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Spontaneous adverse events reporting systems are used internationally to flag new or unexpected adverse drug reactions (ADRs). Disproportionality analysis is a recognised technique, but false alarms may arise. We aimed to determine whether these new ADR signals had subsequently been followed-up with detailed hypothesis-testing studies. We searched PubMed to identify published studies (years 2017-2021) where the authors reported findings of new ADR signals from disproportionality analyses. We used PubMed and forward citation tracking (Google Scholar) to identify any subsequent confirmatory studies of these ADR signals. We screened 414 titles and abstracts and checked the full-text articles of 57 studies. We found signals for 56 suspected new ADRs from 24 drugs. Google Scholar showed that the ADR studies had been cited a median of seven times (range 0-61). However, none of the suspected new ADRs had undergone detailed evaluation in the citing literature. Similarly, our PubMed search did not find any confirmation studies for the 56 suspected new ADRs. Although many suspected new ADR signals have been identified through disproportionality analysis, most signals have not been further verified as being either genuine ADRs or false alarms. Researchers must focus on follow-up studies for these new signals.

Background: Medications with anticholinergic properties are commonly prescribed to older adults. The cumulative anticholinergic effect of all the medications a person takes is referred to as the 'anticholinergic burden' because of its potential to cause adverse effects. It is possible that high anticholinergic burden may be a risk factor for development of cognitive decline or dementia. There are various scales available to measure anticholinergic burden but agreement between them is often poor., Objectives: To assess whether anticholinergic burden, as defined at the level of each individual scale, is a prognostic factor for future cognitive decline or dementia in cognitively unimpaired older adults., Search Methods: We searched the following databases from inception to 24 March 2021: MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), and ISI Web of Science Core Collection (ISI Web of Science)., Selection Criteria: We included prospective and retrospective longitudinal cohort and case-control observational studies with a minimum of one year' follow-up that examined the association between an anticholinergic burden measurement scale and future cognitive decline or dementia in cognitively unimpaired older adults., Data Collection and Analysis: Two review authors independently assessed studies for inclusion, and undertook data extraction, assessment of risk of bias, and GRADE assessment. We extracted odds ratios (OR) and hazard ratios, with 95% confidence intervals (CI), and linear data on the association between anticholinergic burden and cognitive decline or dementia. We intended to pool each metric separately; however, only OR-based data were suitable for pooling via a random-effects meta-analysis. We initially established adjusted and unadjusted pooled rates for each available anticholinergic scale; then, as an exploratory analysis, established pooled rates on the prespecified association across scales. We examined variability based on severity of anticholinergic burden., Main Results: We identified 25 studies that met our inclusion criteria (968,428 older adults). Twenty studies were conducted in the community care setting, two in primary care clinics, and three in secondary care settings. Eight studies (320,906 participants) provided suitable data for meta-analysis. The Anticholinergic Cognitive Burden scale (ACB scale) was the only scale with sufficient data for 'scale-based' meta-analysis. Unadjusted ORs suggested an increased risk for cognitive decline or dementia in older adults with an anticholinergic burden (OR 1.47, 95% CI 1.09 to 1.96) and adjusted ORs similarly suggested an increased risk for anticholinergic burden, defined according to the ACB scale (OR 2.63, 95% CI 1.09 to 6.29). Exploratory analysis combining adjusted ORs across available scales supported these results (OR 2.16, 95% CI 1.38 to 3.38), and there was evidence of variability in risk based on severity of anticholinergic burden (ACB scale 1: OR 2.18, 95% CI 1.11 to 4.29; ACB scale 2: OR 2.71, 95% CI 2.01 to 3.56; ACB scale 3: OR 3.27, 95% CI 1.41 to 7.61); however, overall GRADE evaluation of certainty of the evidence was low., Authors' Conclusions: There is low-certainty evidence that older adults without cognitive impairment who take medications with anticholinergic effects may be at increased risk of cognitive decline or dementia., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Real-world epidemiology gives us the unique opportunity to observe large numbers of people, and the actions and events that characterize their encounters with healthcare providers. However, the heterogeneity and sheer diversity of the population and healthcare systems makes it impossible for researchers to compare "like with like" when attempting to draw causal inferences about interventions and outcomes. The critical issue in epidemiological datasets relates to high risk of bias due to confounders that stem from baseline differences between groups. Propensity score (PS) techniques are statistical approaches that have been used to tackle potential imbalance in the comparison groups. The PS is the estimated probability (based on measured baseline covariates) that the patient receives a particular intervention. Patients that share similar PS will most likely have the same distributions of underlying covariates included in the PS. Implementation of PS methods may achieve better balance of covariates, but there is no consensus on the best way of capturing all relevant confounders for incorporation into the PS model. Should covariates be selected by clinical or epidemiological experts, or would data-driven algorithms (machine learning) offer more efficient and reliable methods of estimating PS and controlling for confounding? The PS can be incorporated into the analysis in different ways, each with its own strengths and limitations, and researchers must choose the best fit for their study objectives. PS methods are particularly advantageous in situations where there are large numbers of measured covariates but relatively few outcome events captured in healthcare administrative databases., (© 2019 John Wiley & Sons Ltd.)

Background: Objectively derived search filters for adverse drug effects and complications in surgery have been developed but not for medical device adverse effects., Objective: To develop and validate search filters to retrieve evidence on medical device adverse effects from ovid medline and embase., Methods: We identified systematic reviews from Epistemonikos and the Health Technology Assessment (hta) database. Included studies within these reviews that reported on medical device adverse effects were randomly divided into three test sets and one validation set of records. Using word frequency analysis from one test set, we constructed a sensitivity maximising search strategy. This strategy was refined using two other test sets, then validated., Results: From 186 systematic reviews which met our inclusion criteria, 1984 unique included studies were available from medline and 1986 from embase. Generic adverse effects searches in medline and embase achieved 84% and 83% sensitivity. Recall was improved to over 90%, however, when specific adverse effects terms were added., Conclusion: We have derived and validated novel search filters that retrieve over 80% of records with medical device adverse effects data in medline and embase. The addition of specific adverse effects terms is required to achieve higher levels of sensitivity., (© 2019 The Authors. Health Information and Libraries Journal published by John Wiley & Sons Ltd on behalf of Health Libraries Group.)

Background: The concept of e-Learning has been rapidly accepted as an important component of medical education and is especially adept at teaching clinical skills. However, their impact on learning, particularly in Otolaryngology Head and Neck Surgery (OHNS) medical school curriculum, has yet to be adequately explored. The aim of this pilot study is to develop interactive e-Learning resources and evaluate their impact in enhancing OHNS teaching in medical school., Methods: This pilot study is a randomized controlled trial assessing the effectiveness of e-Learning resources in enhancing the current traditional lecture and tutorial-based teaching of OHNS in medical school. Nineteen final-year medical students from the University of Sydney were recruited for this study, who were randomly allocated into intervention group with additional e-Learning resources (Group A) and control group (Group B). Student knowledge was assessed through objective structured clinical examinations (OSCE) with use of standardized forms for objective scoring. Assessors were blinded to student randomization status. A post-study questionnaire was distributed to assess student feedback on the e-Learning resources., Results: Eight students were allocated to Group A and 11 students to Group B. Group A performed significantly better than Group B in the overall examination scores (78.50 ± 13.88 v. 55.82 ± 8.23; P = < 0.01). With the minimum pass mark of 65%, the majority of students in Group A was able to pass the OSCE assessments, while the majority of students in Group B failed (87.50% v. 9.10%; P = 0.01). The post-test questionnaire on the e-Learning resources showed very favorable feedback from the students' perspective., Conclusion: Results from our pilot study suggests that the use of interactive online e-Learning resources can be a valuable adjunct in supplementing OHNS teaching in medical school, as they are readily accessible and allow flexible on-demand learning. Future studies involving large numbers of medical students are needed to validate these results.

Background: Survival rates have greatly improved as a result of more effective treatments for childhood cancer. Unfortunately, the improved prognosis has been accompanied by the occurrence of late, treatment-related complications. Liver complications are common during and soon after treatment for childhood cancer. However, among long-term childhood cancer survivors, the risk of hepatic late adverse effects is largely unknown. To make informed decisions about future cancer treatment and follow-up policies, it is important to know the risk of, and associated risk factors for, hepatic late adverse effects. This review is an update of a previously published Cochrane review., Objectives: To evaluate all the existing evidence on the association between antineoplastic treatment (that is, chemotherapy, radiotherapy involving the liver, surgery involving the liver and BMT) for childhood cancer and hepatic late adverse effects., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2018, Issue 1), MEDLINE (1966 to January 2018) and Embase (1980 to January 2018). In addition, we searched reference lists of relevant articles and scanned the conference proceedings of the International Society of Paediatric Oncology (SIOP) (from 2005 to 2017) and American Society of Pediatric Hematology/Oncology (ASPHO) (from 2013 to 2018) electronically., Selection Criteria: All studies, except case reports, case series, and studies including fewer than 10 patients that examined the association between antineoplastic treatment for childhood cancer (aged 18 years or less at diagnosis) and hepatic late adverse effects (one year or more after the end of treatment)., Data Collection and Analysis: Two review authors independently performed the study selection and 'risk of bias' assessment. The 'risk of bias' assessment was based on earlier checklists for observational studies. For the original version of the review, two review authors independently performed data extraction. For the update of the review, the data extraction was performed by one reviewer and checked by another reviewer., Main Results: Thirteen new studies were identified for the update of this review. In total, we included 33 cohort studies including 7876 participants investigating hepatic late adverse effects after antineoplastic treatment (especially chemotherapy and radiotherapy) for different types of childhood cancer, both haematological and solid malignancies. All studies had methodological limitations. The prevalence of hepatic late adverse effects, all defined in a biochemical way, varied widely, between 0% and 84.2%. Selecting studies where the outcome of hepatic late adverse effects was well-defined as alanine aminotransferase (ALT) above the upper limit of normal, indicating cellular liver injury, resulted in eight studies. In this subgroup, the prevalence of hepatic late adverse effects ranged from 5.8% to 52.8%, with median follow-up durations varying from three to 23 years since cancer diagnosis in studies that reported the median follow-up duration. A more stringent selection process using the outcome definition of ALT as above twice the upper limit of normal, resulted in five studies, with a prevalence ranging from 0.9% to 44.8%. One study investigated biliary tract injury, defined as gamma-glutamyltransferase (γGT) above the upper limit of normal and above twice the upper limit of normal and reported a prevalence of 5.3% and 0.9%, respectively. Three studies investigated disturbance in biliary function, defined as bilirubin above the upper limit of normal and reported prevalences ranging from 0% to 8.7%. Two studies showed that treatment with radiotherapy involving the liver (especially after a high percentage of the liver irradiated), higher BMI, and longer follow-up time or older age at evaluation increased the risk of cellular liver injury in multivariable analyses. In addition, there was some suggestion that busulfan, thioguanine, hepatic surgery, chronic viral hepatitis C, metabolic syndrome, use of statins, non-Hispanic white ethnicity, and higher alcohol intake (> 14 units per week) increase the risk of cellular liver injury in multivariable analyses. Chronic viral hepatitis was shown to increase the risk of cellular liver injury in six univariable analyses as well. Moreover, one study showed that treatment with radiotherapy involving the liver, higher BMI, higher alcohol intake (> 14 units per week), longer follow-up time, and older age at cancer diagnosis increased the risk of biliary tract injury in a multivariable analysis., Authors' Conclusions: The prevalence of hepatic late adverse effects among studies with an adequate outcome definition varied considerably from 1% to 53%. Evidence suggests that radiotherapy involving the liver, higher BMI, chronic viral hepatitis and longer follow-up time or older age at follow-up increase the risk of hepatic late adverse effects. In addition, there may be a suggestion that busulfan, thioguanine, hepatic surgery, higher alcohol intake (>14 units per week), metabolic syndrome, use of statins, non-Hispanic white ethnicity, and older age at cancer diagnosis increase the risk of hepatic late adverse effects. High-quality studies are needed to evaluate the effects of different therapy doses, time trends, and associated risk factors after antineoplastic treatment for childhood cancer.

Background: Evidence-based guidelines from the World Health Organization (WHO) have recommended a high (80%) fraction of inspired oxygen (FiO 2 ) to reduce surgical site infection in adult surgical patients undergoing general anaesthesia with tracheal intubation. However, there is ongoing debate over the safety of high FiO 2 . We performed a systematic review to define the relative risk of clinically relevant adverse events (AE) associated with high FiO 2 ., Methods: We reviewed potentially relevant articles from the WHO review supporting the recommendation, including an updated (July 2018) search of EMBASE and PubMed for randomised and non-randomised controlled studies reporting AE in surgical patients receiving 80% FiO 2 compared with 30-35% FiO 2 . We assessed study quality and performed meta-analyses of risk ratios (RR) comparing 80% FiO 2 against 30-35% for major complications, mortality, and intensive care admission., Results: We included 17 moderate-good quality trials and two non-randomised studies with serious-critical risk of bias. No evidence of harm with high FiO 2 was found for major AE in the meta-analysis of randomised trials: atelectasis RR 0.91 [95% confidence interval (CI) 0.59-1.42); cardiovascular events RR 0.90 (95% CI 0.32-2.54); intensive care admission RR 0.93 (95% CI 0.7-1.12); and death during the trial RR 0.49 (95% CI 0.17-1.37). One non-randomised study reported that high FiO 2 was associated with major respiratory AE [RR 1.99 (95% CI 1.72-2.31)]., Conclusions: No definite signal of harm with 80% FiO 2 in adult surgical patients undergoing general anaesthesia was demonstrated and there is little evidence on safety-related issues to discourage its use in this population., (Copyright © 2018 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate the outcomes of tracheobronchial stenting in patients with malignant central airway obstruction and assist practitioners in palliative settings in understanding the indications, contraindications and management of tracheobronchial stents., Methods: This retrospective study involved a consecutive case series of palliative patients with central airway obstruction secondary to inoperable cancers who underwent tracheobronchial stenting at a single institution. The European Cooperative Oncology Group (ECOG) scale was used to evaluate patient functional status before and after tracheobronchial stenting., Results: Twenty-three patients underwent tracheobronchial stenting for malignant central airway obstruction. The majority of patients presented with symptoms of worsening dyspnoea (21 of 23; 91%). Postoperatively, there was a significant improvement in mean ECOG performance status from 2.88±0.34 to 1.58±0.50 (p<0.01). There was no intraoperative mortality resulting from tracheobronchial stenting. Five patients (21.74%) re-presented to hospital due to worsening symptoms and required emergency bronchoscopy. Two patients had stent migration, requiring stent replacement. One patient restenosed from tumour granulation, requiring microdebrider to debulk the mass. Two patients had stent failure secondary to external tumour compression, leading to death., Conclusion: Tracheobronchial stenting is a safe and effective procedure that offers rapid palliation of symptoms and improvement in patient functional status., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background There is growing evidence that sleep duration and quality may be associated with cardiovascular harm and mortality. Methods and Results We conducted a systematic review, meta-analysis, and spline analysis of prospective cohort studies that evaluate the association between sleep duration and quality and cardiovascular outcomes. We searched MEDLINE and EMBASE for these studies and extracted data from identified studies. We utilized linear and nonlinear dose-response meta-analysis models and used DerSimonian-Laird random-effects meta-analysis models of risk ratios, with inverse variance weighting, and the I 2 statistic to quantify heterogeneity. Seventy-four studies including 3 340 684 participants with 242 240 deaths among 2 564 029 participants who reported death events were reviewed. Findings were broadly similar across both linear and nonlinear dose-response models in 30 studies with >1 000 000 participants, and we report results from the linear model. Self-reported duration of sleep >8 hours was associated with a moderate increased risk of all-cause mortality, with risk ratio , 1.14 (1.05-1.25) for 9 hours, risk ratio, 1.30 (1.19-1.42) for 10 hours, and risk ratio, 1.47 (1.33-1.64) for 11 hours. No significant difference was identified for periods of self-reported sleep <7 hours, whereas similar patterns were observed for stroke and cardiovascular disease mortality. Subjective poor sleep quality was associated with coronary heart disease (risk ratio , 1.44; 95% confidence interval, 1.09-1.90), but no difference in mortality and other outcomes. Conclusions Divergence from the recommended 7 to 8 hours of sleep is associated with a higher risk of mortality and cardiovascular events. Longer duration of sleep may be more associated with adverse outcomes compared with shorter sleep durations.

Background: Search filter development for adverse effects has tended to focus on retrieving studies of drug interventions. However, a different approach is required for surgical interventions., Objective: To develop and validate search filters for medline and Embase for the adverse effects of surgical interventions., Methods: Systematic reviews of surgical interventions where the primary focus was to evaluate adverse effect(s) were sought. The included studies within these reviews were divided randomly into a development set, evaluation set and validation set. Using word frequency analysis we constructed a sensitivity maximising search strategy and this was tested in the evaluation and validation set., Results: Three hundred and fifty eight papers were included from 19 surgical intervention reviews. Three hundred and fifty two papers were available on medline and 348 were available on Embase. Generic adverse effects search strategies in medline and Embase could achieve approximately 90% relative recall. Recall could be further improved with the addition of specific adverse effects terms to the search strategies., Conclusion: We have derived and validated a novel search filter that has reasonable performance for identifying adverse effects of surgical interventions in medline and Embase. However, we appreciate the limitations of our methods, and recommend further research on larger sample sizes and prospective systematic reviews., (© 2018 The Authors Health Information and Libraries Journal published by John Wiley & Sons Ltd on behalf of Health Libraries Group.)

Background: Although variation in stroke service provision and outcomes have been previously investigated, it is less well known what service characteristics are associated with reduced short- and medium-term mortality., Methods: Data from a prospective multicentre study (2009–12) in eight acute regional NHS trusts with a catchment population of about 2.6 million were used to examine the prognostic value of patient-related factors and service characteristics on stroke mortality outcome at 7, 30 and 365 days post stroke, and time to death within 1 year., Results: A total of 2,388 acute stroke patients (mean (standard deviation) 76.9 (12.7) years; 47.3% men, 87% ischaemic stroke) were included in the study. Among patients characteristics examined increasing age, haemorrhagic stroke, total anterior circulation stroke type, higher prestroke frailty, history of hypertension and ischaemic heart disease and admission hyperglycaemia predicted 1-year mortality. Additional inclusion of stroke service characteristics controlling for patient and service level characteristics showed varying prognostic impact of service characteristics on stroke mortality over the disease course during first year after stroke at different time points. The most consistent finding was the benefit of higher nursing levels; an increase in one trained nurses per 10 beds was associated with reductions in 30-day mortality of 11–28% (P < 0.0001) and in 1-year mortality of 8–12% (P < 0.001)., Conclusions: There appears to be consistent and robust evidence of direct clinical benefit on mortality up to 1 year after acute stroke of higher numbers of trained nursing staff over and above that of other recognised mortality risk factors.

Background: The growing move towards patient-centred care has led to substantial research into improving the health literacy skills of patients and members of the public. Hence, there is a pressing need to assess the methodology used in contemporary randomized controlled trials (RCTs) of interventions directed at health literacy, in particular the quality (risk of bias), and the types of outcomes reported., Methods: We conducted a systematic database search for RCTs involving interventions directed at health literacy in adults, published from 2009 to 2014. The Cochrane Risk of Bias tool was used to assess quality of RCT implementation. We also checked the sample size calculation for primary outcomes. Reported evidence of efficacy (statistical significance) was extracted for intervention outcomes in any of three domains of effect: knowledge, behaviour, health status. Demographics of intervention participants were also extracted, including socioeconomic status., Results: We found areas of methodological strength (good randomization and allocation concealment), but areas of weakness regarding blinding of participants, people delivering the intervention and outcomes assessors. Substantial attrition (losses by monitoring time point) was seen in a third of RCTs, potentially leading to insufficient power to obtain precise estimates of intervention effect on primary outcomes. Most RCTs showed that the health literacy interventions had some beneficial effect on knowledge outcomes, but this was typically for less than 3 months after intervention end. There were far fewer reports of significant improvements in substantive patient-oriented outcomes, such as beneficial effects on behavioural change or health (clinical) status. Most RCTs featured participants from vulnerable populations., Conclusions: Our evaluation shows that health literacy trial design, conduct and reporting could be considerably improved, particularly by reducing attrition and obtaining longer follow-up. More meaningful RCTs would also result if health literacy trials were designed with public and patient involvement to focus on clinically important patient-oriented outcomes, rather than just knowledge, behaviour or skills in isolation.

Aims: We aimed to conduct a meta-analysis of serious adverse events (macro- and microvascular events, falls and fractures, death) associated with hypoglycaemia in older patients., Methods: We searched MEDLINE and EMBASE spanning a ten-year period up to March 2015 (with automated PubMed updates to October 2015). We selected observational studies reporting on hypoglycaemia and associated serious adverse events, and conducted a meta-analysis. We assessed study validity based on ascertainment of hypoglycaemia, adverse events and adjustment for confounders., Results: We included 17 studies involving 1.86 million participants. Meta-analysis of eight studies demonstrated that hypoglycemic episodes were associated with macrovascular complications, odds ratio (OR) 1.83 (95% confidence interval [CI] 1.64, 2.05), and microvascular complications in two studies OR 1.77 (95% CI 1.49, 2.10). Meta-analysis of four studies demonstrated an association between hypoglycaemia and falls or fractures, OR 1.89 (95% CI 1.54, 2.32) and 1.92 (95% CI 1.56, 2.38) respectively. Hypoglycaemia was associated with increased likelihood of death in a meta-analysis of eight studies, OR 2.04 (95% Confidence Interval 1.68, 2.47)., Conclusion: Our meta-analysis raises major concerns about a range of serious adverse events associated with hypoglycaemia. Clinicians should prioritize individualized therapy and closer monitoring strategies to avoid hypoglycaemia in susceptible older patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Purpose: Several risk scores have been developed to predict mortality in intracerebral hemorrhage (ICH). We aimed to systematically determine the performance of published prognostic tools., Methods: We searched MEDLINE and EMBASE for prognostic models (published between 2004 and April 2014) used in predicting early mortality (<6 months) after ICH. We evaluated the discrimination performance of the tools through a random-effects meta-analysis of the area under the receiver operating characteristic curve (AUC) or c-statistic. We evaluated the following components of the study validity: study design, collection of prognostic variables, treatment pathways, and missing data., Results: We identified 11 articles (involving 41,555 patients) reporting on the accuracy of 12 different tools for predicting mortality in ICH. Most studies were either retrospective or post-hoc analyses of prospectively collected data; all but one produced validation data. The Hemphill-ICH score had the largest number of validation cohorts (9 studies involving 3,819 patients) within our systematic review and showed good performance in 4 countries, with a pooled AUC of 0.80 [95% confidence interval (CI)=0.77-0.85]. We identified several modified versions of the Hemphill-ICH score, with the ICH-Grading Scale (GS) score appearing to be the most promising variant, with a pooled AUC across four studies of 0.87 (95% CI=0.84-0.90). Subgroup testing found statistically significant differences between the AUCs obtained in studies involving Hemphill-ICH and ICH-GS scores (p=0.01)., Conclusions: Our meta-analysis evaluated the performance of 12 ICH prognostic tools and found greater supporting evidence for 2 models (Hemphill-ICH and ICH-GS), with generally good performance overall.

Background: Long-term inhaled corticosteroids (ICS) may reduce growth velocity and final height of children with asthma. We aimed to evaluate the association between ICS use of >12 months and growth., Methods: We initially searched MEDLINE and EMBASE in July 2013, followed by a PubMed search updated to December 2014. We selected RCTs and controlled observational studies of ICS use in patients with asthma. We conducted random effects meta-analysis of mean differences in growth velocity (cm/year) or final height (cm) between groups. Heterogeneity was assessed using the I2 statistic., Results: We found 23 relevant studies (twenty RCTs and three observational studies) after screening 1882 hits. Meta-analysis of 16 RCTs showed that ICS use significantly reduced growth velocity at one year follow-up (mean difference -0.48 cm/year (95% CI -0.66 to -0.29)). There was evidence of a dose-response effect in three RCTs. Final adult height showed a mean reduction of -1.20 cm (95% CI -1.90 cm to -0.50 cm) with budesonide versus placebo in a high quality RCT. Meta-analysis of two lower quality observational studies revealed uncertainty in the association between ICS use and final adult height, pooled mean difference -0.85 cm (95% CI -3.35 to 1.65)., Conclusion: Use of ICS for >12 months in children with asthma has a limited impact on annual growth velocity. In ICS users, there is a slight reduction of about a centimeter in final adult height, which when interpreted in the context of average adult height in England (175 cm for men and 161 cm for women), represents a 0.7% reduction compared to non-ICS users.

Background and Purpose: The prospective link between osteoporosis and future risk of stroke requires evidence from large-scale population-based long-term studies., Methods: Calcaneum broadband ultrasound attenuation was measured in the Norfolk cohort of the European Prospective Investigation into Cancer-Norfolk between 1997 and 2000. Incident strokes were ascertained by hospital record linkage and death certificates in March 2009 and December 2011, respectively. A search of MEDLINE and EMBASE was performed to evaluate the relationship between bone mineral density and incident stroke. After data extraction of relevant studies, pooled risk of stroke was estimated using meta-analysis., Results: In 14 290 participants (mean follow-up of 9.3 years; total person-years 132 574), there were 599 incident strokes. Participants in the lowest 10% of the calcaneum broadband ultrasound attenuation distribution had an increased stroke risk (hazard ratio 1.41; 95% confidence intervals, 1.02-1.94) compared with those in the top 30% of the distribution after adjustments. A decrease of ~1 standard deviation in broadband ultrasound attenuation (20 db/MHz) was associated with a 17% increase in relative risk of stroke (95% confidence intervals, 5%-30%). Meta-analysis of 4 studies (25 760 participants, 1237 cases of stroke) found that for every decrease in 1 standard deviation in bone mineral density, there was an increased risk of incident stroke among women (pooled relative risk 1.22; 95% confidence intervals, 1.09-1.37; I2=0%, 3 studies) but not in men (pooled relative risk 1.05; 95% confidence intervals, 0.94-1.17; I(2)=0%, 2 studies)., Conclusions: Bone mineral density predicts total stroke risk. The evidence is stronger in women with regard to the continuous relationship.

Background: Pneumonia is the leading cause of infection related mortality. Multilobar pneumonia (MLP) may have poorer outcomes and is a constituent of some prognostic indices. Our aim was to systematically-review and meta-analyse the impact of multi-lobar involvement in pneumonia., Methods: We searched PubMed in June 2012 for studies reporting on the association between MLP and clinical outcomes. Potentially relevant studies were cross checked by two independent reviewers before final inclusion. Odds-ratios (OR) for the association between MLP and mortality, unfavourable outcomes, and poor treatment response were pooled using random effects meta-analysis., Results: Twenty-two studies were included in this report. There were a total of 11,456 pneumonia patients including 2897 (25.3%) patients with MLP. As there was substantial clinical and statistical heterogeneity in the overall dataset, we limited the main meta-analysis to patients with community-acquired pneumonia (CAP). This showed that MLP was associated with increased mortality, OR 2.57 (95% CI: 1.83-3.61), with no statistical heterogeneity (I(2)=0%). Evidence from other settings suggests that MLP may also be associated with higher likelihood of other poor outcomes such as worsening clinical/radiological status, delayed resolution, and need for mechanical ventilation., Conclusion: MLP appears to be an independent risk factor for mortality in CAP. It may be possible to improve commonly used prognostic indices in CAP by addition of MLP as a criterion., (Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Data from pharmacokinetic and pharmacodynamic studies indicate that the adverse clopidogrel-proton pump inhibitor (PPI) interaction may vary between PPIs, with pantoprazole considered relatively less problematic. We aimed to evaluate systematically whether individual PPIs differ in their risk for cardiovascular events when concomitantly administered with clopidogrel., Methods: We searched MEDLINE, EMBASE and Cochrane Trials Register up to December 2011 for randomized and non-randomized studies that reported adverse cardiovascular events with exposure to specific PPIs in patients receiving clopidogrel. We performed random effects meta-analysis, and assessed heterogeneity using the I(2) statistic., Results: A total of 23 studies with 222,311 participants were included. Meta-analysis of major adverse cardiovascular events was mostly limited by moderate-substantial heterogeneity. Pooled estimates of cardiovascular risk were significantly elevated for individual PPIs such as omeprazole, esomeprazole, lansoprazole, and pantoprazole when used with clopidogrel. However, meta-analysis of adverse cardiovascular risk in seven observational studies reporting on PPI therapy alone (without concomitant clopidogrel) also found an elevated odds ratio of 1.28 (95% CI 1.14-1.44) compared with no clopidogrel/no PPI exposure. Meta-analysis of two randomized controlled trials did not show significant adverse cardiovascular effect from omeprazole or esomeprazole., Conclusions: The absence of consistent evidence on differential cardiovascular risk amongst PPIs (particularly regarding safety of pantoprazole) is in direct opposition to the platelet function and pharmacokinetic data. Our findings of increased cardiovascular risk with PPIs in the absence of clopidogrel suggest that confounding and bias are strong possibilities. The clinical validity or relevance of the hypothesized PPI-clopidogrel interaction remains questionable., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Several studies have raised concern regarding the possible association between proton-pump inhibitors (PPIs) and Clostridium difficile infection (CDI). We aimed to perform a systematic review of incident and recurrent CDI in PPI users, and to evaluate the relative impact of concurrent antibiotic use, or switching acid suppression to histamine-2-receptor antagonists (H2RAs)., Methods: We searched MEDLINE and EMBASE from inception to December 2011 for controlled observational studies that reported on the risk of CDI with and without PPI use. We performed random effects meta-analysis and assessed statistical heterogeneity using the I(2) statistic., Results: We included 42 observational studies (30 case-control, 12 cohort) totalling 313,000 participants overall. Pooled analysis of 39 studies showed a statistically significant association between PPI use and risk of developing CDI, odds ratio (OR) 1.74 (95% confidence interval (CI) 1.47-2.85, P<0.001, I(2)=85%) compared with non-users. A pooled analysis of three studies showed a significant associated risk of recurrent CDI associated with PPIs, OR 2.51 (95% CI 1.16-5.44, P=0.005, I(2)=78%). Subgroup analysis failed to fully clarify the source of the substantial statistical heterogeneity. Adjusted indirect comparison demonstrated that use of H2RAs as an alternative carried a lower-risk OR 0.71 (95% CI 0.53-0.97) compared with PPIs. Conversely, concomitant use of PPI and antibiotics conferred a greater-risk OR 1.96 (95% CI 1.03-3.70) above that of PPIs alone. For PPI and antibiotics, the Rothman's synergy index was 1.36 and attributable proportion of risk from interaction 0.19, indicating an increased risk from interaction beyond the effects of each drug alone., Conclusions: Despite the substantial statistical and clinical heterogeneity, our findings indicate a probable association between PPI use and incident and recurrent CDI. This risk is further increased by concomitant use of antibiotics and PPI, whereas H2RAs may be less harmful.

Purpose: Statins have potential anti-inflammatory effects, but the association between statin use and lower incidence of pneumonia is unclear. We have therefore performed a systematic review on the risk of pneumonia in statin users versus non-users., Methods: MEDLINE and EMBASE were searched in December 2010 for controlled observational studies that reported on the risk of pneumonia in statin users. We performed a random effects meta-analysis and assessed heterogeneity using the I² statistic., Results: A total of 451 citations were screened, and ultimately nine studies (4 case-control, 4 retrospective cohort, 1 prospective cohort) with more than 3 million participants were included in the meta-analysis. Pooled analysis of seven studies that reported unadjusted data failed to show a significantly reduced risk of pneumonia [odds ratio (OR) 0.94, 95% confidence interval (CI) 0.84-1.06, p = 0.33, I² = 79%] in statin users as compared to non-users. However, a significant reduction in the likelihood of pneumonia associated with statin use (n = 8 studies, OR 0.85, 95% CI 0.75-0.97, p = 0.02, I² = 81%) was found in the meta-analysis of adjusted data. Both analyses were limited by substantial statistical heterogeneity. Sensitivity analysis failed to fully clarify the source of heterogeneity, but cohort studies seemed to be less heterogenous (n = 5 studies, OR 0.92, 95% CI 0.84-1.01, I² = 43%)., Conclusion: Our findings indicate that the purported benefit of statins in preventing pneumonia is inconsistent, and of low magnitude, with upper bounds of the confidence interval being close to null. In view of the substantial statistical and clinical heterogeneity in the dataset, there is no convincing evidence to support the therapeutic application of statins for reducing the risk of pneumonia.

Objectives: Many primary studies have considered the association of polymorphisms of folate metabolism and response to 5-fluorouracil (5-FU) and capecitabine in patients with colorectal cancer. The conclusions from these studies have been conflicting and few have considered large cohorts of patients. Therefore, we have completed a systematic review and meta-analyses to summarize some of the findings to date. We conducted searches for any studies that had addressed the prognostic value of genotype analysis of thymidylate synthetase (TYMS), Methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR)., Methods: We collected data on the study designs, and completed meta-analyses to pool congruent data about treatment effect. A narrative summary is presented for 39 studies that describe three TYMS genotypes and two MTHFR genotypes associated with response to 5-FU-based chemotherapy., Results: Data were synthesized from up to 2402 patients for the most commonly studied markers TYMS 5' UTR repeat polymorphism (rs45445694) and MTHFR 677 C>T (rs1801133). We found that the TYMS genotype associated with the lowest protein expression (2R/2R) was significantly associated with improved clinical benefit; the pooled risk ratio was relative risk=1.36 [1.11, 1.65]; P=0.003. Moreover, the same trend was observed for adverse effects; the pooled risk ratio was 2.04 [1.42, 2.95]; P=0.0001., Conclusion: There is a small but statistically significant association between treatment effect (both intended effects and adverse events) and a TYMS genotype associated with low protein expression; however, the effect size is small and therefore indicates limited clinical utility.

Introduction: There is considerable debate surrounding the clinical relevance of an adverse interaction between clopidogrel and proton pump inhibitors (PPIs). Some studies have indicated that PPIs may attenuate the antiplatelet efficacy of clopidogrel, thus leading to increased risk of thrombotic cardiovascular events., Areas Covered: From a literature search of MEDLINE and EMBASE, the authors critically appraised data from systematic reviews, randomised controlled trials and observational studies that evaluated platelet function and clinical outcomes in patients receiving concomitant clopidogrel and PPIs., Expert Opinion: The evidence from platelet function and cardiovascular outcome studies is highly inconsistent. Higher quality data from randomised trials indicate that use of PPI therapy for up to 6 months is unlikely to cause any adverse interaction with clopidogrel, and there are gastrointestinal benefits with PPI use.

Background: There is considerable debate regarding the negative impact of concomitant proton pump inhibitor (PPI) therapy on the antiplatelet efficacy of clopidogrel., Aim: The aim of this study was to perform a systematic review of studies that have evaluated the platelet function of patients receiving clopidogrel alone compared with those receiving both clopidogrel and PPIs., Methods: We searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register in February 2011 for randomized and non-randomized studies that reported platelet function results in patients taking clopidogrel, with or without PPIs., Results: Our review included 19 studies (13 trials and 6 observational studies) involving 4693 patients. There was considerable heterogeneity in the study designs, patient characteristics, laboratory tests of platelet function, and drug exposure (dose and duration of PPI and clopidogrel). There was some evidence against omeprazole, with five of nine studies demonstrating a significant interaction with clopidogrel. The available platelet function data on esomeprazole (six studies) or pantoprazole (six studies) did not demonstrate a significant interaction. Of the six studies that statistically analysed platelet function data with omeprazole compared with pantoprazole, three showed a significantly greater interaction between omeprazole and clopidogrel, whereas three studies with limited sample sizes were unable to find a significant difference in the effects of omeprazole and pantoprazole., Conclusion: Platelet function studies do not demonstrate a clear or consistent interaction between clopidogrel and PPIs. These studies are difficult to interpret given the lack of information on drug exposure (dose and duration), variation in laboratory methodology and lack of genetic information. Consequently, platelet function data are of uncertain clinical relevance in determining the risk of an adverse cardiovascular interaction between PPIs and clopidogrel. Clinicians should continue to clinically assess the gastrointestinal risk of the patients and make their prescribing decision for PPIs based on any anticipated benefits in reducing risk of peptic ulcers and gastrointestinal haemorrhage.

Aims: Recent studies have suggested an increased risk of fractures with proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs). We planned to perform a meta-analysis of fractures in patients taking PPIs and H2RAs., Methods: We searched MEDLINE and EMBASE in September 2010 for observational studies reporting on the risk of fractures with acid-suppressing medication (PPIs and H2RA). We also checked the references lists of included studies and regulatory authority websites for additional data. We performed random effects meta-analysis of odds ratios (OR) according to fracture type and conducted subgroup analyses by duration of exposure. Heterogeneity was assessed using the I(2) statistic., Results: Our review included 12 studies covering 1,521,062 patients. Pooled analysis of PPI use showed significant risk for spine fractures (4 studies, OR 1.50, 95% CI 1.32-1.72, p<0.001, I(2)=0%) but this was not significant for H2RA (3 studies, OR 1.05, 95% CI 0.92-1.19, p=0.50, I(2)=0%). Similarly for hip fractures, there was a significant risk of fractures with PPIs (10 studies, OR 1.23, 95% CI 1.11-1.36, p<0.001, I(2)=72%), but not for H2RAs (9 studies, OR 1.12, 95% CI 0.99-1.27, p=0.06, I(2)=75%), respectively). Analysis of fractures overall (based on all 12 studies covering a mixture of fracture types) yielded an OR of 1.20 (95% CI 1.11-1.30, p<0.001, I(2)=78%) for PPIs, and OR of 1.08 (95% CI 1.00-1.18, p=0.06, I(2)=82%) for H2RA. However, aside from the risk of spine fractures, all the other analyses were limited by substantial heterogeneity. One study that reported on a direct comparison between acid-suppressing medications found an increased risk with PPIs vs. H2RA for hip fractures, OR 1.34 (95% CI 1.14-1.38)., Conclusion: There is some evidence for a modest association between PPI use and risk of fractures, which was not seen with H2RA exposure. The association is most consistent for spine fractures, while there is substantial heterogeneity in the magnitude of risk for other fractures. Clinicians who are concerned about patients with high fracture risk may wish to consider the option of H2RAs instead of PPIs., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: To determine the comparative effects of the thiazolidinediones (rosiglitazone and pioglitazone) on myocardial infarction, congestive heart failure, and mortality in patients with type 2 diabetes., Design: Systematic review and meta-analysis of observational studies., Data Sources: Searches of Medline and Embase in September 2010., Study Selection: Observational studies that directly compared the risk of cardiovascular outcomes for rosiglitazone and pioglitazone among patients with type 2 diabetes mellitus were included., Data Extraction: Random effects meta-analysis (inverse variance method) was used to calculate the odds ratios for cardiovascular outcomes with thiazolidinedione use. The I(2 )statistic was used to assess statistical heterogeneity., Results: Cardiovascular outcomes from 16 observational studies (4 case-control studies and 12 retrospective cohort studies), including 810,000 thiazolidinedione users, were evaluated after a detailed review of 189 citations. Compared with pioglitazone, use of rosiglitazone was associated with a statistically significant increase in the odds of myocardial infarction (n = 15 studies; odds ratio 1.16, 95% confidence interval 1.07 to 1.24; P < 0.001; I(2) = 46%), congestive heart failure (n = 8; 1.22, 1.14 to 1.31; P < 0.001; I(2) = 37%), and death (n = 8; 1.14, 1.09 to 1.20; P < 0.001; I(2) = 0%). Numbers needed to treat to harm (NNH), depending on the population at risk, suggest 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100,000 patients who receive rosiglitazone rather than pioglitazone., Conclusion: Among patients with type 2 diabetes, use of rosiglitazone is associated with significantly higher odds of congestive heart failure, myocardial infarction, and death relative to pioglitazone in real world settings.

Background: There has been recent concern regarding a possible adverse interaction between clopidogrel and proton pump inhibitors (PPIs), coupled with uncertainty as to whether PPIs genuinely help in reducing gastrointestinal (GI) harm., Objective: To perform a meta-analysis of GI outcomes in patients taking clopidogrel, with and without concomitant PPI., Methods: We searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register from inception to March 2010, and checked conference abstracts for randomized and non-randomized studies that reported on adverse GI events (haemorrhage, ulcer, perforation or obstruction) with PPI exposure in patients taking clopidogrel. Relevant studies were subcategorized according to the degree of aspirin (acetylsalicylic acid) co-administration and nature of GI events, where available. We performed random effects meta-analysis for risk of adverse GI events with PPI exposure in clopidogrel-treated patients, and assessed heterogeneity using the I2 statistic., Results: Our review evaluated 71,277 participants in nine retrospective studies and one randomized trial. Exposure to PPI for patients receiving dual antiplatelet therapy (aspirin and clopidogrel in seven studies) was associated with a significant reduction in adverse GI events, odds ratio (OR) 0.38 (95% CI 0.21, 0.68; p=0.001; I2=17%). There was significant heterogeneity in the analysis of patients receiving clopidogrel monotherapy (two studies), and no definite benefit was found. Restricting the analysis to studies specifically reporting upper GI bleeds with any clopidogrel exposure yielded an OR of 0.31 (95% CI 0.19, 0.51; p<0.001; I2=27%) with associated PPI exposure., Conclusions: Use of PPIs is associated with a reduction in adverse GI events (particularly haemorrhages) in patients who are receiving dual antiplatelet therapy. Clinicians should carefully weigh up the evidence for potential GI benefits against the uncertainties surrounding any possible adverse cardiovascular impact of concomitant clopidogrel PPI therapy.

Background: Bisphosphonates are widely used in osteoporosis, but there have been concerns about a potential link between bisphosphonate therapy and atrial fibrillation., Objective: We aimed to systematically evaluate the risk of atrial fibrillation associated with bisphosphonate use., Methods: We searched MEDLINE, regulatory authority websites, pharmaceutical company trial registers and product information sheets for randomized controlled trials (RCTs) and controlled observational studies published in English through to May 2008. We selected RCTs of bisphosphonates versus placebo for osteoporosis or fractures, with at least 3 months of follow-up, and data on atrial fibrillation. For the observational studies, we included case-control or cohort studies that evaluated the risk of atrial fibrillation in patients exposed to bisphosphonates compared with non-exposure. Data on atrial fibrillation as the primary outcome, and stroke and cardiovascular mortality as secondary outcomes, were extracted. DATA SYNTHESIS/RESULTS: We calculated pooled odds ratio (OR) using random effects meta-analysis, and estimated statistical heterogeneity with the I2 statistic. Bisphosphonate exposure was significantly associated with risk of atrial fibrillation serious adverse events in a meta-analysis of four trial datasets (OR 1.47; 95% CI 1.01, 2.14; p = 0.04; I2 = 46%). However, meta-analysis of all atrial fibrillation events (serious and non-serious) from the same datasets yielded a pooled OR of 1.14 (95% CI 0.96, 1.36; p = 0.15; I2 = 0%). We identified two case-control studies, one of which found an association between bisphosphonate exposure (ever users) and atrial fibrillation (adjusted OR 1.86; 95% CI 1.09, 3.15) while the other showed no association (adjusted OR 0.99; 95% CI 0.90, 1.10). Both studies failed to demonstrate a significant association in 'current' users. We did not find a significant increase in the risk of stroke (three trial datasets; OR 1.00; 95% CI 0.82, 1.22; p = 0.99; I2 = 0%) or cardiovascular mortality (three trial datasets; OR 0.86; 95% CI 0.66, 1.13; p = 0.28; I2 = 31%)., Conclusion: While there are some data linking bisphosphonates to serious atrial fibrillation, heterogeneity of the existing evidence, as well as paucity of information on some of the agents, precludes any definitive conclusions on the exact nature of the risk.

Objective: To determine whether anecdotal reports of suspected adverse drug reactions are valuable early warning signals., Design: Systematic literature survey, Data Sources: We evaluated all case reports of adverse drug reactions published in 1997 in five medical journals. Reports were excluded if the adverse reaction had previously been described in earlier publications and was already listed in the product information of the drug reference source (the British National Formulary (BNF) or the Medicines Compendium). We used the Web of Knowledge Citation Index and Medline for 2003 to identify follow-up studies., Main Outcome Measures: Primary: the number of suspected adverse reactions subjected to formal validation studies and the findings of these studies. Secondary: the number of instances in which the warning from the case report was incorporated into the product information., Results: We evaluated 63 suspected adverse reactions and found that most (52/63, 83%) had not yet been subjected to further detailed evaluation. Data from controlled studies that supported the postulated link between the drug and the adverse event were available in only three cases. Of the 48 agents listed in the drug reference sources, details of the suspected reaction were subsequently added to the Medicines Compendium in 15 instances, and to the BNF in seven instances. In each case, only one reaction had been confirmed., Conclusions: Published case reports of suspected adverse reactions are of limited value as suspicions are seldom subjected to confirmatory investigation. Furthermore, these alerts are not incorporated into drug reference sources in a systematic manner.

Aims: To estimate the absolute reduction in the risk of cardiovascular events and absolute increase in gastrointestinal haemorrhage associated with aspirin for individuals with different baseline risks., Methods: Calculation of absolute treatment effects from estimates of: (i) baseline risks for cardiovascular event and gastrointestinal haemorrhage; and (ii) relative risks of these events with treatment. Baseline cardiovascular risks were derived from existing risk scores, and baseline risk of gastrointestinal haemorrhage from an observational cohort study. Changes in relative risks were obtained from clinical trial data. The effects of aspirin treatment were calculated in examples of two individuals with very different baseline risks., Results: Treatment of a healthy 74-year-old man (blood pressure 144/88 mm Hg and no history of gastrointestinal disorder) would reduce his annual risk of a cardiovascular event from 2% to 1.74% (absolute risk reduction 0.26%, number needed to treat 385), but increase the gastrointestinal haemorrhage risk from 0.3% to 0.51% (absolute risk increase 0.21%, number needed to harm 476). In a 66-year-old obese man, following a transient ischaemic attack, and with a history of hospital treatment for a peptic ulcer, the annual risk of a cardiovascular event would be reduced from 5% to 4.35% (absolute risk reduction 0.65%, number needed to treat 153), but the risk of gastrointestinal haemorrhage would increase from 1.08% to 1.83% (absolute risk increase 0.75%, number needed to harm 133)., Conclusions: Estimating benefit and harm by taking into account the baseline risks in each individual allows patients and doctors to judge for themselves the magnitude of the trade-offs involved in taking aspirin.