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Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Corticosteroids are currently recommended as an adjunctive therapy in HIV-negative adults with TBM. However, benefit from corticosteroids in TBM may depend upon host leukotriene A4 hydrolase (LTA4H) genotype and the corresponding inflammatory phenotypes. This article describes the planned analyses for the primary publication of the results of the LAST ACT clinical trial (NCT03100786): ‘Leukotriene A4 hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-negative adults with Tuberculous meningitis’. The primary hypothesis addressed by the trial is that LTA4H genotype, in particular CC or CT genotype, determines whether adjunctive dexamethasone benefits or harms adults with TBM. The trial was an LTA4H genotype stratified, parallel group, randomised, double blind, placebo-controlled multi-centre Phase III trial of dexamethasone given for 6–8 weeks in addition to standard anti-tuberculosis drugs. LTA4H genotype (CC, CT, TT) was determined in all participants prior to randomisation; only those with CC or CT genotype were randomised to dexamethasone or placebo. All TT genotype participants received dexamethasone because prior data indicated survival was increased by dexamethasone in this genotype. The primary endpoint was all-cause death or new neurological event over the first 12 months after randomisation. We took a hybrid trial-design approach which aims to prove non-inferiority of placebo first but also allows claiming superiority of placebo in case dexamethasone causes substantial harm. This statistical analysis plan expands upon and updates the analysis plan outlined in the published study protocol.

Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Corticosteroids are currently recommended as an adjunctive therapy in HIV-negative adults with TBM. However, benefit from corticosteroids in TBM may depend upon host leukotriene A4 hydrolase (LTA4H) genotype and the corresponding inflammatory phenotypes. This article describes the planned analyses for the primary publication of the results of the LAST ACT clinical trial (NCT03100786): ‘Leukotriene A4 hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-negative adults with Tuberculous meningitis’. The primary hypothesis addressed by the trial is that LTA4H genotype, in particular CC or CT genotype, determines whether adjunctive dexamethasone benefits or harms adults with TBM. The trial was an LTA4H genotype stratified, parallel group, randomised, double blind, placebo-controlled multi-centre Phase III trial of dexamethasone given for 6–8 weeks in addition to standard anti-tuberculosis drugs. LTA4H genotype (CC, CT, TT) was determined in all participants prior to randomisation; only those with CC or CT genotype were randomised to dexamethasone or placebo. All TT genotype participants received dexamethasone because prior data indicated survival was increased by dexamethasone in this genotype. The primary endpoint was all-cause death or new neurological event over the first 12 months after randomisation. We took a hybrid trial-design approach which aims to prove non-inferiority of placebo first but also allows claiming superiority of placebo in case dexamethasone causes substantial harm. This statistical analysis plan expands upon and updates the analysis plan outlined in the published study protocol.

Abstract Background Rupture of the anterior cruciate ligament (ACL) is a common injury, primarily affecting young, active individuals. Despite surgical intervention being the more common treatment for patients suffering ACL ruptures, current management is based on limited and generally low-quality evidence. We describe a statistical analysis plan (SAP) for the ACL SNNAP randomised controlled trial, which aims to investigate the necessity of surgical management in patients with ACL injuries. Methods/design ACL SNNAP is a pragmatic, multi-centre, superiority, parallel-group randomised controlled trial in participants with a symptomatic non-acute ACL deficient knee. Participants are allocated in a 1:1 ratio to either non-surgical management (rehabilitation) or surgical management (reconstruction) with the aim of assessing the efficacy and cost-effectiveness. The primary outcome of the study is the Knee Injury and Osteoarthritis Outcome Score (KOOS4) at 18 months post-randomisation. The KOOS4 score at 18 months will be evaluated using a linear regression model adjusting for recruitment centre and baseline KOOS4 scores, allowing for intra-centre correlation. A secondary analysis of the primary outcome will be carried out using an area under the curve (AUC) approach using treatment estimates obtained from a mixed model using baseline, 6 months, 12 months, and 18 months post-randomisation outcome data. Secondary outcomes will be measured at 18 months and will include return to activity/level of sport participation, intervention-related complications, the EQ-5D-5L questionnaire, all 5 individual subscales of the KOOS questionnaire, the ACL-QOL score, expectations of return to activity and cost-effectiveness of the interventions. Missing primary outcome data will be investigated through a sensitivity analysis. Full details of the planned methods for the statistical analysis of clinical outcomes are presented in this paper. The study protocol for the ACL SNNAP trial has been published previously. Discussion The methods of analysis for the ACL SNNAP trial have been described here to minimise the risk of data-driven results and reporting bias. Any deviations from the analysis methods described in this paper will be described in full and justified in the publications of the trial results. Trial registration ISRCTN ISRCTN10110685 . Registered on 16 November 2016

TBM is the most severe form of tuberculosis. Clinical trial data are required to provide an evidence base for adjunctive dexamethasone in HIV-positive individuals with TBM, and to guide clinical practice. This document details the planned analyses at 12 months post randomisation for the ACT HIV clinical trial (NCT03092817); ‘a randomised double-blind placebo-controlled trial of adjunctive dexamethasone for the treatment of HIV co-infected adults with tuberculous meningitis (TBM)’. The primary endpoint of the ACT HIV trial is death (from any cause) over the first 12 months after randomisation. This statistical analysis plan expands upon and updates the analysis plan outlined in the published study protocol.

Background: Rupture of the anterior cruciate ligament (ACL) is a common injury, primarily affecting young, active individuals. Despite surgical intervention being the more common treatment for patients suffering ACL ruptures, current management is based on limited and generally low-quality evidence. We describe a statistical analysis plan (SAP) for the ACL SNNAP randomised controlled trial, which aims to investigate the necessity of surgical management in patients with ACL injuries.Methods/design: ACL SNNAP is a pragmatic, multi-centre, superiority, parallel-group randomised controlled trial in participants with a symptomatic non-acute ACL deficient knee. Participants are allocated in a 1:1 ratio to either non-surgical management (rehabilitation) or surgical management (reconstruction) with the aim of assessing the efficacy and cost-effectiveness. The primary outcome of the study is the Knee Injury and Osteoarthritis Outcome Score (KOOS4) at 18 months post-randomisation. The KOOS4 score at 18 months will be evaluated using a linear regression model adjusting for recruitment centre and baseline KOOS4 scores, allowing for intra-centre correlation. A secondary analysis of the primary outcome will be carried out using an area under the curve (AUC) approach using treatment estimates obtained from a mixed model using baseline, 6 months, 12 months, and 18 months post-randomisation outcome data. Secondary outcomes will be measured at 18 months and will include return to activity/level of sport participation, intervention-related complications, the EQ-5D-5L questionnaire, all 5 individual subscales of the KOOS questionnaire, the ACL-QOL score, expectations of return to activity and cost-effectiveness of the interventions. Missing primary outcome data will be investigated through a sensitivity analysis. Full details of the planned methods for the statistical analysis of clinical outcomes are presented in this paper. The study protocol for the ACL SNNAP trial has been published previously.Discussion: The methods of analysis for the ACL SNNAP trial have been described here to minimise the risk of data-driven results and reporting bias. Any deviations from the analysis methods described in this paper will be described in full and justified in the publications of the trial results.Trial Registration: ISRCTN ISRCTN10110685 . Registered on 16 November 2016. [ABSTRACT FROM AUTHOR]

The knowledge produced in temperate regions is still used today to evaluate environmental problems in the tropics, without taking into consideration environmental differences, such as local conditions, the sensitivity and ecology of species, and exposure routes of contaminants, essential for understanding and determining the fate and toxicity of chemicals. Considering that Environmental Risk Assessment (ERA) studies for tropical systems are scarce and need to be adjusted, the present study aims at contributing to the awareness and development of tropical ecotoxicology. The estuary of the Paraíba River in Northeast Brazil was selected as a model study-case, as it is a large estuary, subjected to a heavy human pressure due to the numerous social, economic and industrial activities. The present study describes the framework for the problem formulation phase of the ERA process; it first includes a detailed integration of the scientific information available on the study area, to then derive the conceptual model, and finally present the analysis plan for the tier 1 screening phase. The latter is designed to be fundamentally supported by the ecotoxicological line of evidence, to ascertain, without delay, where and why there are environmental problems (i.e., adverse biological effects); ecotoxicological tools developed in temperate climates will be optimized to assess water quality in a tropical system. In addition to its intrinsic value for protecting the study area, the results of the present study are expected to provide an important baseline for conducting ERA in similar tropical aquatic systems across the globe. [Display omitted] • Environmental risk assessments (ERA) in subtropical and tropical countries are still limited. • Contaminants exposure characterization is often studied but toxic effects on biota are not. • In the Paraíba River estuary aquatic biota is particularly at risk due to heavy human pressure. • A retrospective tier 1 (preliminary) ERA for the ecotoxicological line of evidence is proposed. • To spatially map ecological risks, a tier 1 analysis plan with short-term lab tests is derived. [ABSTRACT FROM AUTHOR]

Objective: To describe, explain and give practical suggestions regarding important principles and key methodological challenges in the study design, statistical analysis, and reporting of results from in vivo studies.Conclusions: Pre-specifying endpoints and analysis, recognizing the common underlying assumption of statistically independent observations, performing sample size calculations, and addressing multiplicity issues are important parts of an in vivo study. A clear reporting of results and informative graphical presentations of data are other important parts. [ABSTRACT FROM AUTHOR]

This article presents a strategy to improve comparisons in observational studies. We illustrate this strategy by analyzing the case of Chaitén after the volcanic eruptions of 2008. As a result of this natural disaster, that city suffered the overflow of the Blanco River, leaving the city divided between the north and south sectors. The Chilean State declared Chaitén to be uninhabitable until 2011, where it exclusively authorized the occupation of the northern sector. To date, both sectors have been occupied, marking a sharp difference between regular and irregular settlements. We use this distinction to identify the effect that living in an irregular settlement has on trust and cooperation. In order to do this, we analyzed qualitative information and survey data from 2015. In a first step, the analysis of qualitative information indicates a significant process of self-selection of the subjects in the treatment conditions. Then, we designed valid comparisons based on a Full Matching method for analyzing the effects on the dependent variables. The results indicate that, on average, living in irregular settlements increased cooperation. However, there may be a strong heterogeneity in the way that the agents respond to the interventions here analyzed. As a consequence, in order to improve the interpretation of these results, it would be necessary to take into account other factors not observed in the data here analyzed. We finish this study by developing a series of implications for the design and planning of observational studies, in general. [ABSTRACT FROM AUTHOR]

Objective: To identify, characterize, and explore author guides on the role, format, and content of protocols for observational epidemiological studies, particularly cohort and case-control studies., Study Design and Setting: Scoping review. We searched for guides in Medline, Embase, Google Scholar, 10 general medical and epidemiological/public health journals, and 10 major funders' websites. Two review authors extracted data. We classified guides as "main" based on word count and number of protocol items, described such guides more comprehensively and analyzed number of citations as an indicator of uptake., Results: Thirty-nine protocol guides were included intended for cohort studies (n = 3), case-control studies (n = 1), or epidemiological studies in general (n = 35). Content and format were highly variable. Several guides had a broader focus than protocol development, e.g., also including study conduct and reporting. The guideline developmental process was often reported sparsely. One guide, intended for interventional studies, combined a systematic preparatory process with a primary focus on protocol development. We categorized seven guides as 'main'. In general the guides were cited infrequently, indicating limited uptake., Conclusion: Guides for authors of protocols for observational epidemiological studies varied highly in format and content. We suggest that such guides should routinely be based on a systematic preparatory process., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The need for the integration of the assessment of human and ecological risks in contaminated areas, such as derelict mines, widely increases. The risk assessment process is becoming a powerful tool to provide sound scientific bases for decision-making processes. In Portugal, the risk assessment process is in its early years and the lack of multidisciplinary teams of experts is frequently mentioned as the main obstacle to its implementation. Therefore, the majority of the reclamation actions are based on impact assessment studies that usually are characterized by few biological and toxicological considerations. In order to account for some of these constraints, the ecological risk assessment framework proposed by the U.S. Environmental Protection Agency was used to plan the assessment of human and ecological risks posed by the high concentrations of metals scattered in the vicinity of S. Domingos mine, a cuprous pyrite mine located in the Southeast Alentejo (Portugal). This study presents the problem formulation phase of the assessment. It includes all the scientific information available for the area, a conceptual model, and an analysis plan for the risk assessment process. Following a tiered approach, several tasks were planned in order to acquire chemical, toxicological, and ecological information, in order to compensate for the lack of toxicity data for site-specific species. [ABSTRACT FROM AUTHOR]

TBM is the most severe form of tuberculosis. Clinical trial data are required to provide an evidence base for adjunctive dexamethasone in HIV-positive individuals with TBM, and to guide clinical practice. This document details the planned analyses at 12 months post randomisation for the ACT HIV clinical trial (NCT03092817); 'a randomised double-blind placebo-controlled trial of adjunctive dexamethasone for the treatment of HIV co-infected adults with tuberculous meningitis (TBM)'. The primary endpoint of the ACT HIV trial is death (from any cause) over the first 12 months after randomisation. This statistical analysis plan expands upon and updates the analysis plan outlined in the published study protocol., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Donovan J et al.)

Qualification of a biomarker for use in a medical product development program requires a statistical strategy that aligns available evidence with the proposed context of use (COU), identifies any data gaps to be filled and plans any additional research required to support the qualification. Accumulating, interpreting and analyzing available data is outlined, step-by-step, illustrated by a qualified enrichment biomarker example and a safety biomarker in the process of qualification. The detailed steps aid requestors seeking qualification of biomarkers, allowing them to organize the available evidence and identify potential gaps. This provides a statistical perspective for assessing evidence that parallels clinical considerations and is intended to guide the overall evaluation of evidentiary criteria to support a specific biomarker COU.