The near triad and associated visual problems

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Case-Finding Strategies for Drug-Resistant Tuberculosis: Protocol for a Scoping Review.

BACKGROUND Transmission of drug-resistant tuberculosis (DR-TB) is ongoing. Finding individuals with DR-TB and initiating treatment as early as possible is important to improve patient clinical outcomes and to break the chain of transmission to control the pandemic. To our knowledge systematic reviews assessing effectiveness, cost-effectiveness, acceptability, and feasibility of different case-finding strategies for DR-TB to inform research, policy, and practice have not been conducted, and it is unknown whether enough research exists to conduct such reviews. It is unknown whether case-finding strategies are similar for DR-TB and drug-susceptible TB and whether we can draw on findings from drug-susceptible reviews to inform decisions on case-finding strategies for DR-TB. OBJECTIVE This protocol aims to describe the available literature on case-finding for DR-TB and to describe case-finding strategies. METHODS We will screen systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that specifically sought to improve DR-TB case detection. We will exclude studies that invited individuals seeking care for TB symptoms, those including individuals already diagnosed with TB, or laboratory-based studies. We will search the academic databases including MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL, Epistemonikos, and PROSPERO with no language or date restrictions. We will screen titles, abstracts, and full-text articles in duplicate. Data extraction and analyses will be performed using Excel (Microsoft Corp). RESULTS We will provide a narrative report with supporting figures or tables to summarize the data. A systems-based logic model, developed from a synthesis of case-finding strategies for drug-susceptible TB, will be used as a framework to describe different strategies, resulting pathways, and enhancements of pathways. The search will be conducted at the end of 2021. Title and abstract screening, full text screening, and data extraction will be undertaken from January to June 2022. Thereafter, analysis will be conducted, and results compiled. CONCLUSIONS This scoping review will chart existing literature on case-finding for DR-TB-this will help determine whether primary studies on effectiveness, cost-effectiveness, acceptability, and feasibility of different case-finding strategies for DR-TB exist and will help formulate potential questions for a systematic review. We will also describe case-finding strategies for DR-TB and how they fit into a model of case-finding pathways for drug-susceptible TB. This review has some limitations. One limitation is the diverse, inconsistent use of intervention terminology within the literature, which may result in missing relevant studies. Poor reporting of intervention strategies may also cause misunderstanding and misclassification of interventions. Lastly, case-finding strategies for DR-TB may not fit into a model developed from strategies for drug-susceptible TB. Nevertheless, such a situation will provide an opportunity to refine the model for future research. The review will guide further research to inform decisions on case-finding policies and practices for DR-TB. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/40009

Number of sputum specimens during treatment follow-up of tuberculosis patients: two or one?

SETTING: National Institute for Research in Tuberculosis clinics in Chennai and Madurai, India. OBJECTIVE: To examine the pattern of serial smears (negative-negative [NN], negative-positive [NP], positive-negative [PN], positive-positive [PP]) during treatment follow-up of culture-confirmed new smear-positive tuberculosis (TB) patients, and the proportion of culture-negatives in each category. DESIGN: We reviewed the records and extracted follow-up smear (fluorescent microscopy) and culture (Löwenstein-Jensen) results of patients enrolled in clinical trials from January 2000 to August 2012 and treated with the Category I regimen (2EHRZ(3)/4HR(3)). Data entry and analysis were performed using EpiData. RESULTS: Among 520 patients (176 infected with the human immunodeficiency virus), the proportions of culture-negative patients with NN, discordant (PN or NP) and PP patterns were approximately 98%, 80% and 40%, respectively. The smear-positive culture-negative phenomenon was more frequent in follow-up smear results graded 1+, followed by 2+ and 3+. CONCLUSION: There is justification for discontinuing the examination of second specimens during treatment follow-up among TB patients. However, a positive result on the first smear needs to be confirmed by a second positive result before making clinical management decisions. The World Health Organization may need to reconsider its recommendation on this issue

Secondary analysis of tuberculosis stigma data from a cluster randomised trial in Zambia and South Africa (ZAMSTAR).

SETTING: Zambian and South African TB and HIV Reduction (ZAMSTAR) cluster-randomised trial (CRT) communities, 2006-2009. OBJECTIVES: To develop TB stigma items, and evaluate changes in them in response to a household intervention aimed at reducing TB transmission and prevalence but not tailored to reduce stigma. DESIGN: TB stigma was measured at baseline and 18 months later among 1826 recently diagnosed TB patients and 1235 adult members of their households across 24 communities; 12 of 24 communities were randomised to receive the household intervention. We estimated the impact of the household intervention on TB stigma using standard CRT analytical methods. RESULTS: Among household members, prevalence of blame and belief in transmission myths fell in both study arms over time: adjusted prevalence ratios (aPRs) comparing the household intervention with the non-household intervention arm were respectively 0.61 (95%CI 0.26-1.44) and 0.77 (95%CI 0.48-1.25) at 18-month follow-up. Among TB patients, at baseline a low percentage experienced social exclusion and poor treatment by health staff and a relatively high percentage reported 'being made fun of', with little change over time. Disclosure of TB status increased over time in both study arms. Internalised stigma was less prevalent in the household arm at both baseline and follow-up, with an aPR of 0.85 (95%CI 0.41-1.76). Variability in stigma levels between countries and across communities was large. CONCLUSION: Robust TB stigma items were developed. TB stigma was not significantly reduced by the household intervention, although confidence intervals for estimated intervention effects were wide. We suggest that stigma-specific interventions are required to effectively address TB stigma

A genotype-guided strategy for oral P2Y₁₂ Inhibitors in primary PCI

BACKGROUND: It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y12 inhibitors. METHODS: We conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events - defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria - at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome). RESULTS: For the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.0 to 0.7; P<0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P = 0.04). CONCLUSIONS: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy for selection of oral P2Y12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.)

Revealing determinants of translation efficiency via whole-gene codon randomization and machine learning

It has been known for decades that codon usage contributes to translation efficiency and hence to protein production levels. However, its role in protein synthesis is still only partly understood. This lack of understanding hampers the design of synthetic genes for efficient protein production. In this study, we generated a synonymous codon-randomized library of the complete coding sequence of red fluorescent protein. Protein production levels and the full coding sequences were determined for 1459 gene variants in Escherichia coli. Using different machine learning approaches, these data were used to reveal correlations between codon usage and protein production. Interestingly, protein production levels can be relatively accurately predicted (Pearson correlation of 0.762) by a Random Forest model that only relies on the sequence information of the first eight codons. In this region, close to the translation initiation site, mRNA secondary structure rather than Codon Adaptation Index (CAI) is the key determinant of protein production. This study clearly demonstrates the key role of codons at the start of the coding sequence. Furthermore, these results imply that commonly used CAI-based codon optimization of the full coding sequence is not a very effective strategy. One should rather focus on optimizing protein production via reducing mRNA secondary structure formation with the first few codons

Mortality in South African children and adolescents routinely treated for tuberculosis

BACKGROUND: In South Africa, tuberculosis (TB) is a leading cause of death among those abstract, 20 years of age. We describe changes in TB mortality among children and adolescents in South Africa over a 13-year period, identify risk factors for mortality, and estimate excess TBrelated mortality. METHODS: Retrospective analysis of all patients ,20 years of age routinely recorded in the national electronic drug-susceptible TB treatment register (2004–2016). We developed a multivariable Cox regression model for predictors of mortality and used estimates of mortality among the general population to calculate standardized mortality ratios (SMRs). RESULTS: Between 2004 and 2016, 729 463 children and adolescents were recorded on TB treatment; 84.0% had treatment outcomes and 2.5% (18 539) died during TB treatment. The case fatality ratio decreased from 3.3% in 2007 to 1.9% in 2016. In the multivariable Cox regression model, ages 0 to 4, 10 to 14, and 15 to 19 years (compared with ages 5 to 9 years) were associated with increased risk of mortality, as was HIV infection, previous TB treatment, and extrapulmonary involvement. The SMR of 15 to 19-year-old female patients was more than double that of male patients the same age (55.3 vs 26.2). Among 10 to 14-year-olds and those who were HIV-positive

Mortality during tuberculosis treatment in South Africa using an 8-year analysis of the national tuberculosis treatment register

n 2011, the South African HIV treatment eligibility criteria were expanded to allow all tuberculosis (TB) patients lifelong ART. The impact of this change on TB mortality in South Africa is not known. We evaluated mortality in all adults (≥ 15 years old) treated for drug-susceptible TB in South Africa between 2009 and 2016. Using a Cox regression model, we quantified risk factors for mortality during TB treatment and present standardised mortality ratios (SMR) stratified by year, age, sex, and HIV status. During the study period, 8.6% (219,618/2,551,058) of adults on TB treatment died. Older age, male sex, previous TB treatment and HIV infection (with or without the use of ART) were associated with increased hazard of mortality. There was a 19% reduction in hazard of mortality amongst all TB patients between 2009 and 2016 (adjusted hazard ratio: 0.81 95%CI 0.80–0.83). The highest SMR was in 15–24-year-old women, more than double that of men (42.3 in 2016). Between 2009 and 2016, the SMR for HIV-positive TB patients increased, from 9.0 to 19.6 in women, and 7.0 to 10.6 in men. In South Africa, case fatality during TB treatment is decreasing and further interventions to address specific risk factors for TB mortality are required. Young women (15–24-year olds) with TB experience a disproportionate burden of mortality and interventions targeting this age-group are needed