Performance of Existing and Novel Symptom- and Antigen Testing-Based COVID-19 Case Definitions in a Community Setting.

Point-of-care antigen tests are an important tool for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection, yet are less clinically sensitive than real-time reverse-transcription polymerase chain reaction (RT-PCR), affecting their efficacy as screening procedures. Our goal in this analysis was to see whether we could improve this sensitivity by considering antigen test results in combination with other relevant information, namely exposure status and reported symptoms. In November 2020, we collected 3,419 paired upper respiratory specimens tested by RT-PCR and the Abbott BinaxNOW (Abbott Laboratories, Abbott Park, Illinois) antigen test at 2 community testing sites in Pima County, Arizona. We used symptom, exposure, and antigen-testing data to evaluate the sensitivity and specificity of various symptom definitions in predicting RT-PCR positivity. Our analysis yielded 6 novel multisymptom case definitions with and without antigen test results, the best of which overall achieved a Youden's J index of 0.66, as compared with 0.53 for antigen testing alone. Using a random forest as a guide, we show that this definition, along with our others, does not lose the ability to generalize well to new data despite achieving optimal performance in our sample. Our methodology is broadly applicable, and our code is publicly available to aid public health practitioners in developing or fine-tuning their own case definitions.

Using Machine Learning Techniques and National Tuberculosis Surveillance Data to Predict Excess Growth in Genotyped Tuberculosis Clusters.

The early identification of clusters of persons with tuberculosis (TB) that will grow to become outbreaks creates an opportunity for intervention in preventing future TB cases. We used surveillance data (2009-2018) from the United States, statistically derived definitions of unexpected growth, and machine-learning techniques to predict which clusters of genotype-matched TB cases are most likely to continue accumulating cases above expected growth within a 1-year follow-up period. We developed a model to predict which clusters are likely to grow on a training and testing data set that was generalizable to a validation data set. Our model showed that characteristics of clusters were more important than the social, demographic, and clinical characteristics of the patients in those clusters. For instance, the time between cases before unexpected growth was identified as the most important of our predictors. A faster accumulation of cases increased the probability of excess growth being predicted during the follow-up period. We have demonstrated that combining the characteristics of clusters and cases with machine learning can add to existing tools to help prioritize which clusters may benefit most from public health interventions. For example, consideration of an entire cluster, not only an individual patient, may assist in interrupting ongoing transmission.

Performance of existing and novel surveillance case definitions for COVID-19 in household contacts of PCR-confirmed COVID-19.

BACKGROUND: Optimized symptom-based COVID-19 case definitions that guide public health surveillance and individual patient management in the community may assist pandemic control. METHODS: We assessed diagnostic performance of existing cases definitions (e.g. influenza-like illness, COVID-like illness) using symptoms reported from 185 household contacts to a PCR-confirmed case of COVID-19 in Wisconsin and Utah, United States. We stratified analyses between adults and children. We also constructed novel case definitions for comparison. RESULTS: Existing COVID-19 case definitions generally showed high sensitivity (86-96%) but low positive predictive value (PPV) (36-49%; F-1 score 52-63) in this community cohort. Top performing novel symptom combinations included taste or smell dysfunction and improved the balance of sensitivity and PPV (F-1 score 78-80). Performance indicators were generally lower for children (< 18 years of age). CONCLUSIONS: Existing COVID-19 case definitions appropriately screened in household contacts with COVID-19. Novel symptom combinations incorporating taste or smell dysfunction as a primary component improved accuracy. Case definitions tailored for children versus adults should be further explored.

Tuberculosis disease and infection among household contacts of bacteriologically confirmed and non-confirmed tuberculosis patients.

OBJECTIVE: To compare the prevalence of tuberculosis infection and disease in household contacts of patients with bacteriologically confirmed tuberculosis disease and contacts of non-bacteriologically confirmed disease in western Kenya. METHODS: We enrolled newly diagnosed index patients and their household contacts from March 2014 to June 2016. All contacts were evaluated with a symptom questionnaire, tuberculin skin test (TST) and HIV test. Clinical evaluation and sputum testing were performed for those with symptoms, positive TST result or HIV infection. RESULTS: We enrolled 1155 contacts of 330 index patients with bacteriologically confirmed tuberculosis and 192 contacts of 55 index patients with non-bacteriologically confirmed tuberculosis. 3.5% of contacts of patients with bacteriologically confirmed tuberculosis were diagnosed with tuberculosis, whereas no contacts of index patients with non-bacteriologically confirmed tuberculosis were. Of those diagnosed with tuberculosis disease, 58.5% reported symptoms, 34.1% reported no symptoms but had positive TST results, and 7.3% had neither symptoms nor positive TST but were HIV-positive. Among 872 contacts with a TST result, 50.9% of contacts of index patients with bacteriologically confirmed tuberculosis and 41.0% of contacts of index patients with non-bacteriologically confirmed tuberculosis had a positive result (prevalence ratio = 1.16, 95% confidence interval 0.92-1.48). CONCLUSION: In a high-burden setting, tuberculosis disease was more prevalent among contacts of patients with bacteriologically confirmed tuberculosis than contacts of patients with non-bacteriologically confirmed disease. TST was feasible to perform and helped to detect cases that would have been missed had only symptomatic contacts been evaluated.

OBJECTIF: Comparer la prévalence de l'infection et de la maladie tuberculeuses chez les contacts familiaux des patients atteints de tuberculose confirmée bactériologiquement et les contacts de maladies non bactériologiquement confirmées dans l'ouest du Kenya. MÉTHODES: Nous avons recruté des patients indice nouvellement diagnostiqués et leurs contacts familiaux de mars 2014 à juin 2016. Tous les contacts ont été évalués à l'aide d'un questionnaire sur les symptômes, le test cutané à la tuberculine (TCT) et le test VIH. Une évaluation clinique et des tests d'expectoration ont été effectués pour les personnes présentant des symptômes, un résultat positif au TCT ou une infection par le VIH. RÉSULTATS: Nous avons recruté 1.155 contacts de 330 patients index avec une tuberculose confirmée bactériologiquement et 192 contacts de 55 patients indice avec une tuberculose non confirmée bactériologiquement. 3,5% des contacts des patients atteints de tuberculose confirmée bactériologiquement ont été diagnostiqués avec la tuberculose, alors qu'aucun contact des patients indice avec une tuberculose non bactériologiquement confirmée ne l'a été. Parmi les personnes diagnostiquées avec une tuberculose, 58,5% ont signalé des symptômes, 34,1% n'ont signalé aucun symptôme mais avaient des résultats positifs au TCT, et 7,3% n'avaient ni symptômes ni TCT positifs mais étaient VIH positifs. Parmi 872 contacts avec un résultat TCT, 50,9% des contacts des patients indice avec une tuberculose confirmée bactériologiquement et 41,0% des contacts des patients indice avec une tuberculose non bactériologiquement confirmée avaient un résultat positif (rapport de prévalence = 1,16, intervalle de confiance à 95%: 0,92-1,48 ). CONCLUSION: Dans un contexte de charge élevée, la maladie tuberculose était plus fréquente chez les contacts des patients atteints de tuberculose confirmée bactériologiquement que chez les contacts des patients atteints de la maladie non bactériologiquement confirmée. Le TCT était réalisable et a aidé à détecter les cas qui auraient été ratés si seuls les contacts symptomatiques avaient été évalués.

Opioid Prescribing Rates in Nonmetropolitan and Metropolitan Counties Among Primary Care Providers Using an Electronic Health Record System - United States, 2014-2017.

Drug overdose is the leading cause of unintentional injury-associated death in the United States. Among 70,237 fatal drug overdoses in 2017, prescription opioids were involved in 17,029 (24.2%) (1). Higher rates of opioid-related deaths have been recorded in nonmetropolitan (rural) areas (2). In 2017, 14 rural counties were among the 15 counties with the highest opioid prescribing rates.* Higher opioid prescribing rates put patients at risk for addiction and overdose (3). Using deidentified data from the Athenahealth electronic health record (EHR) system, opioid prescribing rates among 31,422 primary care providers† in the United States were analyzed to evaluate trends from January 2014 to March 2017. This analysis assessed how prescribing practices varied among six urban-rural classification categories of counties, before and after the March 2016 release of CDC's Guideline for Prescribing Opioids for Chronic Pain (Guideline) (4). Patients in noncore (the most rural) counties had an 87% higher chance of receiving an opioid prescription compared with persons in large central metropolitan counties during the study period. Across all six county groups, the odds of receiving an opioid prescription decreased significantly after March 2016. This decrease followed a flat trend during the preceding period in micropolitan and large central metropolitan county groups; in contrast, the decrease continued previous downward trends in the other four county groups. Data from EHRs can effectively supplement traditional surveillance methods for monitoring trends in opioid prescribing and other areas of public health importance, with minimal lag time under ideal conditions. As less densely populated areas appear to indicate both substantial progress in decreasing opioid prescribing and ongoing need for reduction, community health care practices and intervention programs must continue to be tailored to community characteristics.

Chief complaint classification with recurrent neural networks.

Syndromic surveillance detects and monitors individual and population health indicators through sources such as emergency department records. Automated classification of these records can improve outbreak detection speed and diagnosis accuracy. Current syndromic systems rely on hand-coded keyword-based methods to parse written fields and may benefit from the use of modern supervised-learning classifier models. In this paper, we implement two recurrent neural network models based on long short-term memory (LSTM) and gated recurrent unit (GRU) cells and compare them to two traditional bag-of-words classifiers: multinomial naïve Bayes (MNB) and a support vector machine (SVM). The MNB classifier is one of only two machine learning algorithms currently being used for syndromic surveillance. All four models are trained to predict diagnostic code groups as defined by Clinical Classification Software, first to predict from discharge diagnosis, and then from chief complaint fields. The classifiers are trained on 3.6 million de-identified emergency department records from a single United States jurisdiction. We compare performance of these models primarily using the F1 score, and we measure absolute model performance to determine which conditions are the most amenable to surveillance based on chief complaint alone. Using discharge diagnoses, the LSTM classifier performs best, though all models exhibit an F1 score above 96.00. Using chief complaints, the GRU performs best (F1 = 47.38), and MNB with bigrams performs worst (F1 = 39.40). We also note that certain syndrome types are easier to detect than others. For example, chief complaints using the GRU model predicts alcohol-related disorders well (F1 = 78.91) but predicts influenza poorly (F1 = 14.80). In all instances, the RNN models outperformed the bag-of-words classifiers suggesting deep learning models could substantially improve the automatic classification of unstructured text for syndromic surveillance.

Tuberculosis Caused by Mycobacterium africanum, United States, 2004-2013.

Mycobacterium africanum is endemic to West Africa and causes tuberculosis (TB). We reviewed reported cases of TB in the United States during 2004-2013 that had lineage assigned by genotype (spoligotype and mycobacterial interspersed repetitive unit variable number tandem repeats). M. africanum caused 315 (0.4%) of 73,290 TB cases with lineage assigned by genotype. TB caused by M. africanum was associated more with persons from West Africa (adjusted odds ratio [aOR] 253.8, 95% CI 59.9-1,076.1) and US-born black persons (aOR 5.7, 95% CI 1.2-25.9) than with US-born white persons. TB caused by M. africanum did not show differences in clinical characteristics when compared with TB caused by M. tuberculosis. Clustered cases defined as >2 cases in a county with identical 24-locus mycobacterial interspersed repetitive unit genotypes, were less likely for M. africanum (aOR 0.1, 95% CI 0.1-0.4), which suggests that M. africanum is not commonly transmitted in the United States.

Mind the gap: TB trends in the USA and the UK, 2000-2011.

BACKGROUND: TB remains a major public health concern, even in low-incidence countries like the USA and the UK. Over the last two decades, cases of TB reported in the USA have declined, while they have increased substantially in the UK. We examined factors associated with this divergence in TB trends between the two countries. METHODS: We analysed all cases of TB reported to the US and UK national TB surveillance systems from 1 January 2000 through 31 December 2011. Negative binominal regression was used to assess potential demographic, clinical and risk factor variables associated with differences in observed trends. FINDINGS: A total of 259,609 cases were reported. From 2000 to 2011, annual TB incidence rates declined from 5.8 to 3.4 cases per 100,000 in the USA, whereas in the UK, TB incidence increased from 11.4 to 14.4 cases per 100,000. The majority of cases in both the USA (56%) and the UK (64%) were among foreign-born persons. The number of foreign-born cases reported in the USA declined by 15% (7731 in 2000 to 6564 in 2011) while native-born cases fell by 54% (8442 in 2000 to 3883 in 2011). In contrast, the number of foreign-born cases reported in the UK increased by 80% (3380 in 2000 to 6088 in 2011), while the number of native-born cases remained largely unchanged (2158 in 2000 to 2137 in 2011). In an adjusted negative binomial regression model, significant differences in trend were associated with sex, age, race/ethnicity, site of disease, HIV status and previous history of TB (p<0.01). Among the foreign-born, significant differences in trend were also associated with time since UK or US entry (p<0.01). INTERPRETATION: To achieve TB elimination in the UK, a re-evaluation of current TB control policies and practices with a focus on foreign-born are needed. In the USA, maintaining and strengthening control practices are necessary to sustain the progress made over the last 20 years.

Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial.

RATIONALE: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown. OBJECTIVES: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment. METHODS: Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase. MEASUREMENTS AND MAIN RESULTS: A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively). CONCLUSIONS: Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).

Common roots: a contextual review of HIV epidemics in black men who have sex with men across the African diaspora.

Pooled estimates from across the African diaspora show that black men who have sex with men (MSM) are 15 times more likely to be HIV positive compared with general populations and 8·5 times more likely compared with black populations. Disparities in the prevalence of HIV infection are greater in African and Caribbean countries that criminalise homosexual activity than in those that do not criminalise such behaviour. With the exception of US and African epidemiological studies, most studies of black MSM mainly focus on outcomes associated with HIV behavioural risk rather than on prevalence, incidence, or undiagnosed infection. Nevertheless, black MSM across the African diaspora share common experiences such as discrimination, cultural norms valuing masculinity, concerns about confidentiality during HIV testing or treatment, low access to HIV drugs, threats of violence or incarceration, and few targeted HIV prevention resources.

Comparisons of disparities and risks of HIV infection in black and other men who have sex with men in Canada, UK, and USA: a meta-analysis.

BACKGROUND: We did a meta-analysis to assess factors associated with disparities in HIV infection in black men who have sex with men (MSM) in Canada, the UK, and the USA. METHODS: We searched Embase, Medline, Google Scholar, and online conference proceedings from Jan 1, 1981, to Dec 31, 2011, for racial comparative studies with quantitative outcomes associated with HIV risk or HIV infection. Key words and Medical Subject Headings (US National Library of Medicine) relevant to race were cross-referenced with citations pertinent to homosexuality in Canada, the UK, and the USA. Data were aggregated across studies for every outcome of interest to estimate overall effect sizes, which were converted into summary ORs for 106,148 black MSM relative to 581,577 other MSM. FINDINGS: We analysed seven studies from Canada, 13 from the UK, and 174 from the USA. In every country, black MSM were as likely to engage similarly in serodiscordant unprotected sex as other MSM. Black MSM in Canada and the USA were less likely than other MSM to have a history of substance use (odds ratio, OR, 0·53, 95% CI 0·38-0·75, for Canada and 0·67, 0·50-0·92, for the USA). Black MSM in the UK (1·86, 1·58-2·18) and the USA (3·00, 2·06-4·40) were more likely to be HIV positive than were other MSM, but HIV-positive black MSM in each country were less likely (22% in the UK and 60% in the USA) to initiate combination antiretroviral therapy (cART) than other HIV-positive MSM. US HIV-positive black MSM were also less likely to have health insurance, have a high CD4 count, adhere to cART, or be virally suppressed than were other US HIV-positive MSM. Notably, despite a two-fold greater odds of having any structural barrier that increases HIV risk (eg, unemployment, low income, previous incarceration, or less education) compared with other US MSM, US black MSM were more likely to report any preventive behaviour against HIV infection (1·39, 1·23-1·57). For outcomes associated with HIV infection, disparities were greatest for US black MSM versus other MSM for structural barriers, sex partner demographics (eg, age, race), and HIV care outcomes, whereas disparities were least for sexual risk outcomes. INTERPRETATION: Similar racial disparities in HIV and sexually transmitted infections and cART initiation are seen in MSM in the UK and the USA. Elimination of disparities in HIV infection in black MSM cannot be accomplished without addressing structural barriers or differences in HIV clinical care access and outcomes. FUNDING: None.

An algorithm for tuberculosis screening and diagnosis in people with HIV.

BACKGROUND: Tuberculosis screening is recommended for people with human immunodeficiency virus (HIV) infection to facilitate early diagnosis and safe initiation of antiretroviral therapy and isoniazid preventive therapy. No internationally accepted, evidence-based guideline addresses the optimal means of conducting such screening, although screening for chronic cough is common. METHODS: We consecutively enrolled people with HIV infection from eight outpatient clinics in Cambodia, Thailand, and Vietnam. For each patient, three samples of sputum and one each of urine, stool, blood, and lymph-node aspirate (for patients with lymphadenopathy) were obtained for mycobacterial culture. We compared the characteristics of patients who received a diagnosis of tuberculosis (on the basis of having one or more specimens that were culture-positive) with those of patients who did not have tuberculosis to derive an algorithm for screening and diagnosis. RESULTS: Tuberculosis was diagnosed in 267 (15%) of 1748 patients (median CD4+ T-lymphocyte count, 242 per cubic millimeter; interquartile range, 82 to 396). The presence of a cough for 2 or 3 weeks or more during the preceding 4 weeks had a sensitivity of 22 to 33% for detecting tuberculosis. The presence of cough of any duration, fever of any duration, or night sweats lasting 3 or more weeks in the preceding 4 weeks was 93% sensitive and 36% specific for tuberculosis. In the 1199 patients with any of these symptoms, a combination of two negative sputum smears, a normal chest radiograph, and a CD4+ cell count of 350 or more per cubic millimeter helped to rule out a diagnosis of tuberculosis, whereas a positive diagnosis could be made only for the 113 patients (9%) with one or more positive sputum smears; mycobacterial culture was required for most other patients. CONCLUSIONS: In persons with HIV infection, screening for tuberculosis should include asking questions about a combination of symptoms rather than only about chronic cough. It is likely that antiretroviral therapy and isoniazid preventive therapy can be started safely in people whose screening for all three symptoms is negative, whereas diagnosis in most others will require mycobacterial culture.

Association between tuberculin skin test result and clinical presentation of tuberculosis disease.

BACKGROUND: The tuberculin skin test (TST) is used to test for latent tuberculosis (TB) infection and support the diagnosis of active TB. However, little is known about the relationship between the TST result and the clinical presentation of TB disease. METHODS: We analyzed US TB surveillance data, 1993-2010, and used multinomial logistic regression to calculate the association between TST result (0-4 mm [negative], 5-9 mm, 10-14 mm, and ≥ 15 mm) and clinical presentation of disease (miliary, combined pulmonary and extrapulmonary, extrapulmonary only, non-cavitary pulmonary, and cavitary pulmonary). For persons with pulmonary disease, multivariate logistic regression was used to calculate the odds of having acid-fast bacilli (AFB) positive sputum. RESULTS: There were 64,238 persons with culture-confirmed TB included in the analysis, which was stratified by HIV status and birthplace (US- vs. foreign-born). Persons with a TST ≥ 15 mm were less likely to have miliary or combined pulmonary and extrapulmonary disease, but more likely to have cavitary pulmonary disease than non-cavitary pulmonary disease. Persons with non-cavitary pulmonary disease with a negative TST were significantly more likely to have AFB positive sputum. CONCLUSIONS: Clinical presentation of TB disease differed according to TST result and persons with a negative TST were more likely to have disseminated disease (i.e., miliary or combined pulmonary and extrapulmonary). Further study of the TST result may improve our understanding of the host-pathogen relationship in TB disease.

Substitution of rifapentine for rifampin during intensive phase treatment of pulmonary tuberculosis: study 29 of the tuberculosis trials consortium.

BACKGROUND: Rifapentine administered 5 days per week has potent activity in mouse models of antituberculosis chemotherapy, but efficacy and safety data are limited in humans. We compared the antimicrobial activity and safety of rifapentine vs rifampin during the first 8 weeks of pulmonary tuberculosis treatment. METHODS: In total, 531 adults with sputum smear-positive pulmonary tuberculosis were randomized to rifapentine 10 mg/kg/dose or rifampin 10 mg/kg/dose, administered 5 days per week for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. Coprimary outcomes were negative sputum culture on liquid and on solid media at completion of intensive phase. RESULTS: Negative cultures on solid media occurred in 145 of 174 participants (83.3%) in the rifampin group and 171 of 198 participants (86.4%) in the rifapentine group (difference, 3.0%; 95% confidence interval [CI]: -4.3, 10.5); negative cultures in liquid media occurred in 110 of 169 (65.1%) in the rifampin group and 133 of 196 (67.9%) in the rifapentine group (difference, 2.8%; 95% CI: -6.9, 12.4). Among 529 participants who received study therapy, 40 of 254 participants (15.7%) in the rifampin group and 40 of 275 participants (14.5%) in the rifapentine group prematurely discontinued treatment (P=.79). CONCLUSIONS: The rifapentine regimen was safe but not significantly more active than a standard rifampin regimen, by the surrogate endpoint of culture status at completion of intensive phase. Assessment of higher exposures to rifapentine for tuberculosis treatment is warranted. CLINICAL TRIALS REGISTRATION: NCT00694629.

Seasonality of tuberculosis in the United States, 1993-2008.

BACKGROUND: Although seasonal variation in tuberculosis incidence has been described in several recent studies, the mechanism underlying this seasonality remains unknown. Seasonality of tuberculosis disease may indicate the presence of season-specific risk factors that could potentially be controlled if they were better understood. We conducted this study to determine whether tuberculosis is seasonal in the United States and to describe patterns of seasonality in specific populations. METHODS: We performed a time series decomposition analysis of tuberculosis cases reported to the Centers for Disease Control and Prevention from 1993 through 2008. Seasonal amplitude of tuberculosis disease (the difference between the months with the highest and lowest mean case counts), was calculated for the population as a whole and for populations with select demographic, clinical, and epidemiologic characteristics. RESULTS: A total of 243 432 laboratory-confirmed tuberculosis cases were reported over a period of 16 years. A mean of 21.4% more cases were diagnosed in March, the peak month, compared with November, the trough month. The magnitude of seasonality did not vary with latitude. The greatest seasonal amplitude was found among children aged <5 years and in cases associated with disease clusters. CONCLUSIONS: Tuberculosis is a seasonal disease in the United States, with a peak in spring and trough in late fall. The latitude independence of seasonality suggests that reduced winter sunlight exposure may not be a strong contributor to tuberculosis risk. Increased seasonality among young children and clustered cases suggests that disease that is the result of recent transmission is more influenced by season than disease resulting from activation of latent infection.

Ethical justification for conducting public health surveillance without patient consent.

Public health surveillance by necessity occurs without explicit patient consent. There is strong legal and scientific support for maintaining name-based reporting of infectious diseases and other types of public health surveillance. We present conditions under which surveillance without explicit patient consent is ethically justifiable using principles of contemporary clinical and public health ethics. Overriding individual autonomy must be justified in terms of the obligation of public health to improve population health, reduce inequities, attend to the health of vulnerable and systematically disadvantaged persons, and prevent harm. In addition, data elements collected without consent must represent the minimal necessary interference, lead to effective public health action, and be maintained securely.

Improving participant understanding of informed consent in an HIV-prevention clinical trial: a comparison of methods.

Empirical research on informed consent has shown that study participants often do not fully understand consent information. This study assessed participant understanding of three mock consent approaches describing an HIV-prevention clinical trial in Lilongwe, Malawi prior to trial implementation. Pregnant women (n = 297) were systematically selected from antenatal-care waiting lines and sequentially allocated to receive an enhanced standard consent form (group 1), a context-specific consent form (group 2), or context-specific counseling cards (group 3). Understanding of research concepts and study procedures was assessed immediately postintervention and at 1-week follow-up. At postintervention, participants in groups 2 and 3 understood more about research concepts and study procedures compared with group 1. Group 3 participants also understood more about study procedures compared with group 2. At follow-up, participants in groups 2 and 3 continued to understand more about research concepts and study procedures. Context-specific approaches improved understanding of consent information in this study.

Menstrual irregularities and vaginal bleeding after COVID-19 vaccination reported to v-safe active surveillance, USA in December, 2020-January, 2022: an observational cohort study.

BACKGROUND: Anecdotal reports of menstrual irregularities after receiving COVID-19 vaccines have been observed in post-authorisation and post-licensure monitoring. We aimed to identify and classify reports of menstrual irregularities and vaginal bleeding after COVID-19 vaccination submitted to a voluntary active surveillance system. METHODS: This observational cohort study included recipients of a COVID-19 vaccine who were aged 18 years and older and reported their health experiences to v-safe, a voluntary smartphone-based active surveillance system for monitoring COVID-19 vaccine safety in the USA, from Dec 14, 2020, to Jan 9, 2022. Responses to survey questions on reactions after vaccination were extracted, and a pre-trained natural language inference model was used to identify and classify free-text comments related to menstruation and vaginal bleeding in response to an open-ended prompt about any symptoms at intervals after vaccination. Related responses were further categorised into themes of timing, severity, perimenopausal and postmenopausal bleeding, resumption of menses, and other responses. We examined associations between symptom theme and respondent characteristics, including vaccine type and dose number received, solicited local and systemic reactions reported, and health care sought. FINDINGS: 63 815 respondents reported on menstrual irregularities or vaginal bleeding, which included 62 679 female respondents (1·0% of 5 975 363 female respondents aged ≥18 years). Common themes identified included timing of menstruation (70 981 [83·6%] responses) and severity of menstrual symptoms (56 890 [67·0%] responses). Other themes included menopausal bleeding (3439 [4·0%] responses) and resumption of menses (2378 [2·8%] responses). Respondents submitting reports related to menopausal bleeding were more likely to seek health care than were those submitting reports related to other menstruation and vaginal bleeding themes. INTERPRETATION: Reports of heterogeneous symptoms related to menstruation or vaginal bleeding after COVID-19 vaccination are being submitted to v-safe, although this study is unable to characterise the relationship of these symptoms to COVID-19 vaccination. Methods that leverage pretrained models to interpret and classify unsolicited signs and symptoms in free-text reports offer promise in the initial evaluation of unexpected adverse events potentially associated with use of newly authorised or licensed vaccines. FUNDING: Centers for Disease Control and Prevention.

Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies.

BACKGROUND: The World Health Organization recommends the screening of all people living with HIV for tuberculosis (TB) disease, followed by TB treatment, or isoniazid preventive therapy (IPT) when TB is excluded. However, the difficulty of reliably excluding TB disease has severely limited TB screening and IPT uptake in resource-limited settings. We conducted an individual participant data meta-analysis of primary studies, aiming to identify a sensitive TB screening rule. METHODS AND FINDINGS: We identified 12 studies that had systematically collected sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status. Bivariate random-effects meta-analysis and the hierarchical summary relative operating characteristic curves were used to evaluate the screening performance of all combinations of variables of interest. TB disease was diagnosed in 557 (5.8%) of 9,626 people living with HIV. The primary analysis included 8,148 people living with HIV who could be evaluated on five symptoms from nine of the 12 studies. The median age was 34 years. The best performing rule was the presence of any one of: current cough (any duration), fever, night sweats, or weight loss. The overall sensitivity of this rule was 78.9% (95% confidence interval [CI] 58.3%-90.9%) and specificity was 49.6% (95% CI 29.2%-70.1%). Its sensitivity increased to 90.1% (95% CI 76.3%-96.2%) among participants selected from clinical settings and to 88.0% (95% CI 76.1%-94.4%) among those who were not previously screened for TB. Negative predictive value was 97.7% (95% CI 97.4%-98.0%) and 90.0% (95% CI 88.6%-91.3%) at 5% and 20% prevalence of TB among people living with HIV, respectively. Abnormal chest radiographic findings increased the sensitivity of the rule by 11.7% (90.6% versus 78.9%) with a reduction of specificity by 10.7% (49.6% versus 38.9%). CONCLUSIONS: Absence of all of current cough, fever, night sweats, and weight loss can identify a subset of people living with HIV who have a very low probability of having TB disease. A simplified screening rule using any one of these symptoms can be used in resource-constrained settings to identify people living with HIV in need of further diagnostic assessment for TB. Use of this algorithm should result in earlier TB diagnosis and treatment, and should allow for substantial scale-up of IPT.

Optimizing drug inventory management with a web-based information system: The TBTC Study 31/ACTG A5349 experience.

INTRODUCTION: Efficient management of study drug inventory shipments is critical to keep research sites enrolling into multisite clinical treatment trials. A standard manual drug-management process used by the Tuberculosis Trials Consortium (TBTC), did not accommodate import permit approval timelines, shipment transit-times and time-zone differences. We compared a new web-based solution with the manual process, during an international 34-site clinical trial conducted by the TBTC and the AIDS Clinical Trials Group (ACTG); TBTC Study 31/ACTG A5349. MATERIAL AND METHODS: We developed and implemented a technological solution by integrating logistical and regulatory requirements for drug importation with statistical simulations that estimated stock-out times in an online Drug Management Module (DMM). We measured the average shipment-related drug stock-outs and time to drug availability, to assess the efficiency of the DMM compared to the manual approach. RESULTS: An Interrupted Time-Series (ITS) analysis showed a 15.4% [p-value = 0.03; 95% C.I. (-28.8%, -2.0%)] reduction in average shipment-related study drug stock-out after DMM implementation. The DMM streamlined the restocking process at study sites, reducing median transit-time for sites associated with a depot by 2 days [95% C.I. (-3.0, -1.0)]. Under the DMM, study drugs were available for treatment assignment on the day received, compared to one day after receipt under the manual process. DISCUSSION: The DMM provided TBTC's Data and Coordinating Center and site staff with more efficient procedures to manage and consistently maintain study drug inventory at enrolling sites. This DMM framework can improve efficiency in future multicenter clinical trials. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (Identifier: NCT02410772) on April 8, 2015.