participants were included in the review. Of them, seven were randomised controlled trials ( RCTs), seven were uncontrolled before-after studies and two were crossover trials. Analysis of the included articles revealed a high variability of study designs and findings. Generally, the risk of bias was low-to-unclear for RCTs and high for crossover studies, whilst the before-after studies exhibited several structural limitations. Nine studies used polysomnography/polygraphy/electromyography for SB diagnosis, whilst others were based on history taking and clinical examination. Most of them featured small samples and were short term. Of the studies using objective SB evaluations, eight showed positive results for almost every type of OA in reducing SB activity, with a higher decrease for devices that are designed to provide a certain extent of mandibular advancement. Among the studies using a subjective SB evaluation, one demonstrated a significant reduction in SB activity, and additional two showed a myorelaxant effect of OA in SB patients. Although many positive studies support the efficiency of OA treatment for SB, accepted evidence is insufficient to support its role in the long-term reduction of SB activity. Further studies with larger samples and sufficient treatment periods are needed to obtain more acknowledgements for clinical application. [ABSTRACT FROM AUTHOR]

Background Little information is available as to the safety of midazolam when used as an oral sedative. Aim To evaluate the side effects and other adverse outcomes following use of oral midazolam for behaviour management in paediatric dentistry. Design A review of published literature relating to the safety and side effects of oral midazolam for use in paediatric dental procedures was conducted. Both randomised controlled trials and non-randomised studies were assessed. Reported side effects were recorded and classified as either significant or minor. The percentage prevalence of significant or minor side effects per episode of treatment was calculated. Results Sixteen papers of randomised controlled trials met the inclusion criteria. None of the side effects recorded were considered as significant. Minor side effects were reported ( n = 68, 14%), with nausea and vomiting being the most frequently recorded ( n = 30, 6%). Eleven papers of non-randomised studies were included. No significant side effects were recorded. Minor side effects were recorded ( n = 157, 8%), with paradoxical reaction being the most common at 3.8%. Conclusion Significant side effects associated with oral midazolam usage for behaviour management in children and adolescents requiring dental treatment appear to be rare. Minor side effects are more common but determining precise figures is complicated by poor reporting. [ABSTRACT FROM AUTHOR]

SHIFT has been one of the largest RCTs in the field of systemic family therapy in the UK. The study took place over five years, including three major centres with fifteen Trusts and twenty‐five family therapists who worked with a manualized treatment in CAMHS with adolescents who self‐harmed. While the results are not available at the time of this publication, this paper will briefly describe the pre‐ existing factors which were helpful in developing a successful bid, clinical and managerial elements of ‘real world research’ of complex psychological processes and the construction of the manualized systemic family therapy. It also offers examples of some of the unanticipated events in the life of such a large trial. Practitioner Points: Large trials develop from small studies and clinicians are urged to look for opportunities for research partnershipsInvestment in time for consideration of difficult issues as they arise is essential for effective trial managementThe balance between research rigour and ‘real life’ practice is an inevitable area of tension and requires consideration of both immediate and outcome consequences 尝试和痛苦 – 一种随机对照试验对比下的把干预当作惯常和在实施过程中出现的重要事件上的反思的家庭治疗 人工家庭治疗 摘要: SHIFT目前是英国家庭治疗领域最大的随机对照试验之一。本研究历时5年, 囊括了三个主要的中心在内的15个信托, 25位曾在CAMHS对自残青少年进行人工治疗的家庭治疗师。因为在发表这篇文章的时候, 结果还没有出来, 本文将简短地描述1）有助发展成功bid的已经存在的因素, 2）临床以及管理方面的复杂心理过程的”真实情况研究”元素, 3）以及人工系统家庭治理的建构。本文还提供了生活在这样一种大的的尝试下的一些意想不到事件的例子。 对实践者有用的几点建议: 大的尝试发展自小的研究, 临床工作者急需寻找研究合作者的机会困难事件需要及时解决, 不然就会对有效尝试管理产生重要影响研究活力和”真实生活”实践的平衡是一种不可避免的引起紧张的领域, 这需要对当下和结果的同时考虑 关键词：实证实践, 研究, 儿童和青少年精神健康, 培训 [ABSTRACT FROM AUTHOR]

Background and purpose Regular rehabilitation is not sufficient for regaining function after a hip fracture, and more targeted interventions for home-dwelling elderly hip-fracture patients are needed. This paper describes the protocol of a study assessing the effectiveness and cost effectiveness of a task specific progressive gait and balance exercise programme for hip-fracture patients, performed 4 months after the fracture. Methods/design A single blind two-arm pragmatic randomised controlled trial was conducted with 142 hip-fracture patients randomized to a 10-week home-based exercise programme or to practice as usual 4 months following the surgery. Inclusion criteria were age >70 years and being home dwelling prior to the fracture. Exclusion criteria are life expectancy <3 months and inability to walk 10 m prior to the fracture. The content and organization of the programme was developed in collaboration between physiotherapy researchers and primary health-care physiotherapists. Participants were followed for 1 year post-surgery, evaluating short-term and long-term effects of the programme. The primary outcome is gait speed, and the secondary outcomes are spatial and temporal gait parameters, free living physical behaviour by activity monitoring, mobility performance, activities of daily living, fear of falling, cognitive function, depression and health-related quality of life. Cost-effectiveness analysis is planned. Discussion This paper describes a task specific exercise programme aimed to improve gait and balance after a hip fracture. Inclusion started in February 2011, and the last 1-year follow-up is performed in March 2014. Broad inclusion criteria and physiotherapy-guided home-based exercises may facilitate the participation from frail patients and thereby increase the generalizability of the findings. Development and completion of the intervention within routine clinical practice will enlighten the implementation of results into clinical practice. Results may add new insight into how physiotherapy can improve gait and thereby activity and functioning in everyday life and have implications on future content and organization of physiotherapy after a hip fracture. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article presents the results of a randomised controlled trial regarding the efficacy of carprofen and local anaesthesia in reducing the disbudding pain in calves. Researchers concluded that the use of systemic carprofen and lidocaine local anaesthetics can reduce the pain-related behaviours of calves in 24 hours after the disbudding procedure. Details on the methods and weaknesses of the study are also given.

Evidence‐based medicine (EBM) proponents have argued that mechanistic evidence concerning medical treatments should be considered secondary to evidence derived from randomized controlled trials (RCTs). One common criticism of RCTs is that they often do not yield results that are generalizable to clinical practice, and that for clinical practice application, mechanistic evidence is needed. However, proponents of EBM have argued that mechanistic reasoning is often unreliable and thus not very useful. Here we suggest an important role of mechanistic explanation that has been left out of this discussion entirely, namely, its importance in a patient's decision of whether or not to take certain drugs. We argue that in certain cases, knowing how a treatment works is just as important for the patient as knowing whether it does. In this paper, we explore how and why giving patients mechanistic information can be an important factor in obtaining informed consent for medical treatment, focusing on the example case of hormonal contraceptives. [ABSTRACT FROM AUTHOR]

Aim The aim of this systematic review was to evaluate the efficacy of anti-plaque chemical formulations for managing gingivitis, in 6-month, home-use, randomised clinical trials ( RCTs). Material and Methods A protocol was designed, including inclusion and exclusion criteria to identify RCTs assessing gingival and/or bleeding indices. Electronic and hand-searches identified relevant papers, which were screened and evaluated for inclusion. Full-papers were retrieved and relevant information was extracted (also plaque indices), including quality and risk of bias. Mean treatment effects were calculated to obtain weighted mean differences ( WMD) and 95% confidence intervals. Results After the process of screening and selection, 87 articles with 133 comparisons, were included in the review. The additional effects of the tested products were statistically significant in terms of Löe & Silness gingival index (46 comparisons, WMD −0.217), modified gingival index ( n = 23, −0.415), gingivitis severity index ( n = 26, −14.939%) or bleeding index ( n = 23, −7.626%), with significant heterogeneity. For plaque, additional effects were found for Turesky (66 studies, WMD −0.475), Silness & Löe ( n = 26, −0.109), and plaque severity ( n = 12, −23.4%) indices, with significant heterogeneity. Conclusion Within the limitations of the present study, formulations with specific agents for chemical plaque control provide statistically significant improvements in terms of gingival, bleeding and plaque indices. [ABSTRACT FROM AUTHOR]

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Behavioral treatments in the management of primary headache disorders in adults and children are increasingly being recognized as effective; however, the level and durability of their effectiveness is still a matter of debate. This review aims to provide more updated information on the effects of behavioral therapies in adults and adolescents with primary headache disorders, with a special focus on new and emerging behavioral treatments. Methods: We searched SCOPUS for peer‐reviewed papers that reported randomized controlled trial or observational studies addressing behavioral treatment for headache disorders published in the period January 2010 to October 2017. Results: A total of 22 publications, in which 2110 participants were recruited, were included in the review. Most of the studies referred to cognitive behavioral therapies, and a reduction of headache frequency higher than 35% was generally reported irrespective of the approach. In addition, valuable impact disability and quality of life was observed, as well as improvements in depression, anxiety, self‐efficacy, and intake of medications. Conclusions: Behavioral approaches are effective and less prone to produce side or harmful effects, which makes them a valid option particularly for women who are pregnant or nursing, people with other chronic conditions requiring pharmacological treatments putting them at risk for drug‐drug interactions, and children. [ABSTRACT FROM AUTHOR]

Purpose To critically appraise scientific evidence regarding the efficacy of nutritional supplementation with omega-3 and omega-6 fatty acids for the treatment of dry eye syndrome (DES). Methods A systematic review of randomized clinical trials was performed. Two independent reviewers selected and analysed the scientific papers that met inclusion and exclusion criteria. Objective and subjective efficacy outcomes were assessed. Results The trials involved a total of 2591 patients in fifteen independent studies. All studies were published between 2005 and 2015. The supplements used were mostly omega-3 and omega-6 in different proportions. Subjective improvement was measured using mainly Ocular Surface Disease Index ( OSDI) test and Dry Eye Severity Score ( DESS) test: significant differences in favour of the experimental group were found in seven of the studies. The objective amelioration was assessed by lacrimal function parameters: Tear break-up time ( TBUT) significantly increased in nine studies and Schirmer's test in four studies. Conclusion We observed a discrete improvement in the parameters of tear function. Scientific evidence is not strong enough to systematically recommend the use of omega-3 and omega-6 fatty acids as a standalone treatment of DES independently from its aetiology. However, they could be considered as an effective alternative to topical treatment in patients with DES secondary to certain pathologies. [ABSTRACT FROM AUTHOR]

Exposure-based psychological interventions currently represent the empirically best established first line form of cognitive-behavioural therapy for all types of anxiety disorders. Although shown to be highly effective in both randomized clinical and other studies, there are important deficits: (1) the core mechanisms of action are still under debate, (2) it is not known whether such treatments work equally well in all forms of anxiety disorders, including comorbid diagnoses like depression, (3) it is not known whether an intensified treatment with more frequent sessions in a shorter period of time provides better outcome than distributed sessions over longer time intervals. This paper reports the methods and design of a large-scale multicentre randomized clinical trial (RCT) involving up to 700 patients designed to answer these questions. Based on substantial advances in basic research we regard extinction as the putative core candidate model to explain the mechanism of action of exposure-based treatments. The RCT is flanked by four add-on projects that apply experimental neurophysiological and psychophysiological, (epi)genetic and ecological momentary assessment methods to examine extinction and its potential moderators. Beyond the focus on extinction we also involve stakeholders and routine psychotherapists in preparation for more effective dissemination into clinical practice. [ABSTRACT FROM AUTHOR]

Background Central venous catheters (CVCs) facilitate the administration of intravenous drugs, fluids, blood products and parenteral nutrition to patients with either chronic disease or critical illness. Despite a pivotal role within medical management, a common complication associated with CVC use is occlusion of the CVC lumen(s). CVC occlusion can interrupt and cause serious delays in administration of treatment interventions. Objectives The primary objective of this review was to assess the efficacy and safety of different interventions used to restore patency of occluded CVC lumens, in adults and children. Search methods We identified trials by searching the Cochrane Central Register of Clinical Trials (CENTRAL) ( The Cochrane Library 2011, Issue 9); OvidSP MEDLINE (1950 to September 2011); OvidSP EMBASE (1980 to September 2011) and NHS Evidence CINAHL (1982 to September 2011). We also searched clinical trial registers, handsearched reference lists, contacted pharmaceutical companies and authors of publications that met the inclusion criteria to identify trials. Selection criteria We selected randomized controlled trials which investigated the efficacy of an intervention (chemical, surgical or drug) used to restore patency to an occluded CVC lumen, in either adults or children. Data collection and analysis Three authors independently assessed those studies that met the inclusion criteria for quality and extracted the relevant data using a standardized form. Main results No studies were found that investigated the efficacy and safety of either chemical or surgical interventions. Seven studies (eight papers) with a total of 632 participants were identified from the search. They investigated different comparisons, strengths of thrombolytic or anticoagulant drug interventions for treating CVC lumen occlusion thought to be caused by a thrombus. There was low quality evidence from a meta-analysis of two studies suggesting that urokinase (various strengths) was more effective than placebo for restoring patency to occluded CVC lumens in adults and children with underlying medical conditions (relative risk (RR) 2.09, 95% confidence interval (CI) 1.47 to 2.95), with a number needed to treat of 4 (95% CI 2 to 8). There was insufficient evidence to draw conclusions on the safety of urokinase. The overall quality of the evidence provided by these studies was low to very low due to one or more domains being assessed as either at 'unclear risk of bias' or 'high risk of bias'. Furthermore, the total number of participants in these studies was small and consequently may lead to spurious results. Authors' conclusions There is inadequate evidence to draw strong conclusions on the efficacy or safety of the drug interventions included in this review. There is some low quality evidence from a meta-analysis of two studies investigating urokinase (various strengths) and some very low evidence from two single studies investigating alteplase 2 mg/2 mL that suggest that these two drug interventions may be effective in treating withdrawal or total occlusion of CVC lumens caused by thrombosis. Further high quality, sufficiently powered research is still required to look at the efficacy and safety of urokinase, alteplase and other chemical, surgical and drug interventions for treating CVC lumen occlusion. Research studies which exclusively include child participants are especially warranted. Plain Language Summary Interventions for restoring patency of occluded central venous catheter lumens A central venous catheter is a small, hollow tube that is inserted into a large vein in either the chest, neck or groin. Central venous catheters enable healthcare professionals to administer drugs and other fluids directly into the blood stream, in order to treat critically ill patients or those patients with a long-term condition. In certain chronic conditions, patients or their carers may also be involved with the administration of treatment interventions via the central venous catheter. Occasionally, the catheter lumens can become blocked with either a blood clot or a treatment intervention solidifying in the tube, or due to the position of the tube inside the vein. If the catheter does become blocked it may mean that the patient has to undergo further surgery to remove and replace the blocked catheter. No studies were found investigating the efficacy and safety of surgical interventions (brush, snare or guidewire exchange) or chemical interventions (hydrochloric acid, sodium bicarbonate, 70% ethanol solution) to unblock the catheter. Our search identified seven studies (eight papers), with a total of 632 participants, that investigated different drug comparisons or compared different strengths of drug therapies for treating catheters that were either completely or partially blocked with a blood clot. This review has found low to very low quality evidence suggesting that thrombolytic drugs (urokinase and alteplase) could be effective in unblocking central venous catheter lumens blocked by blood clots. However, the total number of participants included in these trials was small and consequently the results of the analysis may well be over exaggerated. There were also issues with the way the studies were conducted that could possibly have introduced bias. In conclusion, more research is required to establish the efficacy and safety of different treatment interventions used to unblock occluded central venous catheter lumens. Particularly, there is a need for studies exclusively in children. [ABSTRACT FROM AUTHOR]

Objective: To assess methods, quality and outcomes of systematic reviews (SRs) conducted to evaluate the effectiveness of root coverage (RC) procedures in the treatment of recession-type defects (RTD). Methods: MEDLINE and EMBASE were searched up to and including April 2010 to identify SRs investigating the effectiveness/efficacy of surgical interventions for the treatment of patients with RTD. Searching was conducted independently by two reviewers, and data extraction was based on the methodological criteria applied and on the effects of interventions reported by each SR. The checklist proposed by Glenny and colleagues, the Overview Quality Assessment Questionnaire and the "Assessment of Multiple systematic Reviews", instrument were used to assess the quality of SRs. Additionally, the methodological criteria applied by included reviews were compared with those proposed by the Cochrane Collaboration. Results: Search strategy identified 716 potentially eligible articles, of which 12 papers regarding 10 SRs were included in the study. Results from different SRs showed that subepithelial connective tissue grafts associated or not to coronally advanced flaps can be used to reduce recession depth and improve the width of keratinized tissue. All quality assessment tools showed that most of the SRs were of good methodological quality, but they also highlighted key points that could be improved in future reviews. Only two SRs followed in full the guidelines proposed by the Cochrane Collaboration. Conclusions: All SRs agree that RC may be anticipated by different surgical procedures. However, differences in the methodological quality between reviews were quite evident, and thus making a clear indication that there is a need of standardization of the methods that will be applied by future SRs. As a result, a standardized checklist for reporting SRs was proposed by the authors. [ABSTRACT FROM AUTHOR]

Background Psychological interventions for bipolar disorders typically produce mixed outcomes and modest effects. The need for a more effective intervention prompted the development of a new cognitive behavioural therapy, based on an integrative cognitive model ('Think Effectively About Mood Swings' [TEAMS] therapy). Unlike previous interventions, TEAMS addresses current symptoms and comorbidities, and helps clients achieve long-term goals. A pilot randomized controlled trial (the TEAMS trial) of the therapy has recently concluded. This study explored participants' experiences of TEAMS, recommendations for improvement and experiences of useful changes post-therapy. Methods Fourteen TEAMS therapy participants took part in semi-structured interviews. Their accounts were analysed using interpretative thematic analysis. Two researchers coded the dataset independently. Member checks were conducted of the preliminary themes. Results Two overarching themes; 'useful elements of therapy' and 'changes from therapy' encompassed 12 emerging subthemes. Participants appreciated having opportunities to talk and described the therapy as person-centred and delivered by caring, approachable and skilled therapists. Some recommended more sessions than the 16 provided. Helpful therapeutic techniques were reported to be, normalization about moods, methods to increase understanding of moods, relapse-prevention, reappraisal techniques and metaphors. However, some did not find therapeutic techniques helpful. Post-therapy, many reported changes in managing mood swings more effectively and in their thinking (although some participants reported changes in neither). Many described increased acceptance of themselves and of having bipolar disorder, increased productivity and reduced anxiety in social situations. Conclusions The present study evaluates participants' therapy experiences in detail, including aspects of therapy viewed as helpful, and meaningful post-therapy outcomes. Copyright © 2016 John Wiley & Sons, Ltd. Key Practitioner Message This is the first paper to qualitatively explore people's experiences of individual psychotherapy for bipolar disorders. It highlights elements of psychotherapy described as particularly helpful or unhelpful and the clinical changes viewed as most impactful., Participants reported benefitting in a number of ways from TEAMS therapy. They valued learning to reappraise and problem-solve situations and manage moods., Participants identified TEAMS techniques as helpful, such as exploring advantages and disadvantages of moods, and building healthy self-states. [ABSTRACT FROM AUTHOR]

Aim To report the evidence on the effect of mechanical and/or chemical plaque control in the simultaneous management of gingivitis and caries. Material and Methods A protocol was designed to identify randomized ( RCTs) and controlled ( CCTs) clinical trials, cohort studies and prospective case series ( PCS), with at least 6 months of follow-up, reporting on plaque, gingivitis and caries. Relevant information was extracted from full papers, including quality and risk of bias. Meta-analyses were performed whenever possible. Results After the screening of 1,373 titles, 15 RCTs, 10 CCTs and 2 PCS were included. Low to moderate evidence support that combined professional and self-performed mechanical plaque control significantly reduces standardized plaque index [ n = 4; weighted mean difference ( WMD) = 1.294; 95% CI (0.445; 2.144); p = 0.003] and gingivitis scores [ n = 4; WMD = 1.728; 95% CI (0.631; 2.825); p = 0.002]. The addition of fluoride to mechanical plaque control is relevant for caries management [ n = 5; WMD = 1.159; 95% CI (0.145; 2.172); p = 0.025] while chlorhexidine rinses are relevant for gingivitis. Conclusion Mechanical plaque control procedures are effective in reducing plaque and gingivitis. The addition of fluoride to mechanical plaque control is significant for caries management. Chlorhexidine rinse has a positive effect on gingivitis and inconclusive role in caries. [ABSTRACT FROM AUTHOR]

Objective We aimed to explore whether the prevalence of manic switch was underestimated in randomized controlled trials ( RCTs) compared to observational studies ( OSs). Method Meta-analyses and simple and systematic reviews were identified by two reviewers in a blinded, standardized manner. All relevant references were extracted to include RCTs and OSs that provided data about manic switch prevalence after antidepressant treatment for a major depressive episode. The primary outcome was manic switch prevalence in the different arms of each study. A meta-regression was conducted to quantify the impact of certain variables on manic switch prevalence. Results A total of 57 papers (35 RCTs and 22 OSs) were included in the main analysis. RCTs underestimated the rate of manic switch [0.53 (0.32-0.87)]. Overestimated prevalence was related to imipraminics [1.85 (1.22-2.79)]; to serotonin-norepinephrine reuptake inhibitors [1.74 (1.06-2.86)]; and to other classes of drugs [1.58 (1.08-2.31)], compared to placebo treatment. The prevalence of manic switch was lower among adults than among children [0.2 (0.07-0.59)]; and higher [20.58 (8.41-50.31)] in case of bipolar disorder. Conclusion Our results highlight an underestimation of the rates of manic switch under antidepressants in RCTs compared to the rates observed in observational studies. [ABSTRACT FROM AUTHOR]

A repeated dose of an oral triptan has been shown in randomized controlled trials (RCTs) to be ineffective as a treatment for no or partial response 2 hours after initial dosing but effective as treatment for headache recurrence. In the official prescription information in the United States, the United Kingdom, and Denmark repeated dosing of all seven oral triptans are recommended for headache recurrence but some triptans are also recommended for no or partial response, a use of a triptan deemed to be not beneficial in European and Canadian migraine guidelines. In summary, not all recommendations are based on evidence from RCTs. In addition, some recommendations are ambiguous and patients need clearer instructions. An example of such a clear British instruction in a patient leaflet instruction is presented at the end of the paper. [ABSTRACT FROM AUTHOR]

ABSTRACT Background The IO route is an established method of obtaining vascular access in children in acute and emergency situations and is now increasingly being used in adults as an alternative to intravenous access, yet a paucity of evidence exists regarding its use, effectiveness and implementation. Aim and objectives The aim of this literature review is to present a detailed investigation critiquing contemporary practices of intraosseous (IO) vascular access in adult patients. Specific objectives identified led to the exploration of clinical contexts, IO device/s and anatomical sites; education and training requirements; implications and recommendations for emergency health care practice and any requirements for further research. Search strategies An exploratory literature review was undertaken in acknowledgement of the broad and complex nature of the project aim. Five electronic search engines were examined iteratively from June 2013 to February 2014. The search terms were 'intraosseous' and 'adult' which were purposely limited because of the exploratory nature of the review. Studies that met the inclusion criteria of primary research articles with an adult focus were included. Research with a paediatric focus was excluded. Secondary research, reviews, case reports, editorials and opinion papers were excluded. Conclusion IO vascular access is considered an alternative intravascular access route although debate considering the preferred anatomical site is ongoing. Documented practices are only established in pre-hospital and specialist emergency department settings; however, variety exists in policy and actual practice. Achieving insertion competence is relatively uncomplicated following minimal preparation although ongoing skill maintenance is less clear. IO vascular access is associated with minimal complications although pain is a significant issue for the conscious patient especially during fluid administration. Relevance to clinical practice The IO route is clearly a valuable alternative to problematic intravascular access. However, further research, including cost effectiveness reviews, is required to gain clarity of whole acute care approaches. [ABSTRACT FROM AUTHOR]

The present paper reports on a 5-year follow-up of a randomized reading intervention in grade 3 in Sweden. An intervention group (n = 57) received daily training for 12 weeks in phoneme/grapheme mapping, reading comprehension and reading speed, whereas a control group (n = 55) participated in ordinary classroom activities. The main aim was to investigate if there were remaining effects of the intervention on reading-related skills. Previous analyses showed that the intervention group performed significantly better than the control group on spelling, reading speed, reading comprehension and phoneme awareness at the immediate post-test with sustained effects 1 year later. Results from the 5-year follow-up show that the only significant difference between the intervention (n = 47) and the control group (n = 37) was on word decoding. There was also a significant interaction effect of group assignment and initial word decoding, in the way that the lowest-performing students benefitted the most from the intervention. Another aim was to examine if the children identified in a screening (n = 2212) as poor readers in grade 2 still performed worse than typical readers. The analyses showed that the typically developing students (n = 66) outperformed the students identified as poor readers in grade 2 on working memory, spelling, reading comprehension and word decoding. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background The primary goals in conducting clinical trials of treatments for alcohol use disorders ( AUDs) are to identify efficacious treatments and determine which treatments are most efficacious for which patients. Accurate reporting of study design features and results is imperative to enable readers of research reports to evaluate to what extent a study has achieved these goals. Guidance on quality of clinical trial reporting has evolved substantially over the past 2 decades, primarily through the publication and widespread adoption of the Consolidated Standards of Reporting Trials statement. However, there is room to improve the adoption of those standards in reporting the design and findings of treatment trials for AUD. Methods This paper provides a narrative review of guidance on reporting quality in AUD treatment trials. Results Despite improvements in the reporting of results of treatment trials for AUD over the past 2 decades, many published reports provide insufficient information on design or methods. Conclusions The reporting of alcohol treatment trial design, analysis, and results requires improvement in 4 primary areas: (i) trial registration, (ii) procedures for recruitment and retention, (iii) procedures for randomization and intervention design considerations, and (iv) statistical methods used to assess treatment efficacy. Improvements in these areas and the adoption of reporting standards by authors, reviewers, and editors are critical to an accurate assessment of the reliability and validity of treatment effects. Continued developments in this area are needed to move AUD treatment research forward via systematic reviews and meta-analyses that maximize the utility of completed studies. [ABSTRACT FROM AUTHOR]

Background Over the past 60 years, the view that 'alcoholism' is a disease for which the only acceptable goal of treatment is abstinence has given way to the recognition that alcohol use disorders ( AUDs) occur on a continuum of severity, for which a variety of treatment options are appropriate. However, because the available treatments for AUDs are not effective for everyone, more research is needed to develop novel and more efficacious treatments to address the range of AUD severity in diverse populations. Here we offer recommendations for the design and analysis of alcohol treatment trials, with a specific focus on the careful conduct of randomized clinical trials of medications and nonpharmacological interventions for AUDs. Methods This paper provides a narrative review of the quality of published clinical trials and recommendations for the optimal design and analysis of treatment trials for AUDs. Results Despite considerable improvements in the design of alcohol clinical trials over the past 2 decades, many studies of AUD treatments have used faulty design features and statistical methods that are known to produce biased estimates of treatment efficacy. Conclusions The published statistical and methodological literatures provide clear guidance on methods to improve clinical trial design and analysis. Consistent use of state-of-the-art design features and analytic approaches will enhance the internal and external validity of treatment trials for AUDs across the spectrum of severity. The ultimate result of this attention to methodological rigor is that better treatment options will be identified for patients with an AUD. [ABSTRACT FROM AUTHOR]

Background Despite harmful drinking causing a significant burden on global health, there is a large treatment gap, especially in low- and middle-income countries. A major barrier to care is the lack of adequately skilled human resources to deliver contextually appropriate treatments. This paper describes the systematic process used to develop Counselling for Alcohol Problems ( CAP), a brief psychological treatment (PT) for delivery by lay counselors in routine primary care settings to men with harmful drinking in India. Methods CAP was developed using a methodology involving 3 sequential steps: (i) identifying potential treatment strategies; (ii) developing a theoretical framework for the treatment; and (iii) evaluating the acceptability and feasibility of the treatment. Results CAP is a 3-phase treatment delivered over 1 to 4 sessions based on a motivational interviewing ( MI) stance and involves the following strategies: assessment and personalized feedback, family engagement, drink refusal skills, skills to address drinking urges, problem-solving skills and handling difficult emotions, and relapse prevention and management. Data from a case series were used to inform several adaptations to enhance the acceptability of CAP to the recipients and feasibility of delivery by lay counselors of the treatment, for example expansion of the target group to include alcohol-dependent patients and the extension of the delivery settings to include home-based delivery. There was preliminary evidence of the effectiveness of CAP. Conclusions CAP is an acceptable brief PT for harmful drinking delivered by lay counselors in primary care whose effectiveness is currently being tested in a randomized controlled trial based in primary care in Goa, India. [ABSTRACT FROM AUTHOR]

Background The effectiveness of two treatment approaches (phonological therapy and articulation therapy) for treatment of 14 children, aged 4;0-6;7 years, with phonologically based speech-sound disorder (SSD) has been previously analysed with severity outcome measures (percentage of consonants correct score, percentage occurrence of phonological processes and phonetic inventory). Considering that the ultimate goal of intervention for children with phonologically based SSD is to improve intelligibility, it is curious that intervention studies focusing on children's phonology do not routinely use intelligibility as an outcome measure. It is therefore important that the impact of interventions on speech intelligibility is explored. Aims This paper investigates the effectiveness of the two treatment approaches (phonological therapy and articulation therapy) using intelligibility measures, both in single words and in continuous speech, as the primary outcome. Methods & Procedures Fourteen children with phonologically based SSD participated in the intervention. The children were randomly assigned to phonological therapy or articulation therapy (seven children in each group). Two assessment methods were used for measuring intelligibility: a word identification task (for single words) and a rating scale (for continuous speech). Twenty-one unfamiliar adults listened and judged the children's intelligibility. Reliability analyses showed overall high agreement between listeners across both methods. Outcomes & Results Significant improvements were noted in intelligibility in both single words (paired t(6) = 4.409, p = 0.005) and continuous speech (asymptotic Z = 2.371, p = 0.018) for the group receiving phonology therapy pre- to post-treatment, but no differences in intelligibility were found for those receiving the articulation therapy pre- to post-treatment, either for single words (paired t(6) = 1.763, p = 0.128) or continuous speech (asymptotic Z = 1.442, p = 0.149). Conclusions & Implications Intelligibility measures were sensitive enough to show changes in the phonological therapy group but not in the articulation therapy group. These findings emphasize the importance of using intelligibility as an outcome measure to complement the results obtained with other severity measures when exploring the effectiveness of speech interventions. This study presents new evidence for the effectiveness of phonological therapy in improving intelligibility with children with SSD. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Holzmann M, Cnattingius S, Nordström L. Lactate production as a response to intrapartum hypoxia in the growth-restricted fetus. BJOG 2012;119:1265-1269. Objective To analyse whether the increase in lactate in response to intrapartum hypoxia differs between small- (SGA), appropriate- (AGA) and large-for-gestational-age (LGA) fetuses. Design Observational cohort study. Setting Ten obstetric units in Sweden. Population A cohort of 1496 women. Methods A secondary analysis of a randomised controlled trial, in which 1496 women with fetal heart rate abnormalities, indicating fetal scalp blood sampling, were randomised to lactate analyses. After delivery, the neonates were divided according to birthweight for gestational age into SGA, AGA and LGA groups. Main outcome measure Lactate concentration in fetal scalp blood. Secondary outcome measures Acid-base balance in cord artery blood and Apgar score <7 at 5 minutes. Results Median lactate concentrations in the SGA, AGA and LGA groups were 3.8, 3.0 and 2.2 mmol/l, respectively (SGA versus AGA, P = 0.017; LGA versus AGA, P = 0.009). In the subgroups with scalp lactate >4.8 mmol/l (lactacidaemia), the corresponding median (range) values were 6.2 (4.9-14.6), 5.9 (4.9-15.9) and 5.7 mmol/l (5.0-7.9 mmol/l), respectively (no significant differences between the groups). The proportions of neonates with cord artery pH < 7.00, metabolic acidaemia or Apgar score <7 at 5 minutes were similar in all weight groups. Conclusion SGA fetuses with fetal heart rate abnormalities have the same ability to produce lactate as a response to intrapartum hypoxia as AGA and LGA fetuses. The risk of a poor outcome associated with high lactate concentration is the same in SGA, AGA and LGA fetuses. Scalp blood lactate analysis is therefore a reliable method for intrapartum fetal surveillance of suspected growth-restricted fetuses scheduled for vaginal delivery at ≥34 weeks of gestation. [ABSTRACT FROM AUTHOR]

A randomized controlled trial is reported in which three treatments were compared for the management of depression in Primary Care. The treatments were Treatment As Usual (TAU) carried out by the General Practitioners, Cognitive-Behaviour Therapy (CBT) or Interpersonal Psychotherapy (IPT). Measurements of depressive symptomatology were taken at Baseline (Time1), at end of treatment (Time2), and at 5-month follow-up (Time3). An initial analysis of the longitudinal data revealed that there were a significant number of missing values, especially in the Time3 follow-up for the TAU group. That is, the missing data were not missing at random within the dataset, which is one of the considerations for usual procedures for replacement of missing values (RMV). The paper presents, therefore, the outcome of different approaches to RMV and their consequences for conclusions about the relative efficacy of the treatment conditions. The results showed that clients in all conditions improved significantly, with at least some analyses showing superiority of IPT and CBT at end of treatment Time 2. However, by the follow-up clients in all conditions performed equally well. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: The short dating period of room temperature-stored platelets (PLTs; 5-7 days) limits their availability at far-forward combat facilities and at remote civilian sites in the United States. PLT cryopreservation in 6% DMSO and storage for up to 2 years may improve timely availability for bleeding patients.Study Design and Methods: A dose escalation trial of DMSO-cryopreserved PLTs (CPPs) compared to standard liquid-stored PLTs (LSPs) was performed in bleeding patients with thrombocytopenia. Within each of four cohorts, six patients received escalating doses of CPP (0.5 unit, 1 unit, and sequential transfusions of 2 and 3 units) and one received a LSP transfusion. Patients were monitored for adverse events (AEs), coagulation markers, PLT responses, and hemostatic efficacy.Results: Patients with a World Health Organization bleeding score of 2 or more received from 0.5 to 3 units of CPP (n = 24) or 1 unit of LSP (n = 4). There were no related thrombotic or other serious AEs experienced. Mild transfusion-related AEs of chills and fever (n = 1), transient increased respiratory rate (n = 1), DMSO-related skin odor (n = 2), and headache (n = 1) were observed after CPP transfusion. Among CPP recipients 14 of 24 (58%) had improved bleeding scores, including three of seven (43%) patients who had intracerebral bleeding. CPP posttransfusion PLT increments were significantly less than those of LSPs; however, days to next transfusion were the same. After transfusion, the CPP recipients had improvements in some variables of thrombin generation tests and thromboelastography.Conclusion: Cryopreserved PLT transfusions appear to be safe and effective when given to bleeding patients with thrombocytopenia. [ABSTRACT FROM AUTHOR]

Objectives Medication adherence contributes to the efficacy-effectiveness gap of treatment in patients with bipolar disorder. This paper aims to examine the challenges involved in improving medication adherence in bipolar disorder, and to extract some suggestions for future directions from the core psychosocial studies that have targeted adherence as a primary or secondary outcome. Methods A search was conducted for articles that focused on medication adherence in bipolar disorder, with emphasis on publications from 1996 to 2008 using Medline, Web of Science, CINAHL PLUS, and PsychINFO. The following key words were used: adherence, compliance, alliance, adherence assessment, adherence measurement, risk factors, psychosocial interventions, and psycho-education. Results There are a number of challenges to understanding non-adherence including the difficulty in defining and measuring it and the various risk factors that need to be considered when aiming to enhance adherence. Nevertheless, the importance of addressing adherence is evidenced by the connection between adherence problems and poor outcome. Despite these challenges, a number of small psychosocial studies targeting adherence as a primary outcome point to the potential usefulness of psycho-education aimed at improving knowledge, attitudes, and adherence behavior, but more large scale randomized controlled trials are needed in this area. Evidence of improved outcomes from larger randomized controlled trials of psychosocial interventions that target medication adherence as a secondary outcome suggests that tackling other factors besides medication adherence may also be an advantage. While some of these larger studies demonstrate an improvement in medication adherence, the translation of these interventions into real life settings may not always be practical. A person centered approach that considers risk factors for non-adherence and barriers to other health behaviors may assist with the development of more targeted briefer interventions. Integral to improving medication adherence is the delivery of psycho-education, and attention needs to be paid to the implementation, and timing of psycho-education. Progress in the understanding of how medicines work may add to the credibility of psycho-education in the future. Conclusions Enhancement of treatment adherence in bipolar patients is a necessary and promising management component as an adjunct to pharmacotherapy. The current literature on psychosocial interventions that target medication adherence in bipolar disorder points to the possibility of refining the concept of non-adherence and adapting psycho-education to the needs of certain subgroups of people with bipolar disorder. Large scale randomized controlled trials of briefer or more condensed interventions are needed that can inform clinical practice. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

It is common for longitudinal clinical trials to face problems of item non-response, unit non-response, and drop-out. In this paper, we compare two alternative methods of handling multivariate incomplete data across a baseline assessment and three follow-up time points in a multi-centre randomized controlled trial of a disease management programme for late-life depression. One approach combines hot-deck (HD) multiple imputation using a predictive mean matching method for item non-response and the approximate Bayesian bootstrap for unit non-response. A second method is based on a multivariate normal (MVN) model using PROC MI in SAS software V8.2. These two methods are contrasted with a last observation carried forward (LOCF) technique and available-case (AC) analysis in a simulation study where replicate analyses are performed on subsets of the originally complete cases. Missing-data patterns were simulated to be consistent with missing-data patterns found in the originally incomplete cases, and observed complete data means were taken to be the targets of estimation. Not surprisingly, the LOCF and AC methods had poor coverage properties for many of the variables evaluated. Multiple imputation under the MVN model performed well for most variables but produced less than nominal coverage for variables with highly skewed distributions. The HD method consistently produced close to nominal coverage, with interval widths that were roughly 7 per cent larger on average than those produced from the MVN model. [ABSTRACT FROM AUTHOR]

Background: Droperidol and 5-HT3-receptor antagonists are among the most potent antiemetics to prevent postoperative nausea and vomiting (PONV). Combinations of these drugs have been used to increase the efficacy of antiemetic treatment. However, so far the quantitative effect of this combination has not been evaluated systematically. Methods: Results from randomised controlled trials investigating the efficacy of 5-HT3-receptor antagonists or droperidol alone versus the combination of both drugs to prevent PONV were included in a meta-analysis. Studies were systematically searched using Medline, EMBASE, the Cochrane-Library, and by manually screening the reference lists of matching review articles and current issues of locally available peer-reviewed anaesthesia journals. Seven papers with data on granisetron published by Fujii and co-workers were not considered. The main end point in each study was defined as occurrence of nausea, retching, or vomiting within 6 h (“early PONV”) and within 48 h (“late PONV”) after surgery. The relative risks (RR) and the numbers needed to treat (NNT) of the pooled data with their corresponding 95% confidence intervals (given in parentheses) were calculated using a random effects model. Results: Eight studies with 881 patients (adults: n=801; children (mean age: 8 yr): n=80) were included in the analysis. Droperidol was applied to 340 patients, 5-HT3-receptor antagonists to 198, and 343 were treated with a combination of both drugs. Seven out of these eight studies reported increased antiemetic efficacy of the combination group compared with the single drugs (droperidol and 5-HT3-receptor antagonists respectively). However, in none of the trials did this difference reach statistical significance. When a meta-analytic analysis based on these results was performed the combination of droperidol with a 5-HT3-recpetor antagonist was not associated with a significantly increased antiemetic efficacy. In 12 to 13 patients a 5-HT3-receptor antagonist has to be added to droperidol prophylaxis to prevent one additional patient from PONV who would have had suffered from PONV when treated with droperidol alone (RR “early PONV”: 1.52 (0.95–2.44); RR “late PONV”: 1.24 (0.89–1.74)). Similar results were obtained when the antiemetic effect of adding droperidol to a prophylaxis with 5-HT3-receptor antagonists was analysed. In this case 10 to 12 patients have to be treated with the 5-HT3-droperidol combination instead of with a 5-HT3-receptor antagonist alone to prevent one additional patient from PONV (RR “early PONV”: 1.55 (0.68–3.52); RR “late PONV”: 1.29 (0.77–2.17)). There were no reports of an increased incidence of adverse effects. Conclusion: The data on the combination of droperidol with 5-HT3-receptor antagonists suggest that there is a trend towards increased efficacy of the combination therapy compared to the single drugs. However, so far there are insufficient data to recommend this combination treatment for prophylaxis. [ABSTRACT FROM AUTHOR]

Background: Vitiligo was an autoimmune disease and some guidelines for the management of vitiligo encouraged the use of NB‐UVB combination therapies to enhance repigmentation. Objectives: To compare the effectiveness of current NB‐UVB combination regimen at the improvement in repigmentation through a systematic review and network meta‐analysis. Methods: We searched the electronic databases for randomized controlled trials related to NB‐UVB combination therapy for vitiligo till October 2022. STATA15.0 software was applied to carrying out data analysis. Results: A total of 28 eligible studies involving 1194 participants were enrolled in the analysis. The NMA results revealed that compared with NB‐UVB, carboxytherapy [OR = 32.35, 95% CI (1.79, 586.05)], Er: YAG laser+ topical 5% 5‐FU [OR = 10.74, 95% CI (4.05, 28.49)], needling/micro‐needling [OR = 3.42, 95% CI (1.18, 9.88)], betamethasone intramuscular injection [OR = 3.08, 95% CI (1.17, 8.13)], topical tacrolimus [OR = 2.54, 95% CI (1.30, 4.94)], and oral Chinese herbal medicine compound [OR = 2.51, 95% CI (1.40, 4.50)] integrated with NB‐UVB were more efficacious in excellent to complete repigmentation response rate (≥75%). Besides, NB‐UVB+ Er: YAG laser+ topical 5% 5‐FU [OR = 0.17, 95% CI (0.04, 0.67)] and NB‐UVB+ needling/micro‐needling [OR = 0.24, 95% CI (0.06, 0.88)] were less likely evaluated as ineffective repigmentation response (≤25%). Conclusions: All combination therapies ranked higher than NB‐UVB monotherapy in inducing successful repigmentation and avoiding failed treatment in patients with vitiligo. Comprehensive consideration, NB‐UVB+ Er: YAG laser+ topical 5% 5‐FU and NB‐UVB+ needling/microneedling would be the preferred therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Haemodialysis plastic cannulae have been limited to incident arterio‐venous fistulae cannulation or in those who require a more flexible in situ access device. The feasibility of plastic cannulae in prevalent patients on haemodialysis has not been reported. Objective: To determine the feasibility of plastic cannulae in prevalent haemodialysis patients. Design: Prospective feasibility crossover randomised control trial. Participants: Adults diagnosed with chronic kidney disease G5 requiring haemodialysis three or more times per week via a native arteriovenous fistula previously cannulated for at least 6 weeks. Measurements: Cannulation success rate, cannulation manipulation type, arterial and venous needle pressure. Patient needle‐related anxiety as measured by the 4‐item Patient Health Questionnaire and Meditation in Dialysis Questionnaire and nurse satisfaction. Results: Eight patients completed 12 weeks plastic canulae and metal needles. Plastic cannulae were less likely to be successful in cannulation compared to metal needles (odds ratio = 0.15; 95% confidence interval [CI]: 0.05–0.48; p = 0.001). There was no effect of type of needle on the change in arterial needle pressure or change in venous needle pressure and no effect of plastic needle on repositioning (relative risk [RR] = 1.09; 95% CI: 0.385, 3.089; p =.871) or gauze pillow application (RR = 0.936; 95% CI: 0.467, 1.874; p =.851) than metal needles, relative to no manipulation. There were low rates of psychological distress or needle‐related anxiety towards plastic or metal needles. Conclusions: Plastic cannulae are feasible in prevalent haemodialysis patients, however, metal needles are still preferred in a haemodialysis center that has historically used metal needles. [ABSTRACT FROM AUTHOR]

Background: Fluid treatment in sepsis is a challenge and clinical equipoise exists regarding intravenous (IV) volumes. We aimed to determine whether a 24‐h protocol restricting IV fluid was feasible in adult patients with sepsis without shock presenting to the emergency department (ED). Methods: The REFACED Sepsis trial is an investigator‐initiated, multicenter, randomized, open‐label, feasibility trial, assigning sepsis patients without shock to 24 h of restrictive, crystal IV fluid administration or standard care. In the IV fluid restriction group fluid boluses were only permitted if predefined criteria for hypoperfusion occurred. Standard care was at the discretion of the treating team. The primary outcome was total IV crystalloid fluid volumes at 24 h after randomization. Secondary outcomes included total fluid volumes, feasibility measures, and patient‐centered outcomes. Results: We included 123 patients (restrictive 61 patients and standard care 62 patients) in the primary analysis. A total of 32% (95% confidence interval [CI] 28%–37%) of eligible patients meeting all inclusion criteria and no exclusion criteria were included. At 24 h, the mean (±SD) IV crystalloid fluid volumes were 562 (±1076) ml versus 1370 (±1438) ml in the restrictive versus standard care group (mean difference –801 ml, 95% CI −1257 to −345 ml, p = 0.001). Protocol violations occurred in 21 (34%) patients in the fluid‐restrictive group. There were no differences between groups in adverse events, use of mechanical ventilation or vasopressors, acute kidney failure, length of stay, or mortality. Conclusions: A protocol restricting IV crystalloid fluids in ED patients with sepsis reduced 24‐h fluid volumes compared to standard care. A future trial powered toward patient‐centered outcomes appears feasible. [ABSTRACT FROM AUTHOR]

Emergency Use Authorization (EUA) allows the US Food and Drug Administration (FDA) to expedite the availability of therapeutics in the context of a public health emergency. To date, an evidentiary standard for clinical efficacy to support an EUA has not yet been established. This review examines the clinical data submitted in support of EUA for antiviral and anti‐inflammatory therapeutics for coronavirus disease 2019 (COVID‐19) through December of 2021 and the resilience of the authorization as new clinical data arose subsequent to the authorization. In the vast majority of cases, EUA was supported by at least one well‐powered randomized controlled trial (RCT) where statistically significant efficacy was demonstrated. This included branded medications already approved for use outside of the context of COVID‐19. When used, the standard of a single RCT seemed to provide adequate evidence of clinical efficacy, such that subsequent clinical studies generally supported or expanded the EUA of the therapeutic in question. The lone generic agent that was granted EUA (chloroquine/hydroxychloroquine) was not supported by a well‐controlled RCT, and the EUA was withdrawn within 3 months time. This highlighted not only the ambiguity of the EUA standard, but also the need to provide avenues through which high quality clinical evidence for the efficacy of a generic medication could be obtained. Therefore, maintaining the clinical trial networks assembled during the COVID‐19 pandemic could be a critical component of our preparation for future pandemics. Consideration could also be given to establishing a single successful RCT as regulatory guidance for obtaining an EUA. [ABSTRACT FROM AUTHOR]

Background: Metacognitive training for depression (D‐MCT) is a novel low‐intensity group training for economic treatment of depression. Previous studies demonstrate its efficacy in moderately depressed outpatients. The present study evaluated efficacy and patients' perspective of the D‐MCT in severely depressed psychiatric inpatients. Methods: In a randomized‐controlled trial, 75 individuals with a major depressive disorder (MDD) were allocated to D‐MCT versus euthymic therapy as add‐on (twice a week) to cognitive‐behavioural‐based (CBT) inpatient‐care. Depressive symptoms (HDRS, BDI), dysfunctional (meta)cognition (DAS, MCQ‐30) and subjective appraisal were assessed at baseline, 4 weeks (post) and 3 months (follow‐up). Results: Participants in both conditions showed a large decline in depression at post and follow‐up‐assessment. No superior add‐effect of D‐MCT versus active control emerged for depression severity on top of the inpatient care. However, among patients with a diagnosis of MDD with no (vs. at least one) comorbidity, D‐MCT participants showed a larger decline in depressive (meta‐)cognition at follow‐up with medium‐to‐large effect sizes. D‐MCT was evaluated as superior in overall appraisal, treatment preference, motivation and satisfaction. Limitations: The follow‐up time interval of 3 months may have been too short to detect long‐term effects. There is emerging evidence that modification of (meta)cognition unfolds its full effects only with time. Effects of CBT inpatient‐care on outcome parameters cannot be differentiated. Conclusions: Although D‐MCT as an add‐on was not superior in complete case analyses, results suggest greater benefit for patients with MDD and no comorbidity. D‐MCT proved feasible in acute‐psychiatric inpatient‐care and was highly accepted by patients. Future studies should investigate the role of modified (meta)cognition on long‐term treatment outcome, including dropout and relapse rates. [ABSTRACT FROM AUTHOR]

Licht RW. Limits of the applicability and generalizability of drug trials in mania. Bipolar Disord 2002: 4(Suppl. 1): 66–68. ©Blackwell Munksgaard, 2002 During recent years, the majority of drug trials in mania have been conducted for the purpose of drug approval. On this background, this paper addresses to what extent these trials may actually provide the practising clinician with useful information. One major point is that selection prior to the point of randomization in RCTs in mania may limit the applicability of study results to patients seen in ordinary clinical practice. Limitations in study credibility and study design are also discussed. The need for large scale pragmatic studies using broad inclusion criteria, comparing the various treatments, alone or in combination, is emphasized. [ABSTRACT FROM AUTHOR]

Background Both misoprostol and prostaglandin E2 (PGE2) gel are used for labor induction in women with premature rupture of membranes (PROM). Objectives To evaluate studies comparing the effects of misoprostol and PGE2 gel in labor induction. Search strategy Databases including Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant papers. Selection criteria Randomized controlled trials comparing the use of misoprostol and PGE2 gel for labor induction in women with PROM were included. Data collection and analysis For meta-analyses, the Mantel–Haenszel method was used for dichotomous data, and the inverse variance method was used for continuous data. Main results Four randomized controlled studies (n = 615) were included. There were no significant differences between the two groups in the induction-to-delivery interval (mean difference – 4.44 hours; 95% confidence interval [CI] –9.35 to 0.48), rate of cesarean delivery (odds ratio [OR] 0.90; 95% CI 0.44–1.85), and rate of neonatal intensive care unit admission (OR 0.89; 95% CI 0.57–1.38). Women receiving misoprostol had a significantly higher rate of tachysystole than did those receiving PGE2 gel (OR 4.84; 95% CI 2.46–9.54). Conclusions Misoprostol is as efficacious and safe as PGE2 gel for labor induction in women with PROM. [ABSTRACT FROM AUTHOR]

Background and Objectives: We examined youth recovery outcomes at 6- and 9-months post-participation in an aftercare pilot study called Educating and Supporting inQuisitive Youth in Recovery (ESQYIR) that aimed to investigate the utility of a 12-week mobile texting recovery support intervention.Methods: A total of 80 youth [Mage 20.4 (SD = 3.5)] were randomized to a mobile texting aftercare intervention or an aftercare-as-usual control group. Both groups received identical data collection protocols with psychosocial and behavioral assessments occurring at baseline, during the trial (months 1 and 2), at discharge from the trial (month 3), and 3-, 6-, and 9-month post-intervention follow-ups.Results: Mixed modeling showed that youth who participated in the mobile texting aftercare intervention were less likely to test positive for their primary drug compared to youth in the aftercare-as-usual condition during 6- and 9-months follow-ups (p < .01). Additionally, youth in the aftercare intervention reported significantly higher self-efficacy/confidence to abstain during recovery (p < .05) and were more likely to participate in recovery-related behaviors (self-help and goal-directed extracurricular activities; p < .05) than those in aftercare-as-usual at the 6- and 9-month follow-ups.Conclusions: Results suggest that delivering a structured, behavioral-based wellness aftercare intervention using mobile texting can be an effective for sustaining recovery outcomes in youth over time compared to youth who receive aftercare-as-usual.Scientific Significance: This study shows that a mobile-texting aftercare intervention sustained effects at 6- and 9-months post-intervention for young people in substance use recovery. [ABSTRACT FROM AUTHOR]

Background: The efficacy and safety of sirolimus (SIR)-based graft-versus-host disease (GVHD) prophylaxis in patients who were subjected to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain to be clarified; this meta-analysis was conducted to evaluate these factors.Study Design and Methods: Data from original research were obtained from PubMed, Embase, and Cochrane central register of controlled trials databases. Randomized controlled trials (RCTs) evaluating the efficacy of SIR-based prophylaxis in allo-HSCT were included. The risk ratio (RR), with a 95% confidence interval (CI), was used to pool data. The random effects model was used, irrespective of the presence or absence of heterogeneity.Results: Five RCTs were included in the meta-analysis. SIR was observed to significantly decrease the incidence of Grade II to IV acute GVHD (aGVHD; RR, 0.65; 95% CI, 0.47-0.89). However, the incidence of Grade III to IV aGVHD and chronic GVHD was not decreased (RR, 0.91; 95% CI, 0.59-1.40; RR, 1.04; 95% CI, 0.88-1.23, respectively). An analysis of the toxic effects of SIR revealed that SIR effected a significant increase in the incidence of sinusoidal obstructive syndrome (RR, 2.24; 95% CI, 1.26-4.01), while that of thrombotic microangiopathy was not significantly increased (RR, 2.48; 95% CI, 0.87-7.06). Moreover, SIR did not improve event-free survival and overall survival (RR, 0.97; 95% CI, 0.85-1.10; and RR, 0.92; 95% CI, 0.82-1.02, respectively).Conclusion: This meta-analysis indicated that the SIR-based regimen is an effective and safe alternative prophylaxis strategy for GVHD. [ABSTRACT FROM AUTHOR]

Structured Abstract Objective To compare the effectiveness of distraction osteogenesis to orthognathic surgery for the treatment of maxillary hypoplasia in individuals with cleft lip and palate. Method A systematic review of prospective randomized, quasi-randomized or controlled clinical trials. MEDLINE, EMBASE, Scopus, Web of Science, CINAHL, CENTRAL, trial registers and grey literature were searched. Hand searching of five relevant journals was completed. Two reviewers independently completed inclusion assessment. Data extraction and risk of bias assessment were completed by a single reviewer and checked by a second reviewer. Results Five publications all reporting different outcomes of a single randomized controlled trial are included within the review. The quality of the evidence was low with a high risk of bias. Both surgical interventions produce significant soft tissue improvement. Horizontal relapse of the maxilla was statistically significantly greater following orthognathic surgery. There was no statistically significant difference in speech and velo-pharyngeal function between the interventions. Maxillary distraction initially lowered social self-esteem, but this improved with time resulting in higher satisfaction with life in the long term. Conclusions The low quality of evidence included within the review means there is insufficient evidence to conclude whether there is a difference in effectiveness between maxillary distraction and osteotomy for the treatment of cleft-related maxillary hypoplasia. There is a need for further high-quality randomized controlled trials to allow conclusive recommendations to be made. [ABSTRACT FROM AUTHOR]

Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real‐world evidence (RWE) in the evaluation of new treatments or products. The RWE label has been used to refer to a variety of departures from the methods of traditional randomized controlled trials. Recognizing this complexity and potential confusion, the National Academies of Science, Engineering, and Medicine convened a series of workshops to clarify and address questions regarding the use of RWE to evaluate new medical treatments. Those workshops identified three specific dimensions in which RWE studies might differ from traditional clinical trials: use of real‐world data (data extracted from health system records or data captured by mobile devices), delivery of real‐world treatment (open‐label treatments delivered in community settings by community practitioners), and real‐world treatment assignment (including nonrandomized comparisons and variations on random assignment such as before‐after or stepped‐wedge designs). For any RWE study, decisions regarding each of these dimensions depends on the specific research question, characteristics of the potential study settings, and characteristics of the settings where study results would be applied. [ABSTRACT FROM AUTHOR]

Aims We reviewed randomized controlled trials (RCTs) to compare the efficacy and safety of initial dipeptidyl peptidase-IV ( DPP-IV) inhibitors and metformin combination therapy with equal-dosage metformin monotherapy in type 2 diabetes. Methods We conducted a systematic review of English articles using MEDLINE and EMBASE. Search terms included randomized controlled trial, controlled clinical trial, random allocation, sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, duotogliptin and dipeptidyl peptidase IV inhibitor. Double-blinded RCTs comparing DPP-IV inhibitors initially combined with metformin and metformin monotherapy in non-pregnant drug-naive adults with type 2 diabetes were included for this study. Extraction of articles was performed by two authors using predefined data fields. Meta-analysis was used when studies were homogeneous enough, and data were shown and not combined if no formal meta-analysis was performed. Results Five RCTs met the inclusion criteria. By analysis of different outcomes, patients receiving initial combination of DPP-IV inhibitors and metformin showed a greater reduction in haemoglobinA1c ( HbA1c) from baseline [weighted mean difference ( WMD), −0.55%; 95% confidence interval ( CI), −0.63 to −0.46%], a higher rate of achieving target of HbA1c < 7% [risk ratio ( RR), 1.55; 95% CI, 1.43-1.67], a significantly lower fasting plasma glucose ( FPG) ( WMD, −0.97 mmol/l; 95% CI, −1.26 to −0.68 mmol/l),while the initial combination therapy and monotherapy did not show a significant difference in incidence of total adverse events ( AEs, 51.8 vs. 53.7%, respectively; RR, 0.96; 95% CI, 0.91-1.02), gastrointestinal AEs (18.2 vs. 19.4%, respectively; RR, 0.94; 95% CI, 0.82-1.07), drug-related AEs ( RR, 0.88; 95% CI, 0.74-1.03) and discontinuation due to AEs ( RR, 0.85; 95% CI, 0.61-1.20). The following outcomes were not included for meta-analysis: change from baseline in postprandial glycaemia, β-cell function, insulin sensitivity and body weight as well as incidence of hypoglycaemia. The analyses of these trials revealed that the change from baseline of the postprandial glycaemia and index of β-cell function were greater while the RRs for incidence of hypoglycaemia and body weight increase had no statistical significance. Conclusions Compared with equal-dosage metformin monotherapy, the initial combination of metformin and DPP-IV inhibitors were more effective in glycaemic control without additional risk of AEs, therefore it can be considered as a beneficial therapeutic regimen for drug-naive type 2 diabetes patients. [ABSTRACT FROM AUTHOR]

Purpose To assess the efficacy of petrolatum jelly for the prevention of diaper rash and to evaluate the relationship between the occurrence of diaper rash and certain treatments and type of nutrition. Design and Methods A randomized clinical trial was carried out with two parallel groups ( n = 213) at the neonatal care unit of Donostia University Hospital in San Sebastián, Guipuzcoa Province, Spain. Results There was a lower incidence of diaper rash in the experimental group with petrolatum jelly (17.1%) than the control group (22.2%), but the difference was not statistically significant ( p =.39). The use of antibiotics and oral 50% glucose as well as an increased number of stools are associated with a higher incidence of diaper rash, while breastfeeding and phototherapy are protective factors. Practice Implications Prevention is strengthened by a better understanding of the risk factors. [ABSTRACT FROM AUTHOR]

Background: Pilonidal disease occurs when hair invading the natal cleft causes inflammation and abscess formation. Opinions vary on best practice, and most procedures have considerable morbidity and high recurrence rates of 6-40%. Objectives: This study systematically reviews the use of fibrin glue in the treatment of pilonidal disease. Outcomes measured were healing time and recurrence rate. Data source: ScienceDirect and PubMed databases were searched for relevant literature, yielding seven papers including five small trials. The total number of patients receiving fibrin glue treatments across all trials was 85. There were no exclusion criteria in this review. Results: Fibrin glue treatments had equivalent or better reported healing times than conventional therapies at an average of 2-6 weeks, and low recurrence rates between 0 and 17% at follow-up periods between 4 and 28 months. Considerable heterogeneity in study methodologies and surgical techniques prevented statistical significance or aggregate figures from being determined. Conclusions: There appears to be early promise for the use of fibrin glue in the treatment of pilonidal disease and an impetus for definitive research. [ABSTRACT FROM AUTHOR]

Objective: To compare the outcome of patients with dry traumatic tympanic membrane perforation after spontaneous healing and gelfoam patching with or without perforation edge approximation. Design: Prospective clinical study. Setting: University-affiliated teaching hospital. Participants: Ninety-one patients with acute dry traumatic tympanic membrane perforation inverted or everted edges were recruited. They were randomly allocated to three groups: spontaneous healing (n = 31), gelfoam patching (n = 30) and edge-approximation plus gelfoam patching (n = 30). Otoscopy and tympanometry were performed before the treatment and at follow-up visits. Main outcome measures: Healing rate, healing time, ear infection rate and morphological changes during healing process. Results: The overall healing rate was 85% in the spontaneous healing group, lower than that in the two gelfoam patching groups (97%), but the difference failed to reach a statistical significance (P > 0.05). The average healing time was 30 ± 10.1 days in the spontaneous healing group, significantly longer (P < 0.01) than that in the other two groups (16 ± 5.6 and 18 ± 4.7 days, respectively). Middle ear infection rate did not differ significantly (7%, 3% and 3%, respectively). Spontaneous healing resulted in formation of scabs at the perforation edges, which was effectively prevented by gelfoam patching. Conclusions: Gelfoam patching may facilitate healing of traumatically perforated tympanic membrane. Approximation of folded perforation edges is not necessary in gelfoam patching. [ABSTRACT FROM AUTHOR]

Background and Purpose: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored.Experimental Approach: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg x kg(-1)) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed.Key Results: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone C(max) was correlated with SPT assessment (rho(S)= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers.Conclusions and Implications: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism. [ABSTRACT FROM AUTHOR]

Hypertonic saline has been in clinical use for many decades. Its osmotic and volume-expanding properties make it theoretically useful for a number of indications in critical care. This literature review evaluates the use of hypertonic saline in critical care. The putative mechanism of action is presented, followed by a narrative review of its clinical usefulness in critical care. The review was conducted using the Scottish Intercollegiate Guidelines Network method for the review of cohort studies, randomised-controlled trials and meta-analyses. The review focuses specifically on blood pressure restoration and outcome benefit in both haemorrhagic and non-haemorrhagic shock, and the management of raised intracranial pressure. Issues of clinical improvement and outcome benefit are addressed. Hypertonic saline solutions are effective for blood pressure restoration in haemorrhagic, but not other, types of shock. There is no survival benefit with the use of hypertonic saline solutions in shock. Hypertonic saline solutions are effective at reducing intracranial pressure in conditions causing acute intracranial hypertension. There is no survival or outcome benefit with the use of hypertonic saline solutions for raised intracranial pressure. Recommendations for clinical use and future directions of clinical research are presented. [ABSTRACT FROM AUTHOR]