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Background: The COVID-19 pandemic negatively impacted tuberculosis (TB) treatment services, including directly observed therapy (DOT) programs used to promote medication adherence. We compared DOT adherence embedded in a research study before and after COVID-19 lockdowns in South Africa., Methods: We analyzed data from 263 observational study participants undergoing drug susceptible (DS)-TB DOT between May 2017 to March 2022. Participants enrolled before October 2019 were considered 'pre-COVID-19' and those enrolled after September 2020 were considered 'post-COVID-19 lockdown groups. Negative binomial regression models were used to compare DOT non-adherence rates between the two lockdown groups. We then conducted a sensitivity analysis which only included participants enrolled in the immediate period following the first COVID-19 lockdown., Results: DOT non-adherence rate was higher in the post-COVID-19 lockdown group (aIRR = 1.42, 95% CI = 1.04-1.96; p = 0.028) compared to pre-COVID-19 lockdown period, adjusting for age, sex, employment status, household hunger, depression risk, and smoked substance use. DOT non-adherence was highest immediately following the initial lockdown (aIRR = 1.74, 95% CI = 1.17-2.67; p = 0.006)., Conclusion: The COVID-19 lockdowns adversely effected adherence to TB DOT in the period after lockdowns were lifted. The change in DOT adherence persisted even after adjusting for socioeconomic and behavioral variables. We need a better understanding of what treatment adherence barriers were exacerbated by COVID-19 lockdowns to improve outcomes in post-pandemic times., Trial Registration: ClinicalTrials.gov Registration Number: NCT02840877. Registered on 19 July 2016., (© 2024. The Author(s).)

There is substantial heterogeneity in disease presentation for individuals with TB disease, which may correlate with disease outcomes. We estimated disease outcomes by disease severity at presentation among individuals with TB during the pre-chemotherapy era.We extracted data on people with TB enrolled between 1917 and 1948 in the USA, stratified by three disease severity categories at presentation using the U.S. National Tuberculosis Association diagnostic criteria. These criteria were based largely on radiographic findings ("minimal", "moderately advanced", and "far advanced"). We used Bayesian parametric survival analysis to model the survival distribution overall, and by disease severity and Bayesian logistic regression to estimate the severity-level specific natural recovery odds within 3 years.People with minimal TB at presentation had a 2% (95% CrI 0-11%) probability of TB death within 5 years vs. 40% (95% CrI 15-68) for those with far advanced disease. Individuals with minimal disease had 13.62 times the odds (95% CrI 9.87-19.10) of natural recovery within 3 years vs. those with far advanced disease.Mortality and natural recovery vary by disease severity at presentation. This supports continued work to evaluate individualized (e.g., shortened or longer) regimens based on disease severity at presentation, identified using radiography..

BACKGROUND: An estimated 40% of people who developed TB in 2021 were not diagnosed or treated. Pre-chemotherapy era data are a rich resource on survival of people with untreated TB. We aimed to identify heterogeneities in these data to inform their more precise use. METHODS: We extracted survival data from pre-chemotherapy era papers reporting TB-specific mortality and/or natural recovery data. We used Bayesian parametric survival analysis to model the survival distribution, stratifying by geography (North America vs. Europe), time (pre-1930 vs. post-1930), and setting (sanitoria vs. non-sanitoria). RESULTS: We found 12 studies with TB-specific mortality data. Ten-year survival was 69% in North America (95% CI 54-81) and 36% in Europe (95% CI 10-71). Only 38% (95% CI 18-63) of non-sanitorium individuals survived to 10 years compared to 69% (95% CI 41-87) of sanitoria/hospitalized patients. There were no significant differences between people diagnosed pre-1930 and post-1930 (5-year survival pre-1930: 65%, 95% CI 44-88 vs. post-1930: 72%, 95% CI 41-94). CONCLUSIONS: Mortality and natural recovery risks vary substantially by location and setting. These heterogeneities need to be considered when using pre-chemotherapy data to make inferences about expected survival of people with undiagnosed TB.

BACKGROUND: Smoking of illicit drugs may lead to more rapid TB disease progression or late treatment presentation, yet research on this topic is scant. We examined the association between smoked drug use and bacterial burden among patients newly initiated on drug-susceptible TB (DS-TB) therapy. METHODS: Data from 303 participants initiating DS-TB treatment in the Western Cape Province, South Africa, were analyzed. Smoked drug use was defined as self-reported or biologically verified methamphetamine, methaqualone and/or cannabis use. Proportional hazard and logistic regression models (adjusted for age, sex, HIV status and tobacco use) examined associations between smoked drug use and mycobacterial time to culture positivity (TTP), acid-fast bacilli sputum smear positivity and lung cavitation. RESULTS: People who smoked drugs (PWSD) comprised 54.8% ( n = 166) of the cohort. TTP was faster for PWSD (hazard ratio 1.48, 95% CI 1.10-1.97; P = 0.008). Smear positivity was higher among PWSD (OR 2.28, 95% CI 1.22-4.34; P = 0.011). Smoked drug use (OR 1.08, 95% CI 0.62-1.87; P = 0.799) was not associated with increased cavitation. CONCLUSIONS: PWSD had a higher bacterial burden at diagnosis than those who do not smoke drugs. Screening for TB among PWSD in the community may facilitate earlier linkage to TB treatment and reduce community transmission.

Background: In January 2022, US guidelines shifted to recommend isolation for 5 days from symptom onset, followed by 5 days of mask-wearing. However, viral dynamics and variant and vaccination impact on culture conversion are largely unknown., Methods: We conducted a longitudinal study on a university campus, collecting daily anterior nasal swabs for at least 10 days for reverse-transcription polymerase chain reaction (RT-PCR) testing and culture, with antigen rapid diagnostic testing (RDT) on a subset. We compared culture positivity beyond day 5, time to culture conversion, and cycle threshold trend when calculated from diagnostic test, from symptom onset, by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, and by vaccination status. We evaluated sensitivity and specificity of RDT on days 4-6 compared with culture., Results: Among 92 SARS-CoV-2 RT-PCR-positive participants, all completed the initial vaccine series; 17 (18.5%) were infected with Delta and 75 (81.5%) with Omicron. Seventeen percent of participants had positive cultures beyond day 5 from symptom onset, with the latest on day 12. There was no difference in time to culture conversion by variant or vaccination status. For 14 substudy participants, sensitivity and specificity of day 4-6 RDT were 100% and 86%, respectively., Conclusions: The majority of our Delta- and Omicron-infected cohort culture-converted by day 6, with no further impact of booster vaccination on sterilization or cycle threshold decay. We found that rapid antigen testing may provide reassurance of lack of infectiousness, though guidance to mask for days 6-10 is supported by our finding that 17% of participants remained culture-positive after isolation., Competing Interests: Potential conflicts of interest. D. H. H. reports funding from the Centers for Disease Control and Prevention for GeoSentinel (1 U01CK000632-01-00) paid to institution and unrelated to this study; personal consulting fees from Major League Soccer, Equinox, Xenophon Strategies, PGA of America; legal consulting fees from Hamilton, Miller & Birthisel, LLP; an unpaid role as data and safety monitoring board chair for a randomized trial to determine the effect of vitamin D and zinc supplementation for improving treatment outcomes among coronavirus disease 2019 patients in India (COVEDZ); and an unpaid volunteer position as secretary–treasurer for the GeoSentinel Foundation, Inc. C. M. K. reports grants or contracts unrelated to this work from NIH NIGMS, Uniformed Services University, BU, and DARPA; consulting fees paid to author from Adventus Research + Consulting, Inc; a leadership or fiduciary role on the Biomedical Engineering Society Board (member) and the American Institute for Medical and Biological Engineering; and 3.0% ownership and cofounder of BioSens8, LLC. J. H. C. reports funding (supports SARS-CoV-2 variant) from Mass CPR/Evergrande and consulting fees paid to author from Cell Signaling Technologies. T. C. B. reports grants or contracts unrelated to this work from Gilead Sciences, Inc and Fujifilm Pharmaceuticals U.S.A., Inc. Z. Z. reports grants or contracts unrelated to this work. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The occurrence and timing of mycobacterial culture conversion is used as a proxy for tuberculosis treatment response. When researchers serially sample sputum during tuberculosis studies, contamination or missed visits leads to missing data points. Traditionally, this is managed by ignoring missing data or simple carry-forward techniques. Statistically advanced multiple imputation methods potentially decrease bias and retain sample size and statistical power., Methods: We analyzed data from 261 participants who provided weekly sputa for the first 12 weeks of tuberculosis treatment. We compared methods for handling missing data points in a longitudinal study with a time-to-event outcome. Our primary outcome was time to culture conversion, defined as two consecutive weeks with no Mycobacterium tuberculosis growth. Methods used to address missing data included: 1) available case analysis, 2) last observation carried forward, and 3) multiple imputation by fully conditional specification. For each method, we calculated the proportion culture converted and used survival analysis to estimate Kaplan-Meier curves, hazard ratios, and restricted mean survival times. We compared methods based on point estimates, confidence intervals, and conclusions to specific research questions., Results: The three missing data methods lead to differences in the number of participants achieving conversion; 78 (32.8%) participants converted with available case analysis, 154 (64.7%) converted with last observation carried forward, and 184 (77.1%) converted with multiple imputation. Multiple imputation resulted in smaller point estimates than simple approaches with narrower confidence intervals. The adjusted hazard ratio for smear negative participants was 3.4 (95% CI 2.3, 5.1) using multiple imputation compared to 5.2 (95% CI 3.1, 8.7) using last observation carried forward and 5.0 (95% CI 2.4, 10.6) using available case analysis., Conclusion: We showed that accounting for missing sputum data through multiple imputation, a statistically valid approach under certain conditions, can lead to different conclusions than naïve methods. Careful consideration for how to handle missing data must be taken and be pre-specified prior to analysis. We used data from a TB study to demonstrate these concepts, however, the methods we described are broadly applicable to longitudinal missing data. We provide valuable statistical guidance and code for researchers to appropriately handle missing data in longitudinal studies., (© 2022. The Author(s).)

Background: Throughout the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, healthcare workers (HCWs) have faced risk of infection from within the workplace via patients and staff as well as from the outside community, complicating our ability to resolve transmission chains in order to inform hospital infection control policy. Here we show how the incorporation of sequences from public genomic databases aided genomic surveillance early in the pandemic when circulating viral diversity was limited., Methods: We sequenced a subset of discarded, diagnostic SARS-CoV-2 isolates between March and May 2020 from Boston Medical Center HCWs and combined this data set with publicly available sequences from the surrounding community deposited in GISAID with the goal of inferring specific transmission routes., Results: Contextualizing our data with publicly available sequences reveals that 73% (95% confidence interval, 63%-84%) of coronavirus disease 2019 cases in HCWs are likely novel introductions rather than nosocomial spread., Conclusions: We argue that introductions of SARS-CoV-2 into the hospital environment are frequent and that expanding public genomic surveillance can better aid infection control when determining routes of transmission., Competing Interests: Potential conflicts of interest. W. P. H. is a member of Biobot Analytics’ scientific advisory board. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The coronavirus disease 2019 (COVID-19) pandemic disrupted access to and uptake of hepatitis C virus (HCV) care services in the United States. It is unknown how substantially the pandemic will impact long-term HCV-related outcomes., Methods: We used a microsimulation to estimate the 10-year impact of COVID-19 disruptions in healthcare delivery on HCV outcomes including identified infections, linkage to care, treatment initiation and completion, cirrhosis, and liver-related death. We modeled hypothetical scenarios consisting of an 18-month pandemic-related disruption in HCV care starting in March 2020 followed by varying returns to pre-pandemic rates of screening, linkage, and treatment through March 2030 and compared them to a counterfactual scenario in which there was no COVID-19 pandemic or disruptions in care. We also performed alternate scenario analyses in which the pandemic disruption lasted for 12 and 24 months., Results: Compared to the "no pandemic" scenario, in the scenario in which there is no return to pre-pandemic levels of HCV care delivery, we estimate 1060 fewer identified cases, 21 additional cases of cirrhosis, and 16 additional liver-related deaths per 100 000 people. Only 3% of identified cases initiate treatment and <1% achieve sustained virologic response (SVR). Compared to "no pandemic," the best-case scenario in which an 18-month care disruption is followed by a return to pre-pandemic levels, we estimated a smaller proportion of infections identified and achieving SVR., Conclusions: A recommitment to the HCV epidemic in the United States that involves additional resources coupled with aggressive efforts to screen, link, and treat people with HCV is needed to overcome the COVID-19-related disruptions., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: In January 2022, United States guidelines shifted to recommend isolation for 5 days from symptom onset, followed by 5 days of mask wearing. However, viral dynamics and variant and vaccination impact on culture conversion are largely unknown., Methods: We conducted a longitudinal study on a university campus, collecting daily anterior nasal swabs for at least 10 days for RT-PCR and culture, with antigen rapid diagnostic testing (RDT) on a subset. We compared culture positivity beyond day 5, time to culture conversion, and cycle threshold trend when calculated from diagnostic test, from symptom onset, by SARS-CoV-2 variant, and by vaccination status. We evaluated sensitivity and specificity of RDT on days 4-6 compared to culture., Results: Among 92 SARS-CoV-2 RT-PCR positive participants, all completed the initial vaccine series, 17 (18.5%) were infected with Delta and 75 (81.5%) with Omicron. Seventeen percent of participants had positive cultures beyond day 5 from symptom onset with the latest on day 12. There was no difference in time to culture conversion by variant or vaccination status. For the 14 sub-study participants, sensitivity and specificity of RDT were 100% and 86% respectively., Conclusions: The majority of our Delta- and Omicron-infected cohort culture-converted by day 6, with no further impact of booster vaccination on sterilization or cycle threshold decay. We found that rapid antigen testing may provide reassurance of lack of infectiousness, though masking for a full 10 days is necessary to prevent transmission from the 17% of individuals who remain culture positive after isolation., Main Point: Beyond day 5, 17% of our Delta and Omicron-infected cohort were culture positive. We saw no significant impact of booster vaccination on within-host Omicron viral dynamics. Additionally, we found that rapid antigen testing may provide reassurance of lack of infectiousness.

Globally, an estimated 107 million people have an alcohol use disorder (AUD) leading to 2.8 million premature deaths each year. Tuberculosis (TB) is one of the leading causes of death globally and over 8% of global TB cases are estimated to be attributable to AUD. Social determinants of health such as poverty and undernutrition are often shared among those with AUD and TB and could explain the epidemiologic association between them. However, recent studies suggest that these shared risk factors do not fully account for the increased risk of TB in people with AUD. In fact, AUD has been shown to be an independent risk factor for TB, with a linear increase in the risk for TB with increasing alcohol consumption. While few studies have focused on potential biological mechanisms underlying the link between AUD and TB, substantial overlap exists between the effects of alcohol on lung immunity and the mechanisms exploited by Mycobacterium tuberculosis ( Mtb ) to establish infection. Alcohol misuse impairs the immune functions of the alveolar macrophage, the resident innate immune effector in the lung and the first line of defense against Mtb in the lower respiratory tract. Chronic alcohol ingestion also increases oxidative stress in the alveolar space, which could in turn facilitate Mtb growth. In this manuscript, we review the epidemiologic data that links AUD to TB. We discuss the existing literature on the potential mechanisms by which alcohol increases the risk of TB and review the known effects of alcohol ingestion on lung immunity to elucidate other mechanisms that Mtb may exploit. A more in-depth understanding of the link between AUD and TB will facilitate the development of dual-disease interventions and host-directed therapies to improve lung health and long-term outcomes of TB., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wigger, Bouton, Jacobson, Auld, Yeligar and Staitieh.)

Background: Coronavirus disease 2019 (COVID-19) vaccine trials and post-implementation data suggest that vaccination decreases infections. We examine vaccination's impact on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case rates and viral diversity among health care workers (HCWs) during a high community prevalence period., Methods: In this prospective cohort study, HCW received 2 doses of BNT162b2 or mRNA-1273. We included confirmed cases among HCWs from 9 December 2020 to 23 February 2021. Weekly SARS-CoV-2 rates per 100,000 person-days and by time from first injection (1-14 and ≥15 days) were compared with surrounding community rates. Viral genomes were sequenced., Results: SARS-CoV-2 cases occurred in 1.4% (96/7109) of HCWs given at least a first dose and 0.3% (17/5913) of HCWs given both vaccine doses. Adjusted rate ratios (95% confidence intervals) were 0.73 (.53-1.00) 1-14 days and 0.18 (.10-.32) ≥15 days from first dose. HCW ≥15 days from initial dose compared to 1-14 days were more often older (46 vs 38 years, P = .007), Latinx (10% vs 8%, P = .03), and asymptomatic (48% vs 11%, P = .0002). SARS-CoV-2 rates among HCWs fell below the surrounding community, an 18% vs 11% weekly decrease, respectively ( P = .14). Comparison of 50 genomes from post-first dose cases did not indicate selection pressure toward known spike antibody escape mutations., Conclusions: Our results indicate an early positive impact of vaccines on SARS-CoV-2 case rates. Post-vaccination isolates did not show unusual genetic diversity or selection for mutations of concern., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: A major challenge for prospective, clinical tuberculosis (TB) research is accurately defining a metric for measuring medication adherence., Objective: We aimed to design a method to capture directly observed therapy (DOT) via mobile health carried out by community workers. The program was created specifically to measure TB medication adherence for a prospective TB cohort in Western Cape Province, South Africa., Methods: Community workers collect daily adherence data on mobile smartphones. Participant-level adherence, program-level adherence, and program function are systematically monitored to assess DOT program implementation. A data dashboard allows for regular visualization of indicators. Numerous design elements aim to prevent or limit data falsification and ensure study data integrity., Results: The cohort study is ongoing and data collection is in progress. Enrollment began on May 16, 2017, and as of January 12, 2021, a total of 236 participants were enrolled. Adherence data will be used to analyze the study's primary aims and to investigate adherence as a primary outcome., Conclusions: The DOT program includes a mobile health application for data collection as well as a monitoring framework and dashboard. This approach has potential to be adapted for other settings to improve the capture of medication adherence in clinical TB research., Trial Registration: Clinicaltrials.gov NCT02840877; https://clinicaltrials.gov/ct2/show/NCT02840877., (©Elizabeth J Ragan, Christopher J Gill, Matthew Banos, Tara C Bouton, Jennifer Rooney, Charles R Horsburgh, Robin M Warren, Bronwyn Myers, Karen R Jacobson. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 16.06.2021.)

To determine the association between immunosuppression and time to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) clearance, we studied 3758 adults retested following initial SARS-CoV-2 infection. Cox proportional hazards models demonstrated delayed PCR clearance with older age, multiple comorbidities, and solid organ transplant but not by degree of immunocompromise. These findings challenge current retesting practices., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: South Africa temporarily banned alcohol and tobacco sales for about 20 weeks during the COVID-19 lockdown. We described changes in alcohol and tobacco consumption after implementation of these restrictions among a small number of participants in a tuberculosis treatment cohort., Method: The timeline follow-back procedure and Fägerstrom test for nicotine dependence was used to collect monthly alcohol and tobacco use information. We report changes in heavy drinking days (HDD), average amount of absolute alcohol (AA) consumed per drinking day, and cigarettes smoked daily during the alcohol and tobacco ban compared to use prior to the ban., Results: Of the 61 participants for whom we have pre-ban and within-ban alcohol use information, 17 (27.9%) reported within-ban alcohol use. On average, participants reported one less HDD per fortnight (interquartile range (IQR): -4, 1), but their amount of AA consumed increased by 37.4 g per drinking occasion (IQR: -65.9 g, 71.0 g). Of 53 participants who reported pre-ban tobacco use, 17 (32.1%) stopped smoking during the ban. The number of participants smoking >10 cigarettes per day decreased from 8 to 1., Conclusions: From these observations, we hypothesize that policies restricting alcohol and tobacco availability seem to enable some individuals to reduce their consumption. However, these appear to have little effect on the volume of AA consumed among individuals with more harmful patterns of drinking in the absence of additional behavior change interventions., Competing Interests: The authors declare no conflicts of interest.

Healthcare workers (HCWs) are at an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel virus that causes Coronavirus Disease (COVID-19). We aim to assess the seroprevalence of SARS-CoV-2 IgG among healthcare workers and compare risk-factors between seropositive and seronegative HCWs. In this observational study, serum samples were collected from HCWs between July 13th to 26th, 2020 at Boston Medical Center (BMC). Samples were subsequently tested for SARS-CoV-2 IgG antibody using the Abbott SARS-CoV-2 IgG assay. Participants also answered a questionnaire capturing data on demographics, history of COVID-19 symptoms, occupation, infection prevention and control measures. Overall, 95 of 1743 (5.5%) participants tested positive for SARS-CoV-2 IgG. Of these, 1.8% of the participants had mild or no COVID-19 symptoms and did not require a diagnostic test. Seropositivity was not associated with gender, occupation, hand hygiene and personal protective equipment (PPE) practices amongst HCWs. However, lack of physical distancing among health care workers in work areas and break room was associated with seropositivity (p = 0.05, p = 0.003, respectively). The majority of the HCWs are negative for SARS-CoV-2 IgG. This data highlights the need to promote infection prevention measures, and the importance of distance amongst co-workers to help mitigate infection rates.

Background: COVID-19 vaccine trials and post-implementation data suggest vaccination decreases SARS-CoV-2 infections. We examine COVID-19 vaccination's impact on SARS-CoV-2 case rates and viral diversity among healthcare workers (HCW) during a high community prevalence period., Methods: A prospective cohort study from Boston Medical Center (BMC)'s HCW vaccination program, where staff received two doses of BNT162b2 or mRNA-1273. We included PCR-confirmed SARS-CoV-2 cases among HCWs from December 09, 2020 to February 23, 2021. Weekly SARS-CoV-2 rates per 100,000 person-day overall and by time from first injection (1-14 and >14 days) were compared with surrounding community rates. Viral genomes were sequenced from SARS CoV-2 positive samples., Results: SARS-CoV-2 cases occurred in 1.4% (96/7109) of HCWs given at least a first dose and 0.3% (17/5913) of HCWs given both vaccine doses. Adjusted SARS-CoV-2 infection rate ratios were 0.73 (95% CI 0.53-1.00) 1-14 days and 0.18 (0.10-0.32) >14 days from first dose. HCW SARS-CoV-2 cases >14 days from initial dose compared to within 14 days were more often older (46 versus 38 years, p=0.007), Latinx (10% versus 8%, p=0.03), and asymptomatic (48% versus 11%, p=0.0002). SARS-CoV-2 rates among HCWs fell below those of the surrounding community, with a 18% versus 11% weekly decrease respectively (p=0.14). Comparison of 48 SARS-CoV-2 genomes sequenced from post-first dose cases did not indicate selection pressure towards known spike-antibody escape mutations., Conclusions: Our results indicate a positive impact of COVID-19 vaccines on SARS-CoV-2 case rates. Post-vaccination isolates did not show unusual genetic diversity or selection for mutations of concern., Main Point: Cases of SARS-CoV-2 among health care workers dropped rapidly with COVID-19 vaccination. Sequencing 48 breakthrough infections (overwhelmingly in 14 days after 1st dose) showed no clear sign of any differences in spike protein compared with time-matched, unvaccinated control sequences.

In 2011, South Africa implemented a policy to decentralize treatment for rifampin-resistant tuberculosis (TB) to reduce durations of hospitalization and enable local treatment. We assessed policy implementation in Western Cape Province, where services expanded from 6 specialized TB hospitals to 406 facilities, by analyzing National Health Laboratory Service data on TB during 2012-2015. We calculated the percentage of patients who visited a TB hospital <1 year after rifampin-resistant TB diagnosis, the median duration of their hospitalizations, and the total distance between facilities visited. We assessed temporal changes with linear regression and stratified results by location. Of 2,878 patients, 65% were from Cape Town. In Cape Town, 29% visited a TB hospital; elsewhere, 68% visited a TB hospital. We found that hospitalizations and travel distances were shorter in Cape Town than in the surrounding areas.

Objectives: The global pandemic of coronavirus disease 2019 (Covid-19) may disproportionately affect persons in congregate settings, including those in residential substance use treatment facilities. To limit the spread of SARS-CoV-2 through congregate settings, universal testing may be necessary. We aimed to determine the point prevalence of SARS-CoV-2 in a residential treatment program setting and to understand the unique challenges of Covid-19 transmission in this setting., Methods: We performed a case series of SARS-CoV-2 rT-PCR testing via nasopharyngeal in a residential substance use treatment program for women in Boston. Staff and residents of the treatment program were tested for SARS-CoV-2. The primary outcome was SARS-CoV-2 test result., Results: A total of 31 residents and staff were tested. Twenty-seven percent (6/22) of the residents and 44% (4/9) of staff tested positive for SARS-CoV-2. All of the SARS-CoV-2 positive residents resided in the same residential unit. Two positive cases resided together with 2 negative cases in a 4-person room. Two other positive cases resided together in a 2-person room. One positive case resided with 2 negative cases in a 3-person room. One positive case resided with a negative case in a 2-person room. Based on test results, residents were cohorted by infection status and continued to participate in addiction treatment on-site., Conclusions: SARS-CoV-2 infection was common among staff and residents within a residential substance use treatment program for women in Boston. Universal SARS-CoV-2 testing in residential substance use programs can be instituted to reduce the risk of further transmission and continue addiction treatment programming when accompanied by adequate space, supplies, and staffing.

South Africa led the world with guidelines on bedaquiline (BDQ) use as a single drug substitution to manage rifampin resistant tuberculosis regimen toxicity. We examined reasons for giving BDQ in a retrospective cohort: >75% of patients were switched to BDQ for toxicity (ototoxicity or renal dysfunction) rather than drug resistance., Competing Interests: The authors have declared that no competing interests exist.

Tuberculosis (TB) is the leading single-agent infectious disease killer worldwide. The World Health Organization (WHO)'s End TB Strategy aims to achieve tuberculosis (TB) elimination by 2030, and in September 2018, the United Nations General Assembly held a High-Level Meeting on TB to address the urgency of the TB epidemic and the health inequalities that continue to propel it. The meeting endorsed an ambitious, comprehensive approach to the TB epidemic that incorporates universal health coverage and tackles the social determinants of this disease. In this article, we provide an overview of the key strategies promoted in this meeting and introduce work by five Rhode Island-based physicians that align with these goals.

In the United States, high concern for iatrogenic reactivation to tuberculosis (TB) disease secondary to prescribed immunosuppression has resulted in increased use of the QuantiFERON-TB Gold In-Tube test (QFT-GIT) to screen for Mycobacterium tuberculosis (Mtb) infection. The aim of our study was to determine indications for QFT-GIT testing and risk factors for indeterminate QFT-GIT results. We retrospectively identified patients with QFT-GIT testing over a six-month period in a tertiary care academic health care system and performed a record review. Inpatients were 11 times more likely to have an indeterminate QFT-GIT result than outpatients (95% CI 7.6-16.2). 61.5% inpatient QFT-GITs were ordered during workup of active TB. Providers treating exogenously or endogenously immunosuppressed patients ordered the most QFT-GITs. We highlight the significant limitations of TB screening tests in the inpatient setting and the need to test earlier in those requiring immunosuppressive therapy to avoid indeterminate results.

Introduction: High mortality among individuals receiving retreatment for tuberculosis (RT-TB) persists, although reasons for these poor outcomes remain unclear., Methods: We retrospectively reviewed 394 RT-TB patients diagnosed between January 2010 and June 2016 in Accra, Ghana., Results: Of RT-TB patients, 161 (40.9%) were treated empirically (negative/absent smear, culture or Xpert), of whom 30.4% (49/161) had only extrapulmonary TB signs or symptoms. Mortality during treatment was 19.4%; 15-day mortality was 10.8%. In multivariable proportional hazards regression, living with HIV (aHR=2.69 [95 CI: 1.51, 4.80], p<0.01) and previous loss-to-follow up (aHR=8.27 (95 CI: 1.10, 62.25), p=0.04) were associated with mortality, while drug susceptibility testing (DST, aHR=0.36 (95 CI: 0.13, 1.01), p=0.052) was protective. Isoniazid resistance was observed in 40% (23/58 tested) and rifampin resistance in 19.1% (12/63 tested)., Conclusion: High rates of extrapulmonary TB and smear/culture negative disease highlight the barriers to achieving DST-driven RT-TB regimens and the need for improved diagnostics. Our finding of poly-drug resistance in rifampin-susceptible cases supports access to comprehensive first line DST. Additionally, interventions to reduce mortality, especially in HIV co-infected RT-TB patients, are urgently needed., Competing Interests: The authors declare no competing interests.

Background: An estimated 10% of tuberculosis (TB) deaths are attributable to problematic alcohol use globally, however the causal pathways through which problem alcohol use has an impact on TB treatment outcome is not clear. This study aims to improve understanding of these mechanisms. Specifically, we aim to 1) assess whether poor TB treatment outcomes, measured as delayed time-to-culture conversion, are associated with problem alcohol use after controlling for non-adherence to TB pharmacotherapy; and 2) to determine whether pharmacokinetic (PK) changes in those with problem alcohol use are associated with delayed culture conversion, higher treatment failure/relapse rates or with increased toxicity., Methods: Our longitudinal, repeated measures, prospective cohort study aims to examine the associations between problem alcohol use and TB treatment outcomes and to evaluate the effect of alcohol on the PK and pharmacodynamics (PD) of TB drugs. We will recruit 438 microbiologically confirmed, pulmonary TB patients with evidence of rifampicin susceptibility in Worcester, South Africa with 200 HIV uninfected patients co-enrolled in the PK aim. Participants are followed for the six months of TB treatment and an additional 12 months thereafter, with sputum collected weekly for the first 12 weeks of treatment, alcohol consumption measures repeated monthly in concert with an alcohol biomarker (phosphatidylethanol) measurement at baseline, and in person directly observed therapy (DOT) using real-time mobile phone-based adherence monitoring. The primary outcome is based on time to culture conversion with the second objective to compare PK of first line TB therapy in those with and without problem alcohol use., Discussion: Globally, an urgent need exists to identify modifiable drivers of poor TB treatment outcomes. There is a critical need for more effective TB treatment strategies for patients with a history of problem alcohol use. However, it is not known whether poor treatment outcomes in alcohol using patients are solely attributable to noncompliance. This study will attempt to answer this question and provide guidance for future TB intervention trials., Trial Registration: Clinicaltrials.gov Registration Number: NCT02840877 . Registered on 19 July 2016.

Background: Current guidelines for treatment of multidrug-resistant tuberculosis (MDR-TB) are largely based on expert opinion and observational data. Fluoroquinolones remain an essential part of MDR-TB treatment, but the optimal dose of fluoroquinolones as part of the regimen has not been defined., Methods/design: We designed a randomized, blinded, phase II trial in MDR-TB patients comparing across levofloxacin doses of 11, 14, 17 and 20 mg/kg/day, all within an optimized background regimen. We assess pharmacokinetics, efficacy, safety and tolerability of regimens containing each of these doses. The primary efficacy outcome is time to culture conversion over the first 6 months of treatment. The study aims to determine the area under the curve (AUC) of the levofloxacin serum concentration in the 24 hours after dosing divided by the minimal inhibitory concentration of the patient's Mycobacterium tuberculosis isolate that inhibits > 90% of organisms (AUC/MIC) that maximizes efficacy and the AUC that maximizes safety and tolerability in the context of an MDR-TB treatment regimen., Discussion: Fluoroquinolones are an integral part of recommended MDR-TB regimens. Little is known about how to optimize dosing for efficacy while maintaining acceptable toxicity. This study will provide evidence to support revised dosing guidelines for the use of levofloxacin as part of combination regimens for treatment of MDR-TB. The novel methodology can be adapted to elucidate the effect of other single agents in multidrug antibiotic treatment regimens., Trial Registration: ClinicalTrials.gov, NCT01918397 . Registered on 5 August 2013.

We describe a case of acute vertebral osteomyelitis with associated prevertebral abscess due to Erysipelothrix rhusiopathiae in an immunocompetent adult with recent known traumatic inoculation from the barb of a fish.

Neurofibromatosis type 1 is a genetic condition associated with increased risk of abnormal brain development. The relationship between a specific type of brain malformation and a distinct cognitive sign/deficiency remains unknown. This study investigated the frequency of brain malformations in children with neurofibromatosis type 1, and the impact of those brain malformations on cognitive performance. A retrospective examination was performed of cranial magnetic resonance imaging and clinical records in 604 neurofibromatosis type 1 patients. Eighteen patients with brain malformations and intellectual evaluations were available and compared to a subset of neurofibromatosis type 1 patients (n = 20) without brain malformations. The most common brain malformations included hypothalamic hamartomas and Chiari I malformation. More complex migration disorders were also observed. Comparisons of cognitive profiles between groups revealed differences in patients with hamartomas compared with those manifesting Chiari I malformations or control subjects. As a group, those with hamartomas demonstrated below-average global intellect, whereas patients with Chiari I or no malformations performed in the average range. Disorders in cell organization, expressed as brain malformations (hamartomas or more complex defects), may comprise part of the expression of organizational and developmental defects in patients with neurofibromatosis type 1 and possibly other rat sarcoma gene-mitogen activated protein kinase pathway disorders., (Copyright © 2012 Elsevier Inc. All rights reserved.)