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Randomized controlled trials are the principal means of establishing the efficacy of drugs. However pre-marketing trials are limited in size and duration and exclude high-risk populations. They have limited statistical power to detect rare but potentially serious adverse events in real-world patients. We summarize the principal methodological challenges in the reporting, analysis and interpretation of safety data in clinical trials using recent examples from systematic reviews. These challenges include the lack of an evidentiary gold standard, the limited statistical power of randomized controlled trials and resulting type 2 error, the lack of adequate ascertainment of adverse events and limited generalizability of trials that exclude high risk patients. We discuss potential solutions to these challenges. Evaluation of drug safety requires careful examination of data from heterogeneous sources. Meta-analyses of drug safety should include appropriate statistical methods and assess the optimal information size to avoid type 2 errors. They should evaluate outcome reporting biases and missing data to ensure reliable and accurate interpretation of findings. Regulatory and academic partnerships should be fostered to provide an independent and transparent evaluation of drug safety.

The association between sodium-glucose cotransporter 2 inhibitors (SGLT2i's) and lower extremity amputation is unclear. To systematically review randomized control trials (RCTs) and observational studies quantifying risk of lower extremity amputations associated with SGLT2i use. We searched PubMed, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials from January 2011 to February 2020 for RCTs and observational studies including lower extremity amputation outcomes for individuals with type 2 diabetes mellitus treated with SGLT2i's vs. alternative treatments or placebo. Two reviewers independently extracted data. Our primary outcome was risk of lower limb amputation. Secondary outcomes included peripheral arterial disease, peripheral vascular disease, venous ulcerations, and diabetic foot infections. We also evaluated the risk of bias. We conducted random and fixed effects relative risk meta-analysis of RCTs. After screening 2,006 studies, 12 RCTs and 18 observational studies were included, of which 7 RCTs and 18 observational studies had at least one event. The random effects meta-analysis of 7 RCTs suggested the absence of a statistically significant association between SGLT2i exposure with evidence of substantial statistical heterogeneity (n = 424/23,716 vs n = 267/18,737 in controls; RR 1.28, CI's 0.93-1.76; I2 = 62.0%; p = 0.12) whereas fixed effects analysis showed an increased risk with statistical heterogeneity (RR 1.27, 1.09-1.48; I2 = 62%; p = 0.003). Subgroup analysis of canagliflozin vs placebo showed a statistically significantly increased risk in a fixed effects meta-analysis (n = 2 RCTs, RR 1.59, 1.26-2.01; I2 = 88%; p = 0.0001) whereas the meta-analysis of dapagliflozin or empagliflozin (n = 2 RCTs each) and a single RCT for ertugliflozin did not show a significantly increased risk. The findings from observational studies were too heterogeneous to be pooled in a meta-analysis and draw meaningful conclusions. Both randomized and observational studies were of generally good methodological quality. Overall, there was no consistent evidence of SGLT2i exposure and increased risk of amputation. The increased risk of amputation seen in the large, long-term Canagliflozin Cardiovascular Assessment Study (CANVAS) trial for canagliflozin, and select observational studies, merits continued exploration.

Network meta-analysis, in the context of a systematic review, is a meta-analysis in which multiple treatments (that is, three or more) are being compared using both direct comparisons of interventions within randomized controlled trials and indirect comparisons across trials based on a common comparator. To ensure validity of findings from network meta-analyses, the systematic review must be designed rigorously and conducted carefully. Aspects of designing and conducting a systematic review for network meta-analysis include defining the review question, specifying eligibility criteria, searching for and selecting studies, assessing risk of bias and quality of evidence, conducting a network meta-analysis, interpreting and reporting findings. This commentary summarizes the methodologic challenges and research opportunities for network meta-analysis relevant to each aspect of the systematic review process based on discussions at a network meta-analysis methodology meeting we hosted in May 2010 at the Johns Hopkins Bloomberg School of Public Health. Since this commentary reflects the discussion at that meeting, it is not intended to provide an overview of the field.

Patients who develop herpes zoster or herpes zoster ophthalmicus may be at risk for cerebrovascular and cardiac complications. We systematically reviewed the published literature to determine the association between herpes zoster and its subtypes with the occurrence of cerebrovascular and cardiac events. Systematic searches of PubMed (MEDLINE), SCOPUS (Embase) and Google Scholar were performed in December 2016. Eligible studies were cohort, case-control, and self-controlled case-series examining the association between herpes zoster or subtypes of herpes zoster with the occurrence of cerebrovascular and cardiac events including stroke, transient ischemic attack, coronary heart disease, and myocardial infarction. Data on the occurrence of the examined events were abstracted. Odds ratios and their accompanying confidence intervals were estimated using random and fixed effects models with statistical heterogeneity estimated with the I2 statistic. Twelve studies examining 7.9 million patients up to 28 years after the onset of herpes zoster met our pre-defined eligibility criteria. Random and fixed effects meta-analyses showed that herpes zoster, type unspecified, and herpes zoster ophthalmicus were associated with a significantly increased risk of cerebrovascular events, without any evidence of statistical heterogeneity. Our meta-analysis also found a significantly increased risk of cardiac events associated with herpes zoster, type unspecified. Our results are consistent with the accumulating body of evidence that herpes zoster and herpes zoster ophthalmicus are significantly associated with cerebrovascular and cardiovascular events.

Rosiglitazone and pioglitazone may increase the incidence of fractures. We aimed to determine systematically the risk of fractures associated with thiazolidinedione therapy and to evaluate the effect of the therapy on bone density. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), other trial registries and product information sheets through June 2008. We selected long-term (≥ 1 year) randomized controlled trials involving patients with type 2 diabetes and controlled observational studies that described the risk of fractures or changes in bone density with thiazolidinediones. We calculated pooled odds ratios (ORs) for fractures and the weighted mean difference in bone density. We analyzed data from 10 randomized controlled trials involving 13 715 participants and from 2 observational studies involving 31 679 participants. Rosiglitazone and pioglitazone were associated with a significantly increased risk of fractures overall in the 10 randomized controlled trials (OR 1.45, 95% confidence interval [CI] 1.18–1.79; p < 0.001). Five randomized controlled trials showed a significantly increased risk of fractures among women (OR 2.23, 95% CI 1.65–3.01; p < 0.001) but not among men (OR 1.00, 95% CI 0.73–1.39; p = 0.98). The 2 observational studies demonstrated an increased risk of fractures associated with rosiglitazone and pioglitazone. Bone mineral density in women exposed to thiazolidinediones was significantly reduced at the lumbar spine (weighted mean difference −1.11%, 95% CI −2.08% to −0.14%; p = 0.02) and hip (weighted mean difference −1.24%, 95%CI −2.34% to −0.67%; p < 0.001) in 2 randomized controlled trials. Long-term thiazolidinedione use doubles the risk of fractures among women with type 2 diabetes, without a significant increase in risk of fractures among men with type 2 diabetes. Une version française de ce résumé est disponible à l'adresse www.cmaj.ca/cgi/content/full/180/1/32/DC1 CMAJ 2009; 180(1):32-9

Pharmacokinetics (PK) has long been differentiated from pharmacodynamics (PD) and biomarkers, yet this distinction undervalues PK's translational relevance. In this Perspective, we propose that PK itself functions as a biomarker that bridges dose, exposure, and response. Using examples from target‐mediated drug disposition, antidrug antibodies, cerebrospinal fluid PK, high‐dose methotrexate therapy, and anti‐infective pharmacology, we illustrate how PK serves as a measurable, predictive, and actionable biomarker that informs drug development, guides decisions, and advances precision medicine.

Background: Vitiligo is an acquired depigmenting skin disorder often associated with social stigma and having a significant psychological impact on patients. The study aimed to determine the correlation between serum levels of copper (Cu), zinc (Zn), selenium (Se), lead (Pb), mercury (Hg), cadmium (Cd), and Cu/Pb, Cu/Hg, Cu/Cd, Se/Hg, Se/Pb, Se/Cd, Zn/Hg, Zn/Pb, and Zn/Cd ratios in vitiligo patients. Materials and methods: In this analytical cross-sectional study, we enrolled 110 vitiligo patients as cases and 110 normal adults as controls. VIDA (Vitiligo Disease Activity Score) and VASI (Vitiligo Area Severity Index) were used to assess the activity and severity of vitiligo in patients. Venous blood samples of all study participants (aged >12 years) were examined for serum levels of Zn, Cu, Se, Pb, Hg, and Cd using inductively coupled plasma mass spectrometry. SPSS.21 version software was used for the analysis of the data. Results: We noted a statistically significant (p-value < 0.05, student's t-test) difference in mean serum levels of Cu, Zn, and Se (microgram/liter) between cases and controls, denoted as 1370.67 ± 484.36 versus 2887.30 ± 3744.15, 1324.50 ± 555.02 versus 1603.81 ± 551.03, 248.95 ± 120.06 versus 287.15 ± 117.37, respectively. A significantly low serum level of Se was observed in female vitiligo patients, unlike controls. Vegetarian patients had low levels of Pb (p-value <0.05) in comparison to non-vegetarian patients. Significantly low Zn/Hg and Cu/Hg ratios were observed in cases compared to controls. Limitations: Our study was limited by a small sample size. Being an observational study done from a single center, chances of inclusion of patients from a limited geographical area cannot be ruled out. Conclusion: Low levels of Zn, Cu, and Se could play a crucial role in the etiopathogenesis of vitiligo, which can vary based on the gender and diet pattern of the patient.

Background Literature indicates that poor psychological wellbeing can have a negative impact on outcomes following hip surgery. However, limited information is available on psychological interventions for adults with a planned hip surgery. This study describes and synthesizes existing interventions to improve psychological wellbeing in hip surgery patients. Methods We conducted a search of articles using seven electronic databases: CINAHL, Cochrane Library, Embase, PubMed, PsycINFO, SPORTDiscus, and Web of Science. We included all original studies ( n  = 12) investigating psychological interventions for adults with a planned hip surgery or recovering from hip surgery. Results Most articles focused on adults aged > 60 and individuals recovering from total hip arthroplasty ( n  = 7). The interventions varied in approach, dose, delivery methods, and timing. The most used approach was self-efficacy enhancing interventions ( n  = 5) followed by patient education ( n  = 2) and motivation-based interventions ( n  = 2). Most interventions ( n  = 9) were delivered post-operatively either in-person or through a combination of in-person and telephone delivery. Two-thirds of the articles ( n  = 8) evaluated the effectiveness of the intervention in a randomized controlled trial, with studies varying in sample size and outcome measures. In general, results indicated that psychological interventions positively influenced patient-reported outcomes, including functional status and health-related quality of life, following hip surgery. Conclusion Psychological interventions were generally found to be helpful in improving psychological wellbeing and patient-reported outcomes, such as functional status and health-related quality of life, following hip surgery. Several gaps in the literature were identified, highlighting the need for further research to strengthen the evidence base for psychological interventions in this population.

Violent attacks on and interferences with hospitals, ambulances, health workers, and patients during conflict destroy vital health services during a time when they are most needed and undermine the long-term capacity of the health system. In Syria, such attacks have been frequent and intense and represent grave violations of the Geneva Conventions, but the number reported has varied considerably. A systematic mechanism to document these attacks could assist in designing more protection strategies and play a critical role in influencing policy, promoting justice, and addressing the health needs of the population. We developed a mobile data collection questionnaire to collect data on incidents of attacks on healthcare directly from the field. Data collectors from the Syrian American Medical Society (SAMS), using the tool or a text messaging system, recorded information on incidents across four of Syria's northern governorates (Aleppo, Idleb, Hama, and Homs) from January 1, 2016, to December 31, 2016. SAMS recorded a total of 200 attacks on healthcare in 2016, 102 of them using the mobile data collection tool. Direct attacks on health facilities comprised the majority of attacks recorded (88.0%; n = 176). One hundred and twelve healthcare staff and 185 patients were killed in these incidents. Thirty-five percent of the facilities were attacked more than once over the data collection period; hospitals were significantly more likely to be attacked more than once compared to clinics and other types of healthcare facilities. Aerial bombs were used in the overwhelming majority of cases (91.5%). We also compared the SAMS data to a separate database developed by Physicians for Human Rights (PHR) based on media reports and matched the incidents to compare the results from the two methods (this analysis was limited to incidents at health facilities). Among 90 relevant incidents verified by PHR and 177 by SAMS, there were 60 that could be matched to each other, highlighting the differences in results from the two methods. This study is limited by the complexities of data collection in a conflict setting, only partial use of the standardized reporting tool, and the fact that limited accessibility of some health facilities and workers and may be biased towards the reporting of attacks on larger or more visible health facilities. The use of field data collectors and use of consistent definitions can play an important role in the tracking incidents of attacks on health services. A mobile systematic data collection tool can complement other methods for tracking incidents of attacks on healthcare and ensure the collection of detailed information about each attack that may assist in better advocacy, programs, and accountability but can be practically challenging. Comparing attacks between SAMS and PHR suggests that there may have been significantly more attacks than previously captured by any one methodology. This scale of attacks suggests that targeting of healthcare in Syria is systematic and highlights the failure of condemnation by the international community and medical groups working in Syria of such attacks to stop them.

Advances in cancer treatment have significantly improved the survival of patients with cancer, but, unfortunately, many of these treatments also have long‐term complications. Cancer treatment‐related cardiotoxicities are becoming a significant clinical problem that a new discipline, Cardio‐Oncology, was established to advance the cardiovascular care of patients with growing cancer populations. Anthracyclines are a class of chemotherapeutic agents used to treat many cancers in adults and children. Their clinical use is limited by anthracycline‐induced cardiotoxicity (AIC), which can lead to heart failure. Early‐onset cardiotoxicity appears within a year of treatment, whereas late‐onset cardiotoxicity occurs > 1 year and even up to decades after treatment completion. The pathophysiology of AIC was hypothesized to be caused by generation of reactive oxygen species that lead to lipid peroxidation, defective mitochondrial biogenesis, and DNA damage of the cardiomyocytes. The accumulation of anthracycline metabolites was also proposed to cause mitochondrial damage and the induction of cardiac cell apoptosis, which induces arrhythmias, contractile dysfunction, and cardiomyocyte death. This paper will provide a general overview of cardiotoxicity focusing on the effect of anthracyclines and their epigenetic molecular mechanisms on cardiotoxicity.