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Objective: To compare the performance of the bias-adjusted meta-analysis to the conventional meta-analysis assessing seasonal influenza vaccine effectiveness among community-dwelling elderly aged 60 years and older. Study Design and Setting: Systematic literature search revealed 14 cohort studies that met inclusion and exclusion criteria. Laboratory-confirmed influenza, influenza-like illness, hospitalization from influenza and/or pneumonia, and all-cause mortality were study outcomes. Potential biases were identified using bias checklists. The magnitude and uncertainty of biases were assessed by expert opinion. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using random effects model. Results: After incorporating biases, overall effect estimates regressed slightly toward no effect, with the largest relative difference between conventional and bias-adjusted ORs for laboratory-confirmed influenza (OR, 0.18; 95% CI: 0.01, 3.00 vs. OR, 0.23; 95% CI: 0.03, 2.04). In most of the studies, CIs widened reflecting uncertainties about the biases. The between-study heterogeneity reduced considerably with the largest reduction for all-cause mortality (I² = 4%, P = 0.39 vs. I² = 91%, P < 0.01). Conclusion: This case study showed that after addressing potential biases influenza vaccine was still estimated effective in preventing hospitalization from influenza and/or pneumonia and all-cause mortality. Increasing the number of assessors and incorporating empirical evidence might improve the new bias-adjustment method. [ABSTRACT FROM AUTHOR]

Abstract: Background: Tardive dyskinesia (TD) is a potentially irreversible consequence of long term treatment with antipsychotic drugs which is according to a well-known theory believed to be related to oxidative stress induced neurotoxicity. Dehydroepiandrosterone (DHEA) is an endogenous antioxidant with neuroprotective activity. The biosynthesis of DHEA depends upon the activity of cytochrome P450c17α (CYP17). The gene that encodes for CYP17 has a (T34C) single nucleotide polymorphism which enhances CYP17 transcription and expression. Objective: To test the hypothesis that carriership of a more active CYP17 variant would result in higher DHEA(S) levels and protect against neurotoxicity which results in orofaciolingual TD (TDof), limb-truncal TD (TDlt) or both (TDsum). Method: Tardive dyskinesia was assessed cross-sectionally in 146 Caucasian psychiatric inpatients from Siberia. Results: Patients who are carriers of the Cyp17 genotype CC have less chance of developing TD compared to patients who are carriers of the Cyp17 genotypes TC or TT (p<0.05). However, these carriers have significant lower circulating DHEAS levels compared to carriers of the Cyp17 genotypes TC and TT (p<0.05). Conversely, carriers of the CYP17 T-allele have significant elevated DHEAS levels. After correcting for gender and age no significant relationship between Cyp17 genotype CC, the T-allelle and the C-allele and the DHEAS concentration of patients was observed. Conclusions: Although an association between the CYP17 CC genotype and TD is indicated, our findings do not support the hypothesis that this is mediated through increased DHEA(S) levels. We believe that the relationship between this polymorphism and neuroprotective effects of steroids is more complex and cannot be elucidated without taking the posttranslational regulation of the enzyme into account. [Copyright &y& Elsevier]

Background: In the Netherlands, antihypertensive treatment for patients with mild hypertension is recommended if the 10-year cardiovascular disease (CVD) risk exceeds 20%. Recent evidence suggests that lifelong CVD risk estimates might be more informative than 10-year ones. In addition, the cost of antihypertensive treatment in the Netherlands has decreased during the last decade. Objective: The aim of this study is to estimate the cost-effectiveness of lowering systolic blood pressure (SBP) in patients ineligible for treatment in both a 10-year and a lifetime horizon. Methods: A Markov model was developed to assess the cost-effectiveness of SBP reduction compared with no reduction in patients with mild hypertension and low CVD risk. Modified SCORE (Systematic Coronary Risk Evaluation) risk estimates were used to predict fatal and nonfatal CVD events. We analyzed scenarios for different age groups, sexes, and SBP reductions. Specifically, SBP reductions due to hydrochlorothiazide (HCT) 25 mg and hypothetical reductions with HCT 12.5 mg-losartan 50 mg combination were assumed. Parameter uncertainty was assessed through a probabilistic sensitivity analysis. Results: In a 10-year horizon, in scenarios of SBP reduction with HCT 25 mg, the incremental cost-effectiveness ratio (ICER) estimates for men varied across different ages in the range of €6032 to €58,217 per life-year gained, whereas for women ICER estimates were in the range of €12,345 to €361,064 per life-year gained. In a lifetime horizon, the cost-effectiveness estimates were favorable for both sexes. In scenarios of hypothetical SBP reductions, more favorable ICER estimates compared with no reduction were found. A large uncertainty around the cost-effectiveness estimates was observed among all scenarios. Conclusion: Larger SBP reductions were found to be cost-effective in both a 10-year and lifetime horizon. These findings might call for more aggressive SBP reductions in patients with mild hypertension. However, a high level of uncertainty surrounds these cost-effectiveness estimates because they are based on CVD risk prediction modeling. [ABSTRACT FROM AUTHOR]

Background: Pediatric musculoskeletal injuries cause moderate to severe pain, which should ideally be addressed upon arrival to the emergency department (ED). Despite extensive research in ED-based pediatric pain treatment, recent studies confirm that pain management in this setting remains suboptimal. The No OUCH study consist of two complementary, randomized, placebo-controlled trials that will run simultaneously for patients presenting to the ED with an acute limb injury and a self-reported pain score of at least 5/10, measured via a verbal numerical rating scale (vNRS). Caregiver/parent choice will determine whether patients are randomized to the two-arm or three-arm trial. In the two-arm trial, patients will be randomized to receive either ibuprofen alone or ibuprofen in combination with acetaminophen. In the three-arm trial, patients can also be randomized to a third arm where they would receive ibuprofen in combination with hydromorphone. This article details the statistical analysis plan for the No OUCH study and was submitted before the trial outcomes were available for analysis.Methods/design: The primary endpoint of the No OUCH study is self-reported pain at 60 min, recorded using a vNRS. The principal safety outcome is the presence of any adverse event related to study drug administration. Secondary effectiveness endpoints include pain measurements using the Faces Pain Scale-Revised and the visual analog scale, time to effective analgesia, requirement of a rescue analgesic, missed fractures, and observed pain reduction using different definitions of successful analgesia. Secondary safety outcomes include sedation measured using the Ramsay Sedation Score and serious adverse events. Finally, the No OUCH study investigates the reasons given by the caregiver for selecting the two-arm (Non-Opioid) or three-arm (Opioid) trial, caregiver satisfaction, physician preferences for analgesics, and caregiver comfort with at-home pain management.Discussion: The No OUCH study will inform the relative effectiveness of acetaminophen and hydromorphone, in combination with ibuprofen, and ibuprofen alone as analgesic agents for patients presenting to the ED with an acute musculoskeletal injury. The data from these trials will be analyzed in accordance with this statistical analysis plan. This will reduce the risk of producing data-driven results and bias in our reported outcomes.Trial Registration: ClinicalTrials.gov NCT03767933 . Registered on December 7, 2018. [ABSTRACT FROM AUTHOR]

Background: Acute gastroenteritis is a leading cause of emergency department visits and hospitalizations among children in North America. Oral-rehydration therapy is recommended for children with mild-to-moderate dehydration, but children who present with vomiting are frequently offered intravenous rehydration in the emergency department (ED). Recent studies have demonstrated that the anti-emetic ondansetron can reduce vomiting, intravenous rehydration, and hospitalization when administered in the ED to children with dehydration. However, there is little evidence of additional benefit from prescribing ondansetron beyond the initial ED dose. Moreover, repeat dosing may increase the frequency of diarrhea. Despite the lack of evidence and potential adverse side effects, many physicians across North America provide multiple doses of ondansetron to be taken following ED disposition. Thus, the Multi-Dose Oral Ondansetron for Pediatric Gastroenteritis (DOSE-AGE) trial will evaluate the effectiveness of prescribing multiple doses of ondansetron to treat acute gastroenteritis-associated vomiting. This article specifies the statistical analysis plan (SAP) for the DOSE-AGE trial and was submitted before the outcomes of the study were available for analysis.Methods/design: The DOSE-AGE study is a phase III, 6-center, placebo-controlled, double-blind, parallel design randomized controlled trial designed to determine whether participants who are prescribed multiple doses of oral ondansetron to administer, as needed, following their ED visit have a lower incidence of experiencing moderate-to-severe gastroenteritis, as measured by the Modified Vesikari Scale score, compared with a placebo. To assess safety, the DOSE-AGE trial will investigate the frequency and maximum number of diarrheal episodes following ED disposition, and the occurrence of palpitations, pre-syncope/syncope, chest pain, arrhythmias, and serious adverse events. For the secondary outcomes, the DOSE-AGE trial will investigate the individual elements of the Modified Vesikari Scale score and caregiver satisfaction with the therapy.Discussion: The DOSE-AGE trial will provide evidence on the effectiveness of multiple doses of oral ondansetron, taken as needed, following an initial ED dose in children with acute gastroenteritis-associated vomiting. The data from the DOSE-AGE trial will be analyzed using this SAP. This will reduce the risk of producing data-driven results and bias in our reported outcomes. The DOSE-AGE study was registered on ClinicalTrials.gov on February 22, 2019.Trial Registration: ClinicalTrials.gov NCT03851835 . Registered on 22 February 2019. [ABSTRACT FROM AUTHOR]