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Background: Stopping trials early because of a favourable interim analysis can exaggerate benefit. This study simulated trials typical of those stopping early for benefit in the real world and estimated the degree to which early stopping likely overestimates benefit.Methods: From 1 million simulated trials, we selected those trials that exceeded interim stopping criteria, and compared apparent benefit when stopped with the true benefit used to generate the data. Each simulation randomly assigned period of observation, number of subjects, and control event rate using normal distributions centred on the same parameters in a template trial typical of real-world "truncated" (i.e. stopped for benefit) trials. The intervention's true relative risk reduction (RRR) was also randomized, and assumed 1% of drugs have a warfarin-like effect (60% RRR), 5% a statin-like effect (35% RRR), 39% an ASA-like effect (15% RRR), 50% no effect (0% RRR), and that 5% would cause harm (modelled as a 20% relative risk increase). Trials had a single interim analysis and a z-value for stopping of 2.782 (O'Brien-Fleming threshold). We also modelled (1) a large truncated trial based on the SPRINT blood pressure trial (using SPRINT's parameters and stopping criteria) and (2) the same typical truncated trials if they instead went to completion as planned with no interim analysis.Results: For typical truncated trials, the true RRR was roughly 2/3 the observed RRR at the time of stopping. RRR was overestimated by an absolute 14.9% (median, IQR 6.4-24.6) in typical truncated trials, by 5.3% (IQR -0.1 to 11.4) in the same trials if instead carried to completion, and by 2.3% (IQR 0.98-1.09) in large SPRINT-like trials. For all models, to keep the absolute RRR overestimate below 5%, 250 events were required.Conclusion: Simulated trials typical of those stopping early for benefit overestimate the true relative risk reduction by roughly 50% (i.e. the true RRR was 2/3 of the observed value). Overestimation was much smaller, and likely unimportant, when simulating large SPRINT-like trials stopping early. Whether trials were large or small, stopped early or not, a minimum 250 events were needed to avoid overestimating relative risk reduction by an absolute 5% or more. [ABSTRACT FROM AUTHOR]

Purpose: Without supporting evidence, clinicians commonly recommend that warfarin be taken in the evening. We conducted a randomized controlled trial to evaluate the effect of administration time (morning vs evening) on the stability of warfarin's anticoagulant effect.Methods: A total of 236 primary care physicians serving 54 western Canadian communities mailed letters of invitation to all their warfarin-using patients. Eligible patients were community-dwelling warfarin users (any indication) with at least 3 months of evening warfarin use and no plans for discontinuation. Participants were randomized (by web-based allocation) to morning vs continued evening warfarin ingestion. We used the Rosendaal method to determine the proportion of time within therapeutic range (TTR) of the international normalized ratio (INR) blood test month 2 to 7 postrandomization vs the 6 months prerandomization. The primary outcome was the percent change in proportion of time outside target INR range (with an a priori minimum clinically important difference of ±20%). All analyses were intention to treat.Results: Between March 8, 2015 and September 30, 2016, we randomized 109 participants to morning and 108 to evening warfarin use. TTR rose from 71.8% to 74.7% in the morning group, and from 72.6% to 75.6% in the evening group, for a change in TTR of 2.9% in the former vs 3.0% in the latter (difference, -0.1%; P = .97; 95% CI for the difference, -6.1% to 5.9%). The difference in percent change in proportion of time outside the therapeutic INR range (obtained via Hodges-Lehmann estimation of the difference in medians) was 4.4% (P = .62; 95% CI for the difference, -17.6% to 27.3%).Conclusions: Administration time has no statistically significant nor clinically important impact on the stability of warfarin's anticoagulant effect. Patients should take warfarin whenever regular compliance would be easiest. [ABSTRACT FROM AUTHOR]

Background: It has been anecdotally reported that nocturnal leg cramps in pregnant women are worse in summer. We analyzed population-level data to determine whether the symptom burden of nocturnal leg cramps is seasonal in the general population. Methods: We examined time-series data for 2 independent measures of the symptom burden of leg cramps: (a) new quinine prescriptions (reflecting new or escalating treatment of leg cramps) from December 2001 to October 2007 among adults aged 50 years and older, which were obtained from linked health care databases that contain the prescribing information for the 4.2 million residents of British Columbia, Canada; and (b) the Internet search volume from February 2004 to March 2012 for the term "leg cramps" (reflecting public interest), which we obtained from Google Trends data and geographically limited to the United States and Australia. We assessed seasonality by determining how well a least-squares sinusoidal model predicted variability in the outcomes. Results: New quinine prescriptions and Internet searches related to leg cramps were both seasonal, with highs in mid-summer and lows in mid-winter, and a peak-to-peak variability that was about two-thirds of the mean. Seasonality accounted for 88% of the observed monthly variability in new quinine prescriptions (p < 0.001) and 70% of the observed variability in Internet searches related to leg cramps (p < 0.001). Interpretation: New quinine prescriptions and Internet searches related to leg cramps were seasonal and roughly doubled between the winter lows and summer highs. Why a disorder of peripheral motor neurons displays such strong seasonality warrants exploration. [ABSTRACT FROM AUTHOR]

The article discusses a study to determine whether treatment for muscle cramps increased after the introduction of the three common prescribed medication drug classes. It cites the use of sequence symmetry analysis to assess individuals prescribed with both quinine and 1 of 3 index drug classes. It suggests for physicians to be aware of the epidemiological association between cramp treatment and the use of inhaled long-acting B-2 (LABAS), potassium-sparing diuretics and thiazidelike diuretics.

Background. Rest cramps (also known as nocturnal leg cramps) are very common in a geriatric population. Oral magnesium supplements are marketed for prophylaxis of such cramps but clinical trials exploring the efficacy of oral magnesium conflict. A therapeutic trial of intravenous magnesium overcomes the limited oral bioavailability of magnesium and better assesses its therapeutic potential. Methods. A double blind, placebo controlled randomized controlled trial was conducted on 46 community-dwelling older adult (69.3 ± 7.7 years) rest cramp sufferers to determine whether 5 consecutive days infusion of 20-mmol (5 g) magnesium sulfate would reduce the frequency of leg cramps per week in the 30 days immediately pre and post infusions. It was also determined whether the response to treatment varied with the extent to which infused magnesium was retained (as measured by 24-hour urinary magnesium excretion). Results. The study population averaged 8.0 cramps per week at baseline. The mean change in number of cramps per week, magnesium versus placebo arms, was −2.4 versus −1.7, p = .51, 95% confidence interval of the difference −3.1 to 1.7. Magnesium retention did not correlate with treatment response. Conclusions. Intravenous magnesium infusion did not reduce the frequency of leg cramps in a group of older adult rest cramp sufferers regardless of the extent to which infused magnesium was retained. Although oral magnesium is widely marketed to older adults for the prophylaxis of leg cramps, our data suggest that magnesium therapy is not indicated for the treatment of rest cramps in a geriatric population. [ABSTRACT FROM PUBLISHER]

Lipopolysaccharides (LPS) from Bacteroides species are less potent than enterobacterial LPS preparations when compared by pyrogenicity and bone resorption assays and by the localized Schwartzman reaction. In this investigation, LPS preparations from Bacteroides intermedius and Bacteroides gingivalis were examined for their capacity to stimulate PGE2 release from human monocytes relative to identical doses of Salmonella typhimurium LPS. In addition, the capacity of recombinant gamma interferon (IFN-γ) to potentiate PGE2 release was examined with each LPS preparation. Monocytes, separated by counterflow centrifugation, were exposed to LPS (1 ng/ml, 100 ng/ml and 10 ng/ml) alone or in combination with IFN-γ (10 Units/ml). PGE2 levels (measured by RIA) were determined in monocyte culture supernatants exposed during the following incubation periods: 0-8, 8-24, 24-48, and 48-72 h. Monocytes treated with Salmonella LPS released 2 to 3-fold greater amounts of PGE2 than cells treated with Bacteroides species LPS preparations. Although IFN-γ alone did not stimulate PGE2 release, Bacteroides-elicited PGE2 release was siginificantly increased when monocytes were cultured concomitantly with IFN-γ. PGE2 release elicited by Salmonella LPS was not significantly affected by interferon. These findings indicate that IFN-γ can markedly potentiate the release of PGE2 from monocytes stimulated with Bacteroides LPS. Furthermore, the observed weakness of these LPS preparations relative to Salmonella LPS can be largely overcome by co-treating monocytes with IFN-γ. [ABSTRACT FROM AUTHOR]

Background: Although statins are often discontinued when myalgia arises, a causal relationship may not always exist. How well-tolerated statins are when rechallenge is blinded and controlled is unclear. Methods and findings: We performed a systematic review and meta-analysis (PROSPERO CRD42023437648) to evaluate the success of statin rechallenge versus matched placebo in those who were previously statin intolerant. Our primary outcome was intolerance; our secondary outcome was the myalgia or global symptom score. Medline, Embase, CINAHL Plus, Scopus, and CENTRAL were searched from inception to May 1, 2023. Eligible trials were randomized controlled trials with parallel or crossover designs examining statin rechallenge in statin-intolerant adults. Two independent reviewers selected studies, extracted data, and assessed risk of bias (Cochrane Collaboration's risk-of-bias tool 1). Relative risk (RR) and mean difference (MD) were estimated using fixed effect Mantel-Haenszel statistics. Of 1,941 studies screened, 8 met our inclusion criteria (8 to 491 participants from Asia, Europe, North America, and Oceana). Compared to placebo, intolerance was more common in statin users [325/906 (36%) vs 233/911 (26%), RR 1.40, 95% CI, 1.23 to 1.60, I2 = 0%, 7 trials, number needed to harm 10] and there was no statistically significant difference in myalgia or global symptom score on a 100-point scale [MD 1.08, 95% CI, -1.51 to 3.67, I2 = 0%, 5 trials]. Limitations include only 1 trial asking participants about intolerable symptoms (vs inferring intolerance from discontinuation or trial withdrawal); the small number of trials; the possibility of attrition bias; and the potential for carryover effects in crossover/n-of-1 trial designs. Conclusions: Of those previously intolerant of statins who were rechallenged with a statin and compared to placebo recipients, medication intolerance was more common amongst statin recipients. However, there was no significant difference in mean myalgia or global symptom score between statin and placebo, and only one-third of those previously believed to be statin intolerant were unable to tolerate a statin on blinded rechallenge; one-quarter were intolerant of placebo. [ABSTRACT FROM AUTHOR]

Background: Polypharmacy is associated with poorer health outcomes in older adults. Other than the associated multimorbidity, factors contributing to this association could include medication adverse effects and interactions, difficulties in managing complicated medication regimes, and reduced medication adherence. It is unknown how reversible these negative associations may be if polypharmacy is reduced. The purpose of this study was to determine the feasibility of implementing an operationalized clinical pathway aimed to reduce polypharmacy in primary care and to pilot measurement tools suitable for assessing change in health outcomes in a larger randomized controlled trial (RCT). Methods: We randomized consenting patients ≥ 70 years old on ≥ 5 long-term medications into intervention or control groups. We collected baseline demographic information and research outcome measures at baseline and 6 months. We assessed four categories of feasibility outcomes: process, resource, management, and scientific. The intervention group received TAPER (team approach to polypharmacy evaluation and reduction), a clinical pathway for reducing polypharmacy using "pause and monitor" drug holiday approach. TAPER integrates patients' goals, priorities, and preferences with an evidence-based "machine screen" to identify potentially problematic medications and support a tapering and monitoring process, all supported by a web-based system, TaperMD. Patients met with a clinical pharmacist and then with their family physician to finalize a plan for optimization of medications using TaperMD. The control group received usual care and were offered TAPER after follow-up at 6 months. Results: All 9 criteria for feasibility were met across the 4 feasibility outcome domains. Of 85 patients screened for eligibility, 39 eligible patients were recruited and randomized; two were excluded post hoc for not meeting the age requirement. Withdrawals (2) and losses to follow-up (3) were small and evenly distributed between arms. Areas for intervention and research process improvement were identified. In general, outcome measures performed well and appeared suitable for assessing change in a larger RCT. Conclusions: Results from this feasibility study indicate that TAPER as a clinical pathway is feasible to implement in a primary care team setting and in an RCT research framework. Outcome trends suggest effectiveness. A large-scale RCT will be conducted to investigate the effectiveness of TAPER on reducing polypharmacy and improving health outcomes. Trial registration: clinicaltrials.gov NCT02562352, Registered September 29, 2015. [ABSTRACT FROM AUTHOR]

The objective of this study is to determine whether human body odors undergo seasonal modulation. We utilized google trends search volume from the United States of America from January 1, 2010 to June 24, 2017 for a number of predetermined body odors. Regression modeling of time series data was completed. Our primary outcome was to determine the proportion of the variability in Internet searches for each unpleasant odor (about the mean) that is explained by a seasonal model. We determined that the seasonal (sinusoidal) model provided a significantly better fit than the null model (best straight line fit) for all searches relating to human body odors (P <.0001 for each). This effect was easily visible to the naked eye in the raw time series data. Seasonality explained 88% of the variability in search volume for flatulence (i.e. R2 = 0.88), 65% of the variability in search volume for axillary odor, 60% of the variability in search volume for foot odor, and 58% of the variability in search volume for bad breath. Flatulence and bad breath tended to peak in January, foot odor in February, and Axillary odor in July. We conclude that searching by the general public for information on unpleasant body odors undergoes substantial seasonal variation, with the timing of peaks and troughs varying with the body part involved. The symptom burden of such smells may have a similar seasonal variation, as might the composition of the commensal bacterial microflora that play a role in creating them [ABSTRACT FROM AUTHOR]

Aims: This study aims to understand factors contributing to nonpublication and publication bias in clinical trials in Canada. Methods: Qualitative interviews were conducted between March 2019 and April 2021 with 34 participants from the Canadian provinces of Alberta, British Columbia and Ontario, including 17 clinical trial investigators, 1 clinical research coordinator, 3 research administrators, 3 research ethics board members and 10 clinical trial participants. We conducted a thematic analysis involving coding of interview transcripts and memo‐writing to identify key themes. Results: Several factors contribute to nonpublication and publication bias in clinical trial research. A core theme was that reporting practices are shaped by incentives within the research system taht favour publication of positive over negative trials. Investigators are discouraged from reporting by experiences or perceptions of difficulty in publishing negative findings but rewarded for publishing positive findings in various ways. Trial investigators more strongly associated positive clinical trials than negative trials with opportunities for industry and nonindustry funding and with academic promotion, bonuses and recognition. Research institutions and ethics boards tended to lack well‐resourced, proactive policies and practices to ensure trial findings are reported in registries or journals. Conclusion: Clinical trial reporting practices in Canada are shaped by incentives favouring reporting of positive over negative trials, such as funding opportunities and academic promotion, bonuses and recognition. Research institutions could help change incentives by adopting performance metrics that emphasize full reporting of results in journals or registries. [ABSTRACT FROM AUTHOR]

A response by Scott R. Garrison to a letter to the editor about his article "Nocturnal Leg Cramps and Prescription Use That Precedes Them: A Sequence Symmetry Analysis," in the 2012, Volume 172, Number 2 issue is presented.

The purpose of this study was to examine the content of physical activity inputs in Canadian family physician electronic medical records. Of 1 225 948 patients aged 18–64 years, a sample of 1535 patients' charts were reviewed. A minority (n = 148; 9.6%) of patients had at least 1 mention of physical activity at any time. Insufficient information existed to determine physical activity domain (21.6%), purpose (50.0%), or meeting of guidelines (98.1%). Novelty: This study examines the physical activity content of what Canadian family physicians document in their electronic medical records. [ABSTRACT FROM AUTHOR]

Background: Polypharmacy in older adults can be associated with negative outcomes including falls, impaired cognition, reduced quality of life, and general and functional decline. It is not clear to what extent these are reversible if the number of medications is reduced. Primary care does not have a systematic approach for reducing inappropriate polypharmacy, and there are few, if any, approaches that account for the patient's priorities and preferences. The primary objective of this study is to test the effect of TAPER (Team Approach to Polypharmacy Evaluation and Reduction), a structured operationalized clinical pathway focused on reducing inappropriate polypharmacy. TAPER integrates evidence tools for identifying potentially inappropriate medications, tapering, and monitoring guidance and explicit elicitation of patient priorities and preferences. We aim to determine the effect of TAPER on the number of medications (primary outcome) and health-related outcomes associated with polypharmacy in older adults.Methods: We designed a multi-center randomized controlled trial, with the lead implementation site in Hamilton, Ontario. Older adults aged 70 years or older who are on five or more medications will be eligible to participate. A total of 360 participants will be recruited. Participants will be assigned to either the control or intervention arm. The intervention involves a comprehensive multidisciplinary medication review by pharmacists and physicians in partnership with patients. This review will be focused on reducing medication burden, with the assumption that this will reduce the risks and harms of polypharmacy. The control group is a wait list, and control patients will be given appointments for the TAPER intervention at a date after the final outcome assessment. All patients will be followed up and outcomes measured in both groups at baseline and 6 months.Discussion: Our trial is unique in its design in that it aims to introduce an operationalized structured clinical pathway aimed to reduce polypharmacy in a primary care setting while at the same time recording patient's goals and priorities for treatment.Trial Registration: Clinical Trials.gov NCT02942927. First registered on October 24, 2016. [ABSTRACT FROM AUTHOR]

Cluster randomized trial design, where groups of participants are randomized instead of individual participants, is increasingly being used in long-term care research. The purpose of this review was to determine the characteristics of cluster randomized trials in long-term care facilities. A medical librarian conducted the literature search. Two independent reviewers reviewed each paper. Studies were included if the design was cluster randomized and participants were from long-term care facilities. For each included study, two independent data extractors captured data on study attributes, including: journal, location, year published, author discipline, funding, methodology, number of participants, and intervention target. The literature search yielded 7,679 unique studies, with 195 studies meeting the selection criteria and being included for data extraction. The included studies were published between 1976 and 2017, with 53% of studies published after 2009. The term cluster randomized was in the title of only 45% of the studies. The studies were conducted worldwide; the United States had the largest number of studies (23%), followed by the United Kingdom (18%). Ten percent of studies were published in journals with an impact factor >10. The most frequent discipline of the first and last authors was medicine (34%), followed by nursing (17%). Forty-nine percent of the studies had government funding, while only 20% had medical industry funding. In studies with <1000 residents, 85% of the studies obtained consent from the resident and/or their proxy, while in studies with ≥ 1000 residents, it was 31%. The most frequent intervention targets were infection (13%), falls/fracture (13%), and behavior/physical restraint (13%). Cluster randomized controlled trials in long-term care have a unique set of characteristics. Results of this review will provide guidance to researchers conducting studies in long-term care facilities. [ABSTRACT FROM AUTHOR]

Background: In 2007, the province of British Columbia implemented incentive payments to primary care physicians for the provision of comprehensive, continuous, guideline-informed care for patients with 2 or more chronic conditions. We examined the impact of this program on primary care access and continuity, rates of hospital admission and costs. Methods: We analyzed all BC patients who qualified for the incentive based on their diagnostic profile. We tracked primary care contacts and continuity, hospital admissions (total, via the emergency department and for targeted conditions), and cost of physician services, hospital care and pharmaceuticals, for 24 months before and 24 months after the intervention. Results: Of 155 754 eligible patients, 63.7% had at least 1 incentive payment billed. Incentive payments had no impact on primary care contacts (change in contacts per patient per month: 0.016, 95% confidence interval [CI] −0.047 to 0.078) or continuity of care (mean monthly change: 0.012, 95% CI −0.001 to 0.024) and were associated with increased total rates of hospital admission (change in hospital admissions per 1000 patients per month: 1.46, 95% CI 0.04 to 2.89), relative to preintervention trends. Annual costs per patient did not decline (mean change: $455.81, 95% CI −$2.44 to $914.08). Interpretation: British Columbia's $240-million investment in this program improved compensation for physicians doing the important work of caring for complex patients, but did not appear to improve primary care access or continuity, or constrain resource use elsewhere in the health care system. Policymakers should consider other strategies to improve care for this patient population. [ABSTRACT FROM AUTHOR]

Background: While journals and reporting guidelines recommend the presentation of confidence intervals, many authors adhere strictly to statistically significant testing. Our objective was to determine what proportions of not statistically significant (NSS) cardiovascular trials include potentially clinically meaningful effects in primary outcomes and if these are associated with authors' conclusions.Methods: Cardiovascular studies published in six high-impact journals between 1 January 2010 and 31 December 2014 were identified via PubMed. Two independent reviewers selected trials with major adverse cardiovascular events (stroke, myocardial infarction, or cardiovascular death) as primary outcomes and extracted data on trial characteristics, quality, and primary outcome. Potentially clinically meaningful effects were defined broadly as a relative risk point estimate ≤0.94 (based on the effects of ezetimibe) and/or a lower confidence interval ≤0.75 (based on the effects of statins).Results: We identified 127 randomized trial comparisons from 3200 articles. The primary outcomes were statistically significant (SS) favoring treatment in 21% (27/127), NSS in 72% (92/127), and SS favoring control in 6% (8/127). In 61% of NSS trials (56/92), the point estimate and/or lower confidence interval included potentially meaningful effects. Both point estimate and confidence interval included potentially meaningful effects in 67% of trials (12/18) in which authors' concluded that treatment was superior, in 28% (16/58) with a neutral conclusion, and in 6% (1/16) in which authors' concluded that control was superior. In a sensitivity analysis, 26% of NSS trials would include potential meaningful effects with relative risk thresholds of point estimate ≤0.85 and/or a lower confidence interval ≤0.65.Conclusions: Point estimates and/or confidence intervals included potentially clinically meaningful effects in up to 61% of NSS cardiovascular trials. Authors' conclusions often reflect potentially meaningful results of NSS cardiovascular trials. Given the frequency of potentially clinical meaningful effects in NSS trials, authors should be encouraged to continue to look beyond significance testing to a broader interpretation of trial results. [ABSTRACT FROM AUTHOR]

Background: In 2007, the province of British Columbia implemented incentive payments to primary care physicians for the provision of comprehensive, continuous, guideline-informed care for patients with 2 or more chronic conditions. We examined the impact of this program on primary care access and continuity, rates of hospital admission and costs.Methods: We analyzed all BC patients who qualified for the incentive based on their diagnostic profile. We tracked primary care contacts and continuity, hospital admissions (total, via the emergency department and for targeted conditions), and cost of physician services, hospital care and pharmaceuticals, for 24 months before and 24 months after the intervention.Results: Of 155 754 eligible patients, 63.7% had at least 1 incentive payment billed. Incentive payments had no impact on primary care contacts (change in contacts per patient per month: 0.016, 95% confidence interval [CI] -0.047 to 0.078) or continuity of care (mean monthly change: 0.012, 95% CI -0.001 to 0.024) and were associated with increased total rates of hospital admission (change in hospital admissions per 1000 patients per month: 1.46, 95% CI 0.04 to 2.89), relative to preintervention trends. Annual costs per patient did not decline (mean change: $455.81, 95% CI -$2.44 to $914.08).Interpretation: British Columbia's $240-million investment in this program improved compensation for physicians doing the important work of caring for complex patients, but did not appear to improve primary care access or continuity, or constrain resource use elsewhere in the health care system. Policymakers should consider other strategies to improve care for this patient population. [ABSTRACT FROM AUTHOR]

Background: Warfarin is an oral anticoagulant medication that disrupts the liver's production of clotting factors. While this medication is highly effective for the prevention of thromboembolic events, it also has a narrow therapeutic range and a vulnerability to interactions with other drugs and vitamin K-containing foods. Warfarin is commonly ingested at dinnertime, the same time of day that dietary vitamin K consumption (found largely in green leafy vegetables) is most variable. While the long half-life of warfarin might make this irrelevant, the ultra short half-life of vitamin K and the possibility of a hepatic first-pass effect for warfarin make it worth evaluating whether morning ingestion of warfarin, when vitamin K levels are consistently low, leads to greater stability of its anticoagulant effect. An examination of the timing of administration on the effectiveness of warfarin has never before been conducted.Methods/design: This is a 7-month Prospective Randomized Open Blinded End-point (PROBE) study in which established evening warfarin users (primary care managed Canadian outpatients in the provinces of British Columbia and Alberta) will be randomized to either switch to morning ingestion of warfarin (the intervention) or to continue with evening use (the control). The primary outcome is the percent change in the proportion of time spent outside the therapeutic range of the international normalized ratio (INR) blood test. Secondary outcomes include change in proportion of time spent within the therapeutic INR range (TTR), percentage of patients with TTR >75 %, percentage of patients with TTR <60 %, and major warfarin-related cardiovascular events (including all-cause mortality, hospitalization for stroke, hospitalization for GI bleeding, and deep venous thrombosis/pulmonary embolism). We will also compare whether day-to-day variability in the consumption of high vitamin K-containing foods at baseline affects the baseline TTR in this cohort of evening warfarin users.Discussion: This study addresses whether the timing of warfarin ingestion influences the stability of its anticoagulant effect. Should morning ingestion prove superior, the safety and effectiveness of this medication, and hence the prevention of stroke, pulmonary embolus, and major hemorrhage, could potentially be improved with no added cost or inconvenience to the patient.Trial Registration: ClinicalTrials.gov: NCT02376803 . Registered on 25 February 2015. [ABSTRACT FROM AUTHOR]

Over the past decade, a large body of observational evidence has suggested an association between lower vitamin D status (25-hydroxyvitamin D) and multiple acute and chronic disorders, including cancer, multiple sclerosis, depression and respiratory tract infections. This evidence has fostered the hypothesis that increasing vitamin D intake may treat and prevent such disorders. Our objective was to perform a critical analysis of the highest-level evidence for ten common beliefs regarding vitamin D for the prevention of falls, fractures and respiratory tract infections, the reduction of cancer incidence/mortality and overall mortality, and the prevention or treatment of depression/mental well-being, rheumatoid arthritis and multiple sclerosis, as well as maximum dosing and regular testing. We searched the Cochrane Database of Systematic Reviews and PubMed (up to August 2014) for randomized controlled trials and systematic reviews/meta-analyses based on those studies. All searches were performed, all evidence reviewed and each section written by at least two authors. The evidence shows that vitamin D supplementation provides some benefit in fracture prevention (likely ∼10-15 % relative reduction), particularly at a dose ≥800 IU and with calcium; a likely benefit in the rate of falls, though it is less clear whether the number of fallers changes; and a possible small (∼5 %) relative reduction in mortality. Evidence does not support the use of vitamin D supplementation for the prevention of cancer, respiratory infections or rheumatoid arthritis. Similarly, evidence does not support vitamin D supplementation for the treatment of multiple sclerosis and rheumatoid arthritis or for improving depression/mental well-being. Regular testing of 25-hydroxyvitamin D is generally not required, and mega-doses (≥300,000 IU) appear to increase harms. Much of the evidence is at high risk of bias, with multiple flaws, including analyses of secondary endpoints, small and underpowered studies, inconsistent results and numerous other issues. Therefore, enthusiasm for a vitamin D panacea should be tempered. [ABSTRACT FROM AUTHOR]

Aims Adverse drug events are an important cause of emergency department visits, unplanned admissions and prolonged hospital stays. Our objective was to synthesize the evidence on the effect of early in-hospital pharmacist-led medication review on patient-oriented outcomes based on observed data. Methods We systematically searched eight bibliographic reference databases, electronic grey literature, medical journals, conference proceedings, trial registries and bibliographies of relevant papers. We included studies that employed random or quasi-random methods to allocate subjects to pharmacist-led medication review or control. Medication review had to include, at a minimum, obtaining a best possible medication history and reviewing medications for appropriateness and adverse drug events. The intervention had to be initiated within 24 h of emergency department presentation or 72 h of admission. We extracted data in duplicate and pooled outcomes from clinically homogeneous studies of the same design using random effects meta-analysis. Results We retrieved 4549 titles of which seven were included, reporting the outcomes of 3292 patients. We pooled data from studies of the same design, and found no significant differences in length of hospital admission (weighted mean difference [WMD] -0.04 days, 95% confidence interval [CI] -1.63, 1.55), mortality (odds ratio [OR] 1.09, 95% CI 0.69, 1.72), readmissions (OR 1.15, 95% CI 0.81, 1.63) or emergency department revisits at 3 months (OR 0.60, 95% CI 0.27, 1.32). Two large studies reporting reductions in readmissions could not be included in our pooled estimates due to differences in study design. Conclusions Wide confidence intervals suggest that additional research is likely to influence the effect size estimates and clarify the effect of medication review on patient-oriented outcomes. This systematic review failed to identify an effect of pharmacist-led medication review on health outcomes. [ABSTRACT FROM AUTHOR]

In our experience, complaints of ankle swelling are more common in summer, typically from patients with no obvious cardiovascular disease. Surprisingly, this observation has never been reported. To objectively establish this phenomenon, we sought evidence of seasonality in the public's Internet searches for ankle swelling. Our data, obtained from Google Trends, consisted of all related Google searches in the United States from January 4, 2004, to January 26, 2016. Consistent with our expectations and confirmed by similar data for Australia, Internet searches for information on ankle swelling are highly seasonal (highest in midsummer), with seasonality explaining 86% of search volume variability. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine the quality of health recommendations and claims made on medical talk shows. DESIGN Prospective observational study. SOURCES Internationally syndicated medical television talk shows that air daily (The Dr Oz Show and The Doctors). INTERVENTIONS Investigators randomly selected 40 episodes of each of The Dr Oz Show and The Doctors from early 2013 and identified and evaluated all recommendations made on each program. A group of experienced evidence reviewers independently searched for, and evaluated as a team, evidence to support 80 randomly selected recommendations from each show. MAIN OUTCOMES MEASURES Percentage of recommendations that are supported by evidence as determined by a team of experienced evidence reviewers. Secondary outcomes included topics discussed, the number of recommendations made on the shows, and the types and details of recommendations that were made. RESULTS We could find at least a case study or better evidence to support 54% (95% confidence interval 47% to 62%) of the 160 recommendations. For recommendations in The Dr Oz Show, evidence supported 46%, contradicted 15%, and was not found for 39%. For recommendations in The Doctors, evidence supported 63%, contradicted 14%, and was not found for 24%. Believable or somewhat believable evidence supported 33% of the recommendations on The Dr Oz Show and 53% on The Doctors. Disclosure of potential conflicts of interest accompanied 0.4% of recommendations. CONCLUSIONS Recommendations made on medical talk shows often lack adequate information on specific benefits or the size of these benefits. Approximately half of the recommendations have either no evidence or are contradicted by the best available evidence. Potential conflicts of interest are rarely addressed. The public should be skeptical about recommendations made on medical talk shows. [ABSTRACT FROM AUTHOR]