922017 research outputs found
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Are we leaving money on the table in infertility RCTs? Trialists should statistically adjust for prespecified, prognostic covariates to increase power.
No full textInfertility RCTs are often too small to detect realistic treatment effects. Large observational studies have been proposed as a solution. However, this strategy threatens to weaken the evidence base further, because non-random assignment to treatments makes it impossible to distinguish effects of treatment from confounding factors. Alternative solutions are required. Power in an RCT can be increased by adjusting for prespecified, prognostic covariates when performing statistical analysis, and if stratified randomization or minimization has been used, it is essential to adjust in order to get the correct answer. We present data showing that this simple, free, and frequently necessary strategy for increasing power is seldom employed, even in trials appearing in leading journals. We use this to motivate a pedagogical discussion and provide a worked example. While covariate adjustment can’t solve the problem of underpowered trials outright, there is an imperative to use sound methodology to maximize the information each trial yields
Ventricular arrhythmias and sudden death in non-ischemic dilated cardiomyopathy: matter of sex or scar?
No full textAimsTo evaluate the association between sex and ventricular arrhythmias (VA) or sudden death (SD) in non-ischemic dilated cardiomyopathy, including analysis of potential confounders.MethodsRetrospective cohort study of consecutive patients with DCM referred for cardiac magnetic resonance (CMR) at two tertiary hospitals. The primary combined endpoint encompassed sustained VA, appropriate ICD therapies, resuscitated cardiac arrest and SD. ResultsWe included 1165 patients with median follow-up of 36 months (interquartile range 20-58 months). The majority of patients (66%) were males. Males and females had similar LVEF but the prevalence of late gadolinium enhancement (LGE) at CMR was significantly higher among males (48% vs 30%, p<0.001). Males had higher cumulative incidence of the primary endpoint (8% vs 4%, p=0.02) and male sex was a significant predictor of the primary endpoint at univariate analysis (HR 1.93, p=0.02). However, LGE had a major confounding effect in the association between sex and the primary outcome: the HR of male sex adjusted for LGE was 1.29 (p=0.37). LGE+ females had significantly higher cumulative incidence of the primary endpoint than LGE- males (13% vs 1.8%, p<0.001).ConclusionsIn patients with DCM, the prevalence of LGE is significantly higher among males, implying a major confounding effect in the association between male sex and VA or SD. LGE+ females have significantly higher risk than LGE- males. These data do not support the inclusion of sex into risk-stratification algorithms for VA or SD in DCM.<br/
IDENTIFYING THE BEST METHODS TO REPORT ON THE POST-VACCINATION SURVEILLANCE OF PHYSICAL SIDE-EFFECTS OF THE COVID-19 VACCINES: A SYSTEMATIC REVIEW
No full textIntroduction: On the 11th of March 2020, the World Health Organisation declared COVID-19 to be a global pandemic. This had led to the development of many novel vaccines for which effective post-vaccination surveillance is essential. This study aims to synthesise post-vaccination surveillance of physical side-effects to learn the best method that can be applied to the surveillance of novel COVID-19 vaccines. Methods: A full systematic search was performed on four databases following the PRISMA guidelines. Following the inclusion and exclusion criteria, and hand-searching the eligible papers, a total of seven studies were included in this review. The risk of bias within studies and their quality was assessed using the Critical Appraisal for Public Health Checklist.Results: The seven studies included were from six countries representing both active and passive surveillance systems. The results showed reliability and reproducibility between data across countries. They also provided a good framework for how post-vaccination surveillance can be performed in low-income countries. Conclusions: The reporting of post-vaccine side-effects is essential. Active and passive systems were essential to encourage reporting of AEFIs and should be encouraged globally. A combination of active and passive surveillance should be used to monitor adverse events relating to the novel COVID-19 vaccines
Prognostic impact of bronchoalveolar lavage galactomannan and Aspergillus culture results on survival in COVID-19 ICU patients: a post-hoc analysis from the European Confederation of Medical Mycology (ECMM) COVID-19-associated pulmonary aspergillosis (CAPA) Study
No full textCritically ill patients with coronavirus disease 2019 (COVID-19) may develop COVID-19-associated pulmonary aspergillosis (CAPA), that impact their chances of survival. Whether positive bronchoalveolar lavage fluid (BALF) mycological tests can be used as a survival proxy remains unknown. We conducted a post-hoc analysis of a previous multicenter, multinational observational study with the aim of assessing the differential prognostic impact of BALF mycological tests, namely positive (≥ 1.0 optical density index) BALF galactomannan (GM) and positive BALF Aspergillus culture alone or in combination in critically ill patients with COVID-19. Of the 592 patients critically ill patients with COVID-19 enrolled in the main study, 218 were included in this post-hoc analysis as they had both test results available. CAPA was diagnosed in 56/218 patients (26%). Most cases were probable CAPA (51/56, 91%) and fewer were proven CAPA (5/56, 9%). In the final multivariable model adjusted for between-center heterogeneity, an independent association with 90-day mortality was observed for the combination of positive BALF GM and positive BALF Aspergillus culture in comparison with both tests negative (hazard ratio 2.53, 95% CI 1.28-5.02, p = 0.008). The other independent predictors of 90-day mortality were increasing age and active malignant disease. In conclusion, the combination of positive BALF GM and positive BALF Aspergillus culture was associated with increased 90-day mortality in critically ill patients with COVID-19. Additional study is needed to explore the possible prognostic value of other BALF markers.Key words: CAPA; GM; biomarker; galactomannan; Aspergillus; COVID-19; BALF.<br/
The role of solvation in proton transfer reactions: implications for predicting salt/co-crystal formation using the ΔpKa rule
No full textThe ΔpKa rule is commonly applied by chemists and crystal engineers as a guideline for the rational design of molecular salts and co-crystals. For multi-component crystals containing acid and base constituents, empirical evidence has shown that ΔpKa > 4 almost always leads to salts, ΔpKa < –1 almost always leads to co-crystals and ΔpKa between –1 and 4 can be either. This paper reviews the theoretical background of the ΔpKa rule and highlights the crucial role of solvation in determining the outcome of the potential proton transfer from acid to base. New data on the frequency of occurrence of co-crystals and salts in multi-component crystal structures containing acid and base constituents show that the relationship between ΔpKa and the frequency of salt/co-crystal formation is influenced by the composition of the crystal. For unsolvated co-crystals/salts, containing only the principal acid and base components, the point of 50% probability for salt/co-crystal formation occurs at ΔpKa ≈ 1.4, while for hydrates of co-crystals and salts, this point is shifted to ΔpKa ≈ –0.5. For acid-base crystals with the possibility for two proton transfers, the overall frequency of occurrence of any salt (monovalent or divalent) versus a co-crystal is comparable to that of the whole data set, but the point of 50% probability for observing a monovalent salt vs a divalent salt lies at ΔpKa,II ≈ –4.5. Hence, where two proton transfers are possible, the balance is between co-crystals and divalent salts, with monovalent salts being far less common. Finally, the overall role played by the “crystal” solvation is illustrated by the fact that acid-base complexes in the intermediate region of ΔpKa tip towards salt formation if ancillary hydrogen bonds can exist. Thus, the solvation strength of the lattice plays a key role in the stabilisation of the ions
Comparison of multiple gene expression platforms for measuring a bladder cancer hypoxia signature
No full textTumour hypoxia status provides prognostic information and predicts response to hypoxia-modifying treatments. We previously derived a 24-gene signature to assess hypoxia in bladder cancer. The objectives here were to: compare platforms for generating signature scores, identify cut-off values for prospective studies, assess intra-tumour heterogeneity and confirm hypoxia relevance. RNA was extracted from prospectively-collected diagnostic biopsies of muscle invasive bladder cancer (51 patients) and gene expression measured using customised Taqman Low Density Array (TLDA) cards, NanoString and Clariom S arrays. Cross-platform transferability of the gene signature was assessed using regression and concordance analysis. Cut-off values were the cohort median expression values. Intra- and inter-tumour variability were determined in a retrospective patient cohort (n=51) with multiple blocks (2-18) from the same tumour. To demonstrate relevance, bladder cancer cell lines were exposed to hypoxia (0.1% oxygen, 24 h), and extracted RNA run on custom TLDA cards. Hypoxia scores showed good agreement between platforms: Clariom S vs TLDA (r=0.72, p<0.0001; concordance 73%); Clariom S vs NanoString (r=0.84, p<0.0001; 78%); TLDA vs NanoString (r=0.80, p<0.0001; 78%). Cut-off values were 0.047 (TLDA), 7.328 (NanoString) and 6.667 (Clariom S). Intra-tumour heterogeneity in gene expression and HS (coefficient of variation 3.9%) was less than inter-tumour (7.9%) variability. Hypoxia scores were higher in bladder cancer cells exposed to hypoxia vs normoxia (p<0.02). Application of the 24-gene bladder cancer hypoxia signature is platform agnostic, cut-off values determined prospectively can be used in a clinical trial, intra-tumour heterogeneity is low and the signature is sensitive to changes in oxygen levels in vitro
Prognostic impact of late gadolinium enhancement at the right ventricular insertion points in non-ischemic dilated cardiomyopathy.
No full textAimsTo evaluate the baseline characteristics and the prognostic implications associated with late gadolinium enhancement limited to the right ventricular insertion points (IP-LGE) or present at both the right ventricular insertion points and the left ventricle (IP&LV-LGE) in non-ischemic dilated cardiomyopathy (DCM). Methods and results Retrospective observational multicenter cohort study including 1165 consecutive patients with DCM evaluated by cardiac magnetic resonance. The primary endpoint included appropriate defibrillator therapies, sustained ventricular tachycardia, resuscitated cardiac arrest or sudden death. The secondary outcome encompassed heart failure hospitalizations, heart transplant, left ventricular assist device implantation and end-stage heart failure death. IP-LGE was found in 72 patients (6%), who had clinical characteristics closer to LGE- than to LGE+ patients. During follow-up (median 36 months), none of the IP-LGE patients experienced the primary endpoint. The cumulative incidence of the primary endpoint was similar between IP-LGE and LGE- patients (p=1) while IP-LGE had significantly lower cumulative incidence as compared to LGE+ patients (p<0.001). As compared to IP-LGE patients, the cumulative incidence of the secondary endpoint was similar in LGE- cases (p=0.86) but tended to be higher in LGE+ patients (p=0.06). Both clinical characteristics and outcomes were similar between IP&LV-LGE patients and the rest of LGE+ cases. ConclusionsIn a large cohort of DCM patients, IP-LGE was associated with similar outcome as compared to LGE- patients and with significant lower risk of ventricular arrhythmias and sudden death as compared to LGE+ cases. Patients with IP&LV-LGE had clinical characteristics and outcomes similar to the rest of LGE+ cases
Childcare Support under Social Security in the UK: Is it Working?
No full textBy facilitating engagement in the labour force and thus potentially contributing to the amelioration of individual poverty, the availability of affordable childcare is an issue of both economic and social significance and is recognised as such across Europe. Since a large majority of the parents who assume caring responsibilities for young children, particularly lone parents, are women, childcare support is also seen as an equality issue in relation to employment. Children’s interest in the parents’ childcare support is also recognised under the UN Convention on the Rights of the Child. Support towards the cost of childcare has been an important feature of the UK social security system since the 1980s and is currently located within Universal Credit (UC) and Working Tax Credit (WTC) legislation. UC and WTC support sits alongside other childcare support schemes, including Tax-free Childcare. For the most disadvantaged, it is however the social security system’s role in this field that has the greatest importance, not least because the imposition of work conditionality and particularly its extension to lone parents with young children is premised on the claimant’s ability to access childcare arrangements. This article evaluates the framework for supporting childcare costs within the social security system in the light of the evidence to date on its operation, including the inherent discrimination that prompted the recent judicial review challenge in Salvato. It highlights flaws in the system and among other things calls for increased monitoring and public scrutiny of its operation
EULAR points to consider when analysing and reporting comparative effectiveness research using observational data in rheumatology
No full textBackgroundComparing treatment effectiveness over time in observational settings is hampered by several major threats, among them confounding and attrition bias. ObjectivesTo develop European Alliance of Associations for Rheumatology (EULAR) points to consider (PtC) when analysing and reporting comparative effectiveness research using observational data in rheumatology. MethodsThe PtC were developed using a three-step process according to the EULAR Standard Operating Procedures. Based on a systematic review of methods currently used in comparative effectiveness studies, the PtC were formulated through two in-person meetings of a multidisciplinary task force and a two-round online Delphi, using expert opinion and a simulation study. Finally, feedback from a larger audience was used to refine the PtC. Mean levels of agreement amongst the task force were calculated. ResultsThree overarching principles and 10 PtC were formulated, addressing, in particular, potential biases relating to attrition or confounding by indication. Building on STROBE guidelines, these PtC insist on the definition of the baseline for analysis and treatment effectiveness. They also focus on the reasons for stopping treatment as an important consideration when assessing effectiveness. Finally, the PtC recommend providing key information on missingness patterns. ConclusionTo improve the reliability of an increasing number of real-world comparative effectiveness studies in rheumatology, special attention is required to reduce potential biases. Adherence to clear recommendations for the analysis and reporting of observational comparative effectiveness studies will improve the trustworthiness of their results.<br/
