A systematic review of endpoint definitions in late phase pulmonary tuberculosis therapeutic trials.

BACKGROUND: Safe, more efficacious treatments are needed to address the considerable morbidity and mortality associated with pulmonary tuberculosis (TB). However, the current practice in TB therapeutics trials is to use composite binary outcomes, which in the absence of standardization may inflate false positive and negative errors in evaluating regimens. The lack of standardization of outcomes is a barrier to the identification of highly efficacious regimens and the introduction of innovative methodologies METHODS: We conducted a systematic review of trials designed to advance new pulmonary TB drugs or regimens for regulatory approval and inform practice guidelines. Trials were primarily identified from the WHO International Clinical Trial Registry Platform (ICTRP). Only trials that collected post-treatment follow-up data and enrolled at least 100 patients were included. Protocols and Statistical Analysis Plans (SAP) for eligible trials from 1995 to the present were obtained from trial investigators. Details of outcome data, both explicit and implied, were abstracted and organized into three broad categories: favorable, unfavorable, and not assessable. Within these categories, individual trial definitions were recorded and collated, and areas of broad consensus and disagreement were identified and described. RESULTS: From 2205 trials in any way related to TB, 51 were selected for protocol and SAP review, from which 31 were both eligible and had accessible documentation. Within the three designated categories, we found broad consensus in the definitions of favorable and unfavorable outcomes, although specific details were not always provided, and when explicitly addressed, were heterogeneous. Favorable outcomes were handled the most consistently but were widely variable with respect to specification. In some cases, the same events were defined differently by different protocols, particularly in distinguishing unfavorable from not assessable events. Death was often interpreted as conditional on cause. Patients who did not complete the study because of withdrawal or loss to follow-up presented a particular challenge to consistent interpretation and analytic treatment of outcomes. CONCLUSIONS: In a review of 31 clinical trials, we found that outcome definitions were heterogeneous, highlighting the need to establish clearer specification and a move towards universal standardization of outcomes across pulmonary TB trials. The ICH E9 (R1) addendum provides guidelines for undertaking and achieving this goal. PROSPERO REGISTRATION: PROSPERO CRD42020197993 . Registration 11 August 2020.

Impacts of variability and change in rainfall on gender of farmers in Anambra, Southeast Nigeria.

Men and women farmers experience different impacts of climate variability and change (CVC). Research on the differentiated impacts of variability and change in rainfall on gender is limited in the study area. This study examined perceptions and experience of men and women farmers on the impacts of CVC, using climate data and farmers' perception from a gender perspective. It examined the effect of CVC on annual and seasonal rainfall, number of rain days, onset and cessation of rainfall; perceived impacts of CVC on annual and seasonal rainfall and compared the measured (meteorological) impacts with the perceived impacts across gender. Mixed methods of qualitative and quantitative data collection and participatory rural approaches were used. Household survey of 50% men and 50% women each were conducted in six farming communities. Data analysis involved the use of annual rainfall trends, Annual Rainfall Anomaly (ARA), Standardized Annual Rainfall Anomaly (SARA), regression analysis percentages and chi-square. Results reveal the occurrences of more dry years than wet years (ARA and SARA <0.00) in the three locations. There were wide variability and changes in inter-annual rainfall in Ogbaru (R2 = 0.0003), Anambra East (R2 = 0.0071) and Ayamelum (R2 = 0.0014). Seasonal rainfall was unevenly distributed from 2007-2016. There were wide variations in dates of onset and cessation of rainy season (R2 = 0.006) and number of rain days (R2 = 0.009). Men and women responses revealed that there were statistically significant (p < 0.005) changes in the onset of rainy season, early cessation of annual rainfall; alteration of growing seasons; frequent flooding and frequent drought. Women felt more impact of food insecurity, water shortage and had more burden of migration due to changes in rainfall. This study concludes that respondents perceived and experienced impacts of CVC which varied across gender. Hence, it recommends the provision of sustainable water and irrigation system which should encourage women's participation in the construction, maintenance and management among others.

Disseminated tuberculosis in human immunodeficiency virus infection: ineffective immunity, polyclonal disease and high mortality.

BACKGROUND: Disseminated tuberculosis (TB) is a major cause of death in patients with the acquired immune-deficiency syndrome (AIDS), but its pathogenesis and clinical features have not been defined prospectively. METHODS: Human immunodeficiency virus (HIV) infected adults with a CD4 count ≥ 200 cells/µl and bacille Calmette-Guérin scar underwent immunologic evaluation and subsequent follow-up. RESULTS: Among 20 subjects who developed disseminated TB, baseline tuberculin skin tests were ≥15 mm in 14 (70%) and lymphocyte proliferative responses to Mycobacterium tuberculosis were positive in 14 (70%). At the time of diagnosis, fever ≥2 weeks plus ≥5 kg weight loss was reported in 16 (80%) patients, abnormal chest X-rays in 7/17 (41%), and positive sputum cultures in 10 (50%); median CD4 count was 30 cells/µl (range 1-122). By insertion sequence (IS) 6110 analysis, 14 (70%) blood isolates were clustered and 3/8 (37%) concurrent sputum isolates represented a different strain (polyclonal disease). Empiric TB treatment was given to eight (40%) patients; 11 (55%) died within a month. CONCLUSIONS: Disseminated TB in HIV occurs with cellular immune responses indicating prior mycobacterial infection, and IS6110 analysis suggests an often lethal combination of reactivation and newly acquired infection. Control will require effective prevention of both remotely and recently acquired infection, and wider use of empiric therapy in patients with advanced AIDS and prolonged fever.