Competing risks, left truncation and late entry effect in A-bomb survivors cohort

The cohort under study comprises A-bomb survivors residing in Hiroshima Prefecture since 1968. After this year, thousands of survivors were newly recognized every year. The aim of this study is to determine whether the survival experience of the late entrants to the cohort is significantly different from the registered population in 1968. Parametric models that account for left truncation and competing risks were developed by using sub-hazard functions. A Weibull distribution was used to determine the possible existence of a late entry effect in Hiroshima A-bomb survivors. The competing risks framework shows that there might be a late entry effect in the male and female groups. Our findings are congruent with previous studies analysing similar populations

Identifying prodromal symptoms at high specificity for Parkinson’s disease

IntroductionTo test drugs with the potential to prevent the onset of Parkinson’s disease (PD), it is key to identify individuals in the general population at high risk of developing PD. This is often difficult because most of the clinical markers are non-specific, common in PD but also common in older adults (e.g., sleep problems).ObjectiveWe aimed to identify the clinical markers at high specificity for developing PD by comparing individuals with PD or prodromal PD to healthy controls.MethodsWe investigated motor and non-motor symptoms (Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part 1 and 2 items) in 64 prodromal PD and 422 PD individuals calculating the odds ratios, adjusting for age and gender, for PD and prodromal PD versus 195 healthy controls. Symptoms at high specificity were defined as having an adjusted odds ratio ≥ 6.ResultsConstipation had an adjusted odds ratio, 6.14 [95% CI: 2.94–12.80] showing high specificity for prodromal PD, and speech difficulties had an adjusted odds ratio, 9.61 [95% CI: 7.88–48.81] showing high specificity for PD. The proportion of participants showing these specific markers was moderate (e.g., prevalence of constipation was 43.75% in prodromal PD, and speech difficulties was 33.89% in PD), suggesting these symptoms may make robust predictors of prodromal PD and PD, respectively.DiscussionClinical markers at high specificity for developing PD could be used as tools in the screening of general populations to identify individuals at higher risk of developing PD

Efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma not receiving inhaled corticosteroids

Background: Asthma is a heterogeneous and complex disease in both its clinical course and response to treatment. IL-13 is central to Type 2 inflammation and contributes to many features of asthma. In a previous Phase 2 study, lebrikizumab, an anti-IL-13 monoclonal antibody, did not significantly improve FEV1 in mild-to-moderate asthma patients not receiving ICS therapy. This Phase 3 study was designed to further assess the efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma treated with daily short-acting β2-agonist therapy alone. Methods: Adult patients with mild-to-moderate asthma were randomised to receive lebrikizumab 125 mg subcutaneously (SC), placebo SC, or montelukast 10 mg orally for 12 weeks, with an 8-week follow-up period. The primary efficacy endpoint was absolute change in pre-bronchodilator FEV1 from baseline at Week 12. Findings: A total of 310 patients were randomised and dosed in the study. The mean absolute change in FEV1 from baseline at Week 12 was higher in the lebrikizumab-treated arm compared with placebo (150 mL versus 67 mL); however, this improvement did not achieve statistical significance (overall adjusted difference of 83 mL [95% CI:-3, 170]; p = .06). Montelukast did not improve FEV1 as compared with placebo. Lebrikizumab was generally safe and well tolerated during the study. Interpretation: Lebrikizumab did not significantly improve FEV1 in mild-to-moderate asthma patients at a dose expected to inhibit the IL-13 pathway. Inhibiting IL-13 in this patient population was not sufficient to improve lung function. These data support the findings of a previous trial of lebrikizumab in patients not receiving ICS

Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson\u27s disease

\ua9 The Author(s) 2024. Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson’s disease. Although in the PASADENA phase 2 study, the primary endpoint (Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) sum of Parts I + II + III) was not met, prasinezumab-treated individuals exhibited slower progression of motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on motor signs progression in prespecified subgroups with faster motor progression. Prasinezumab’s potential effects on disease progression were assessed in four prespecified and six exploratory subpopulations of PASADENA: use of monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn and Yahr stage (2 versus 1); rapid eye movement sleep behavior disorder (yes versus no); data-driven subphenotypes (diffuse malignant versus nondiffuse malignant); age at baseline (≥60 years versus <60 years); sex (male versus female); disease duration (>12 months versus <12 months); age at diagnosis (≥60 years versus <60 years); motor subphenotypes (akinetic–rigid versus tremor-dominant); and motor subphenotypes (postural instability gait dysfunction versus tremor-dominant). In these subpopulations, the effect of prasinezumab on slowing motor signs progression (MDS-UPDRS Part III) was greater in the rapidly progressing subpopulations (for example, participants who were diffuse malignant or taking monoamine oxidase B inhibitors at baseline). This exploratory analysis suggests that, in a trial of 1-year duration, prasinezumab might reduce motor progression to a greater extent in individuals with more rapidly progressing Parkinson’s disease. However, because this was a post hoc analysis, additional randomized clinical trials are needed to validate these findings

Efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma not receiving inhaled corticosteroids

Background: Asthma is a heterogeneous and complex disease in both its clinical course and response to treatment. IL-13 is central to Type 2 inflammation and contributes to many features of asthma. In a previous Phase 2 study, lebrikizumab, an anti-IL-13 monoclonal antibody, did not significantly improve FEV1 in mild-to-moderate asthma patients not receiving ICS therapy. This Phase 3 study was designed to further assess the efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma treated with daily short-acting β2-agonist therapy alone. Methods: Adult patients with mild-to-moderate asthma were randomised to receive lebrikizumab 125 mg subcutaneously (SC), placebo SC, or montelukast 10 mg orally for 12 weeks, with an 8-week follow-up period. The primary efficacy endpoint was absolute change in pre-bronchodilator FEV1 from baseline at Week 12. Findings: A total of 310 patients were randomised and dosed in the study. The mean absolute change in FEV1 from baseline at Week 12 was higher in the lebrikizumab-treated arm compared with placebo (150 mL versus 67 mL); however, this improvement did not achieve statistical significance (overall adjusted difference of 83 mL [95% CI:-3, 170]; p = .06). Montelukast did not improve FEV1 as compared with placebo. Lebrikizumab was generally safe and well tolerated during the study. Interpretation: Lebrikizumab did not significantly improve FEV1 in mild-to-moderate asthma patients at a dose expected to inhibit the IL-13 pathway. Inhibiting IL-13 in this patient population was not sufficient to improve lung function. These data support the findings of a previous trial of lebrikizumab in patients not receiving ICS

The prevalence of intrusive memories in adult depression: A meta-analysis

Background Intrusive memories have typically been associated with post-traumatic stress disorder (PTSD) but some studies have suggested they can also occur in depression-alone. Objective This meta-analysis aimed to estimate the prevalence of intrusive memories in adult depression and to explore methodological and other factors that may moderate this prevalence. Method The databases PsycINFO, PsycARTICLES, MedLine, PubMed, CINAHL and Embase were searched for relevant articles, published up to and including July 2016. Studies measuring point prevalence of intrusive memories in adults aged 18 years or above with depression were included and assessed for quality. Meta-analysis was completed under a random effects model. Results Seven studies measuring point prevalence of intrusive memories in adult depression were included. The overall pooled prevalence estimate calculated was 76.0% (95% CI 59.4 – 89.4%), reducing to 66.0% (95% CI 51.0 – 79.5%) when restricted to intrusive memories experienced within the week prior to assessment. Heterogeneity was high. Between-groups analyses indicated that adults with depression are as likely to experience intrusive memories as adults with PTSD, and more likely to experience intrusive memories than healthy controls (risk ratio of 2.94, 95% CI 1.53 – 5.67). Limitations The strength of conclusions is limited by the small number of studies included. Consideration of the relationship between depression, intrusive memories and trauma exposure is required. Conclusions Intrusive memories are experienced by a large majority of adults with depression and may therefore be an important target for cognitive intervention. Larger scale measurement of clinical outcome is needed with identification of individual factors predicting treatment response

Quantifying, displaying and accounting for heterogeneity in the meta-analysis of RCTs using standard and generalised Q statistics

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background Clinical researchers have often preferred to use a fixed effects model for the primary interpretation of a meta-analysis. Heterogeneity is usually assessed via the well known Q and I2 statistics, along with the random effects estimate they imply. In recent years, alternative methods for quantifying heterogeneity have been proposed, that are based on a 'generalised' Q statistic. Methods We review 18 IPD meta-analyses of RCTs into treatments for cancer, in order to quantify the amount of heterogeneity present and also to discuss practical methods for explaining heterogeneity. Results Differing results were obtained when the standard Q and I2 statistics were used to test for the presence of heterogeneity. The two meta-analyses with the largest amount of heterogeneity were investigated further, and on inspection the straightforward application of a random effects model was not deemed appropriate. Compared to the standard Q statistic, the generalised Q statistic provided a more accurate platform for estimating the amount of heterogeneity in the 18 meta-analyses. Conclusions Explaining heterogeneity via the pre-specification of trial subgroups, graphical diagnostic tools and sensitivity analyses produced a more desirable outcome than an automatic application of the random effects model. Generalised Q statistic methods for quantifying and adjusting for heterogeneity should be incorporated as standard into statistical software. Software is provided to help achieve this aim.Published versio

Parafoveal preview effects from word N+1 and word N+2 during reading: A critical review and Bayesian meta-analysis

The use of gaze-contingent display techniques to study reading has shown that readers attend not only to the currently fixated word, but also to the word to the right of the current fixation. However, a critical look at the literature shows that there are a number of questions that cannot be readily answered from the available literature reviews on the topic. First, there is no consensus on whether readers also attend to the second word to the right of fixation. Second, it is not clear whether parafoveal processing is more efficient in languages such as Chinese. Third, it is not well understood whether the measured effects are confounded by the properties of the parafoveal mask. The present study addressed these issues by performing a Bayesian meta-analysis of 93 experiments that used the boundary paradigm (Rayner, 1975). There were three main findings: 1) the advantage of previewing the second word to the right is modest in size and likely not centred on zero; 2) Chinese readers seem to make a more efficient use of parafoveal processing, but this is mostly evident in gaze duration; 3) there are interference effects associated with using different parafoveal masks that roughly increase when the mask is less word-like