OBJECTIVES:We reconstructed COVID-19 contact networks to examine individual characteristics and network structures that influenced transmission during the 2020-2021 hybrid-learning year at a US university. STUDY DESIGN:Cohort study. METHODS:We used individual-level exposure histories collected through case investigation and contact tracing interviews during the Fall 2020 semester to construct contact tracing networks. We visualized networks and estimated global network statistics and secondary attack rates (SAR). We conducted a bias analysis on the impact of missing cases on these network statistics. RESULTS:During the Fall 2020 semester, we identified 441 COVID-19 cases, 1121 close contacts, and 1206 links between individuals. Most cases were female (62 %), off-campus students (49 %), and symptomatic (82 %). Individuals had a mean of 2.9 direct contacts, and the maximum number of individuals separating any two persons in a network was 8. The overall SAR was 9.7 % (50/518). Contacts of symptomatic cases had a higher SAR compared to contacts of asymptomatic cases (11.8 % [42/356] vs. 4.9 % [8/162]; p = 0.015). Networks were minimally clustered with the greatest clustering observed in September. Bias analyses indicated that missingness in our observed network was unlikely to have been random or based upon symptomaticity. CONCLUSIONS:In this assessment of COVID-19 contact network structure and transmission characteristics, we found minimal clustering, a low proportion of asymptomatic cases, and higher SAR among contacts of symptomatic cases. Symptomatic cases were unlikely to have been oversampled in our observed network. Our findings suggest that university campuses have unique transmission characteristics, even in the context of a hybrid learning environment in which social interactions may be attenuated.

Undernutrition-the leading risk factor for tuberculosis worldwide-is associated with impaired immunity, more extensive disease, delayed sputum conversion, and worse treatment outcomes, including mortality. In this Health Policy, we propose a comprehensive roadmap for integrating nutritional assessment, counselling, and support into tuberculosis treatment as part of person-centred care. At treatment initiation, we recommend standard nutritional assessment with anthropometric measurements and haemoglobin estimation, in addition to macronutrient and micronutrient support alongside nutritional counselling. Weight should be monitored during treatment and lack of weight gain at the end of the intensive phase should prompt an investigation of causes, such as food insecurity, poor treatment adherence, malabsorption, uncontrolled diabetes, or drug resistance. At the end of treatment, we recommend reassessing anthropometric measures to assess nutritional recovery. People with tuberculosis who remain underweight should receive close follow-up to detect early relapse. We call for annual reporting of nutritional metrics by WHO, explicit inclusion of nutritional assessment and care in national strategic plans, domestic or international support of nutritional programmes for people with tuberculosis, increased support for operational research initiatives, and integration of nutritional care into the WHO Multisectoral Accountability Framework at national and regional levels.

Context: The coronavirus disease 2019 (COVID-19) pandemic devastated societies and economies worldwide. Given the major disruptions to higher education, reflection on university responses to the COVID-19 pandemic may provide insights for future outbreaks. Objective: Here, we describe the epidemiology of COVID-19 on the Emory University campus during the 2020-2021 academic year and provide an evaluation of the performance of a university-led program with the purpose of describing the effectiveness of efforts to augment the public health authority’s case investigation and contact tracing efforts during a public health emergency. Design: Evaluation of a case investigation and contact tracing program regarding operations, timeliness, and performance. Main Outcome Measures: We analyzed quality metrics to determine the proportion of cases and contacts interviewed and the time to completion of each step from case diagnosis to testing of contacts. Results: During the 2020-2021 academic year, 1267 COVID-19 cases among Emory students, faculty, and staff were confirmed by polymerase chain reaction, with 1132 reported close contacts. Among cases, the median test turnaround time was 1 day (interquartile range: 1, 2). Among both cases and close contacts, 98% were successfully interviewed. The team called a majority of cases on the same day as their test result was reported to the program (87%; n = 1052). Almost all (98%; n = 1247) cases completed isolation or were advised to isolate during the review period. Close to half (46%; n = 513) of contacts interviewed began quarantine before their interview. Among close contacts interviewed, 13% (n = 145) subsequently converted to an index case. Conclusions: The impact and performance of Emory’s program may provide useful and actionable data for future university-led infectious disease outbreak response programs. The program structure, performance metrics, and information collected via interviews provide practical implications and an organized structure to guide other programs during future outbreaks.

BACKGROUND:There are few data on the treatment of children and adolescents with multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis, especially with more recently available drugs and regimens. We aimed to describe the clinical and treatment characteristics and their associations with treatment outcomes in this susceptible population. METHODS:We conducted a systematic review and individual participant data meta-analysis. Databases were searched from Oct 1, 2014, to March 30, 2020. To be eligible, studies must have included more than five children or adolescents (0-19 years of age) treated for microbiologically confirmed or clinically diagnosed MDR or RR tuberculosis within a defined treatment cohort, and reported on regimen composition and treatment outcomes. Abstracts were screened independently by two authors to identify potentially eligible records. Full texts were reviewed by two authors independently to identify studies meeting the eligiblity criteria. For studies meeting eligiblity criteria, anonymised individual patient data was requested and individiual level data included for analysis. The main outcome assessed was treatment outcome defined as treatment success (cure or treatment completed) versus unfavourable outcome (treatment failure or death). Multivariable logistic regression models were used to identify associations between clinical and treatment factors and treatment outcomes. This study is registered with Prospero (CRD42020187230). FINDINGS:1417 studies were identified through database searching. After removing duplicates and screening for eligibility, the search identified 23 369 individual participants from 42 studies, mostly from India and South Africa. Overall, 16 825 (72·0%) were successfully treated (treatment completed or cured), 2848 died (12·2%), 722 (3·1%) had treatment failure, and 2974 (12·7%) were lost to follow-up. In primary analyses, the median age was 16 (IQR 13-18) years. Of the 17 764 (87·1%) participants with reported HIV status, 2448 (13·8%) were living with HIV. 17 707 (89·6%) had microbiologically confirmed tuberculosis. After adjusting for significant factors associated with treatment outcome, the use of two (adjusted odds ratio [OR] 1·41 [95% CI 1·09-1·82]; p=0·008) or three (2·12 [1·61-2·79]; p<0·0001) WHO-classified group A drugs (bedaquiline, moxifloxacin, levofloxacin, and linezolid) compared with the use of no group A drugs at all was positively associated with treatment success. INTERPRETATION:Younger and clinically diagnosed children are underrepresented among those treated for MDR and RR tuberculosis and should be a focus for case-finding efforts. Overall treatment outcomes in our analysis were better than in adults but lower than the international targets of 90% or more individuals successfully treated. Treatment with more group A drugs was associated with better treatment outcomes in children and adolescents, highlighting the need for more rapid access to these drugs and improved regimens. FUNDING:Unitaid.

BACKGROUND:Nutrition is a critical determinant of tuberculosis (TB), providing a protective effect at high body mass index (BMI) and incurring an increased risk of TB disease at low BMI. Global nutritional transition and interventions to end hunger could directly affect the TB epidemic in high TB burden countries. METHODS:We constructed dynamic TB transmission models for 12 high TB burden countries with low HIV prevalence. We explicitly accounted for the effects of BMI on TB disease progression and treatment outcomes using a meta-analysis of longitudinal cohort studies, incorporating the effect of BMI mediated through diabetes. The models were calibrated to historical trends in TB epidemiology and mean BMI. We estimated potential changes in TB incidence and mortality between 2015 and 2030 under different scenarios of population nutrition. FINDINGS:Compared with a scenario where mean BMI remained at 2015 levels, if past trends in mean BMI continued then by 2030 TB incidence and mortality would decline by a cumulative 14.7% (95% credible interval: 12.7%-16.7%) and 15.6% (12.5%-19.2%), respectively. In comparison, achieving zero hunger by 2030 would reduce incidence and mortality by 32.0% (20.0%-43.8%) and 37.3% (26.1%-49.6%), respectively. If past trends continued and zero hunger was also achieved, incidence and mortality would be reduced by 38.2% (27.0%-49.1%) and 42.4% (32.1%-53.5%), respectively, equivalent to preventing 20.6 million people developing TB disease and averting 5.4 million TB deaths over 15 years in the 12 high-burden countries. CONCLUSIONS:Nutrition transitions and interventions to end hunger could have a major impact on the future epidemiology of TB in high-burden countries. Investment is urgently required to implement and scale up nutritional interventions.

BACKGROUND:The relationship between nutritional status and tuberculosis is critically important but poorly understood. We extended a 2009 review characterizing the relationship between body mass index (BMI) and tuberculosis risk. METHODS:We systematically searched for new studies published between 2009 and 2024 investigating BMI and tuberculosis risk in adults. We extracted estimates of risk in BMI categories, used resampling to assign a median BMI 'dose' within each category, and included these in one-stage dose-response meta-analyses, stratifying results by population group and country tuberculosis burden. We fitted linear models for comparability with the 2009 review and restricted cubic spline models to investigate nonlinear relationships and piecewise linear models. RESULTS:Our analyses showed an inverse dose-response relationship between BMI and tuberculosis risk across all populations in the full underweight to obese range (15.0-35.0 kg/m2). The spline and piecewise linear models showed a nonlinear relationship-in 22 general-population cohorts (n = 24 921 531), there was a steep per-unit reduction in risk for BMI of <25.0 kg/m2 [18.0%, 95% confidence interval (CI): 16.4-19.6], which decreased more gradually for BMI of ≥25.0 kg/m2 (6.9%, 95% CI: 4.6-9.2). In 18 cohorts of people with HIV (n = 162 609), the reduction was 15.3% for BMI of <23.0 kg/m2 (95% CI: 13.1-17.5) and 2.6% (95% CI: -3.1-7.9) for BMI of ≥23.0 kg/m2. In three cohorts of people with diabetes (n = 1 118 424), the reduction was 20.5% for BMI of <24.0 kg/m2 (95% CI: 18.4-22.6) and 13.4% (95% CI: 3.9-22.0) for BMI of ≥24.0 kg/m2. Based on the global BMI distribution, we estimated a relative risk of tuberculosis associated with undernutrition (BMI < 18.5 kg/m2) of 5.0 (95% CI: 4.2-5.9). CONCLUSION:Our results highlight the independent importance of nutritional status as a driver of the tuberculosis epidemic.

Despite 5 years of SARS-CoV-2 research, as well as decades of research on tuberculosis (TB), large gaps remain in understanding the transmission of airborne pathogens. Our aim was to delineate these gaps. Understanding them would enable evidence-based, practical efforts to reduce transmission. Building upon the 2017 Roadmap for TB Transmission Science, we interviewed experts in the field and identified six salient topics harboring holes in knowledge that impede prevention and control efforts. These include 1) fundamental elements of aerobiology, 2) detecting and measuring infectious respiratory particles directly in the air, 3) the infectiousness of asymptomatic TB (by extension, other lung infections) and 4) of calm tidal breathing – including their contributions to global epidemiology, 5) the role of ‘superspreading’ in disease incidence, and 6) the duration of infectiousness of highly drug-resistant TB treated with the newest, all-oral short-course regimens. Based on an extensive literature review, we update advances in science since 2017 and then summarize knowledge gaps and research priorities. Several recent systematic reviews all noted the relatively low quality of published research, so there is an overriding need for high-quality studies to provide evidence for national and international entities upon which to base recommendations, guidelines, and standards.

BACKGROUNDRifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons initiate treatment and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, six-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200 mg linezolid. After U.S. FDA approval in 2019, some U.S. clinicians rapidly implemented BPaL using an initial linezolid 600 mg dose adjusted by serum drug concentrations and clinical monitoring.METHODSData from U.S. patients treated with BPaL between 10/14/2019 and 4/30/2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider-driven, and most had linezolid adjusted by therapeutic drug monitoring (TDM).RESULTSOf 70 patients starting BPaL, two changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and two of these 68 (2.9%) patients relapsed after completion. Using an initial 600 mg linezolid dose daily adjusted by TDM and careful clinical and laboratory monitoring for side effects, supportive care, and expert consultation throughout BPaL treatment, three (4.4%) patients with hematologic toxicity and four (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months.CONCLUSIONSBPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in ATS/CDC/ERS/IDSA 2019 guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the U.S. is feasible.

BACKGROUND:Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring.METHODS:Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring.RESULTS:Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months.CONCLUSIONS:BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.

TB is one of the leading infectious causes of death worldwide with more than 10 million cases and approximately 1.5 million deaths annually. There exists a bidirectional relationship between tuberculosis (TB) and undernutrition. Persons with TB develop undernutrition through numerous mechanisms, most notably anorexia due to cytokines necessary for antimycobacterial immune response. Both macronutrient and micronutrient deficiencies have been associated with TB disease. Conversely, undernutrition is associated with increased severity of TB disease and undernourished individuals are more likely to suffer unfavorable treatment outcomes. Nutritional supplementation was the cornerstone of TB therapy in sanatoria, but was supplanted by more effective pharmacologic therapy. Although some historical data suggest that nutritional supplementation may improve treatment outcomes, studies in the antibiotic era have produced mixed results. Supplementation of multiple micronutrients during treatment has been associated with reduced mortality regardless of HIV status. A careful assessment of nutritional status should be performed before assigning a supplementation regimen although a simplified, more generic approach may be more suitable in some circumstances. Undernourished patients should receive nutritional counseling. Nutritional supplementation may compensate for the effects of TB on metabolism and increase activity of the immune system. Further, supplementation of nutrients may improve treatment adherence and reduce drug toxicity. Most notably, vitamin B6 supplementation can prevent peripheral neuropathy due to isoniazid. Nutritional support must be adapted to each geographic region and socioeconomic context.

Few reports have described how university programs have controlled COVID-19 outbreaks. Emory University established a case investigation and contact tracing program in June 2020 to identify and mitigate transmission of SARS-CoV-2 in the Emory community. In February 2021, this program identified a surge in COVID-19 cases. In this case study, we present details of outbreak investigation, construction of transmission networks to assess clustering and identify groups for targeted testing, and program quality metrics demonstrating the efficiency of case investigation and contact tracing, which helped bring the surge under control. During February 10-March 5, 2021, Emory University identified 265 COVID-19 cases confirmed by nucleic acid testing in saliva or nasopharyngeal samples. Most students with COVID-19 were undergraduates (95%) and were affiliated with Greek life organizations (70%); 41% lived on campus. Network analysis identified 1 epidemiologically linked cluster of 198 people. Nearly all students diagnosed with COVID-19 (96%) were interviewed the same day as their positive test result. Of 340 close contacts, 90% were traced and 89% were tested. The median time from contact interview to first test was 2 days (interquartile range, 0-6 days); 43% received a positive test result during their quarantine. The surge was considered under control within 17 days, after which new cases were no longer epidemiologically linked. Early detection through systematic testing protocols and rapid and near-complete contact tracing, paired with isolation and quarantine measures, helped to contain the surge. Our approach emphasizes the importance of early preparation of adequate outbreak response infrastructure and staff to implement interventions appropriately and consistently during a pandemic.

SETTING: Mulago Hospital, Kampala, Uganda.OBJECTIVE: To quantify Mycobacterium tuberculosis in sputum during the first 8 weeks of pulmonary multidrug-resistant TB (MDR-TB) treatment.DESIGN: We enrolled consecutive adults with pulmonary MDR-TB treated according to national guidelines. We collected overnight sputum samples before treatment and weekly. Sputum samples were cultured on Middlebrook 7H11S agar to measure colony-forming units per mL (cfu/mL) and in MGIT™ 960™ media to measure time to detection (TTD). Linear mixed-effects regression was used to estimate the relational change in log10 cfu/mL and TTD.RESULTS: Twelve adults (median age: 27 years) were enrolled. Half were women, and two-thirds were HIV-positive. At baseline, median log10 cfu/mL was 5.1, decreasing by 0.29 log10 cfu/mL/week. The median TTD was 116.5 h, increasing in TTD by 36.97 h/week. The weekly change was greater in the first 2 weeks (-1.04 log10 cfu/mL/week and 120.02 h/week) than in the remaining 6 weeks (-0.17 log10 cfu/mL/week and 26.11 h/week).CONCLUSION: Serial quantitative culture measures indicate a slow, uneven rate of decline in sputum M. tuberculosis over 8 weeks of standardized pulmonary MDR-TB treatment.

Communicable diseases, alone or in combination with malnutrition, account for most deaths in complex emergencies including refugee settings. Tuberculosis and HIV/AIDS are increasingly becoming an important cause of morbidity and mortality in refugee settings. We described the treatment outcomes of TB patients and explored factors associated with treatment outcomes among TB patients attending two facilities in Kyangwali Refugee Settlement in Kikuube District, 2016-2017. We abstracted data on laboratory-confirmed patient data from TB registers from 2016 to 2017, in Kikuube Health Centre IV and Rwenyawawa Health Centre II, both located in Kyangwali Refugee Settlement. We abstracted data on socio-demographic variables including age and sex. Other variables were height, weight, final treatment outcomes, demographics, HIV status, TB treatment category, and history of TB. Treatment outcomes were categorized into favorable (including patients who were cured or those who completed treatment) and unfavorable (those in whom treatment failed, those who died, those lost to follow-up, or those not evaluated). We used logistic regression to identify factors associated with unfavorable treatment outcomes. We identified a total of 254 TB patients with a median age of 36 (IQR 26-48) years; 69% (175) were male and 54% (137) were refugees. The median weight was 50.4 kg (range 4-198). Overall, 139 (55%) had favorable outcomes while 115 (45%) had unfavorable outcomes. Refugees formed 53% (71) of those with favorable outcomes and 47% (63) of those with unfavorable outcomes 63(47%). We found that increasing age was statistically associated with unfavorable outcomes, while diagnosis with MDR-TB was associated with decreased odds for unfavorable treatment outcomes. The treatment success rate was lower compared to 85% recommended by WHO. However, the rates are similar to that reported by other studies in Uganda. Innovative approaches to improve treatment success rates with particular focus on persons aged 41-80 years should be devised.

CORRESPONDENCEprotects as well as amikacin against fluoroquinolone ADR was reported by a multicountry study [11].Amikacin, the most powerful SLID [12], probably will have the same excellent effect.Capreomycin is weaker than amikacin due to its lower peak serum/minimal inhibitory concentration (MIC) ratio [12].More importantly, amikacin resistance, caused by rrs1401 or rrs1484 mutations, confers complete cross-resistance to kanamycin as well as capreomycin.The original report of amikacin-resistant/capreomycinsusceptible strains [13] was recently corrected after MIC testing [14].Because capreomycin is the only SLID rendered inactive also by tlyA mutations, it is least indicated.In conclusion, when measuring the effect of TB drugs, researchers should take into account their specific action within a well-defined combination.Until a new drug proves to be as powerful, amikacin as well as kanamycin remain essential safeguards of the effectiveness of the core drug, currently the fluoroquinolones and/or bedaquiline for RR-TB treatment.