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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.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.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).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.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 ).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.

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.

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.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.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.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.Centers for Disease Control and Prevention.

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.

SETTING: Efficient tuberculosis (TB) active case-finding strategies are important in settings with high TB burdens and limited resources, such as those in western Kenya.OBJECTIVE: To guide efforts to optimize screening efficiency, we identified the predictors of TB among people screened in health facilities and communities.DESIGN: During February 2015-June 2016, adults aged ≥15 years reporting any TB symptom were identified in health facilities and community mobile screening units, and evaluated for TB. We assessed the predictors of TB using a modified Poisson regression with generalized estimating equations to account for clustering according to screening site.RESULTS: TB was diagnosed in 484 (20.3%) of 2394 symptomatic adults in health facilities and 39 (3.4%) of 1424 in communities. In health facilities, >10% of symptomatic adults in all demographic groups had TB, and no predictors were associated with a ≥2-fold increased risk. In communities, the independent predictors of TB were male sex (adjusted prevalence ratio [aPR] = 4.26, 95%CI 2.43-7.45), HIV infection (aPR 2.37, 95%CI 1.18-4.77), and household TB contact in the last 2 years (aPR 2.84, 95%CI 1.62-4.96).CONCLUSION: Our findings support the notion of general TB screening in health facilities and evaluation of the adult household contacts of TB patients.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), presents with a broad range of symptoms. Existing COVID-19 case definitions were developed from early reports of severely ill, primarily hospitalized, patients. Symptom-based case definitions that guide public health surveillance and individual patient management in the community must be optimized for COVID-19 pandemic control.MethodsWe collected daily symptom diaries and performed RT-PCR on respiratory specimens over a 14-day period in 185 community members exposed to a household contact with COVID-19 in the Milwaukee, Wisconsin and Salt Lake City, Utah metropolitan areas. We interpreted the discriminatory performance (sensitivity, specificity, predictive values, F⍰1 score, Youden’s index, and prevalence estimation) of individual symptoms and common case definitions according to two principal surveillance applications (i.e., individual screening and case counting). We also constructed novel case definitions using an exhaustive search with over 73 million symptom combinations and calculated bias-corrected and accelerated bootstrap confidence intervals stratified by children versus adults.FindingsCommon 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. The top performing novel symptom combinations included taste or smell dysfunction. They also improved the balance of sensitivity and PPV (F⍰1 score 78⍰80) and reduced the number of false positive symptom screens. Performance indicators were generally lower for children (InterpretationExisting COVID-19 case definitions appropriately screened in community members with COVID-19. However, they led to many false positive symptom screens and poorly estimated community prevalence. Absent unlimited, timely testing capacity, more accurate case definitions may help focus public health resources. Novel symptom combinations incorporating taste or smell dysfunction as a primary component better balanced sensitivity and specificity. Case definitions tailored specifically for children versus adults should be further explored.FundingThis research was wholly supported by the U.S. Centers for Disease Control and Prevention.DisclaimerThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry.Research in ContextEvidence before this studyCoronavirus disease 2019 (COVID-19) incidence has accelerated globally over the last several months. As the full spectrum of clinical presentations has come into clearer focus, symptom-based clinical screening and case surveillance has also evolved. Preliminary understanding of the clinical manifestation of COVID-19 was driven primarily by descriptions of hospitalized patients, as early testing algorithms prioritized more severely ill persons with classic lower respiratory symptoms and fever. Since then, more data from ambulatory settings have emerged. We searched PubMed from 1 December 2019 to 21 August 2020 for studies that assessed the diagnostic performance of case surveillance definitions for COVID-19. We found no studies examining the discriminatory performance of case surveillance definitions among contacts with mild to moderate symptoms with documented exposure to persons with COVID-19. Nonetheless, we found nine highly relevant studies: seven original reports and two review articles. Five original studies evaluated individual, self-reported symptoms (two among healthcare workers in the United States, one among healthcare workers in the Netherlands, and one online survey for the general public in Somalia) and concluded that using dysfunction of taste or smell for routine COVID-19 screening likely had utility. The fifth study had a similar conclusion based on self-reported symptoms and laboratory results collected via smartphone from the general public in the United States and the United Kingdom. Another original study modeled the substantial effect that multiple revisions to the COVID-19 case definition had on the reported disease burden in the Chinese population. Lastly, an original study illustrated the shift in discriminatory performance of established influenza surveillance case definitions for influenza between adults and children. Age-specific differences in case definition performance may also apply to COVID-19. Two articles reviewed predictive algorithms to define outpatient COVID-19 illness and risk of hospitalization. The reviewed studies were limited in that they were either restricted to individual signs or symptoms, or they incorporated blood tests or imaging that required in-person access to medical care.Added value of this studyThe discriminatory performance of case surveillance definitions for COVID-19 is important for implementing effective epidemic mitigation strategies. Our study illustrates the performance of case definitions in community members with household exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based solely on symptom profiles. Prior work overrepresented healthcare workers or otherwise studied non-representative populations, and they did not examine across the age spectrum. Our study also provides a novel framework for refining definitions. Using 15 symptoms associated with COVID-19 for all contacts regardless of disease status, we systematically evaluated the discriminatory performance of individual symptoms and previously defined case surveillance definitions across ages and according to two core surveillance applications: 1) screening non-hospitalized individuals to prioritize public health interventions, and 2) estimating the number of non-hospitalized persons with COVID-19 (i.e., community-based syndromic surveillance). We also constructed novel symptom combinations that effectively performed both functions and improved upon widely used case surveillance definitions that may help to target interventions in the absence of unlimited laboratory diagnostic capacity. Our analyses highlight the importance of ongoing re-evaluation of symptom-based surveillance definitions to suit the intended purpose and population under surveillance. Based on our results, which were derived from household members of all ages, case surveillance definition performance may improve if developed separately for adults and children.Implications of all the available evidenceCase definitions for COVID-19 should be tailored to maximize the discriminatory performance dependent upon its intended use. Existing COVID-19 case definitions screened in most community members with COVID-19, but also yielded a high number of false positive results. When unlimited, timely diagnostic testing is not available symptom combinations with improved accuracy (i.e., more balanced sensitivity and specificity) may help focus resources, such as recommending self-isolation among community contacts.

Background The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. Methods We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. Findings We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per μL (the median for the cohort) was 45% (95% CI 38–52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63–87), increasing to 89% (80–94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05–3·08) but not after 30 days (1·25, 0·84–2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16–8·84). Interpretation In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients. Funding This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A .

OBJECTIVE: To evaluate the utility of a broad and nonspecific symptom screen for identifying people with undiagnosed HIV infection. DESIGN: Secondary analysis of operational data collected during implementation of a cluster-randomized trial for tuberculosis case detection. METHODS: As part of the trial, adults reporting cough, fever, night sweats, weight loss, or difficulty breathing for any duration in the past month were identified in health facilities and community-based mobile screening units in western Kenya. Adults reporting any symptom were offered HIV testing. We analysed the HIV testing data from this study, using modified Poisson regression, to identify predictors of new HIV diagnoses among adults with symptoms and initially unknown HIV status. RESULTS: We identified 3818 symptomatic adults, referred 1424 (37%) for testing, of whom 1065 (75%) accepted, and 107 (10%) were newly diagnosed with HIV. The prevalence of new HIV diagnoses was 21% [95% confidence interval (CI) 17–25%] among those tested in health facilities and 5% (95% CI 4–7%) among those tested in mobile units. More men were diagnosed with HIV than women, despite fewer men being screened. People who reported 4–5 symptoms were over twice as likely to be diagnosed with HIV compared to those reporting 1–3 symptoms (adjusted prevalence ratio in health facilities = 2.58, 95% CI 1.65–4.05; adjusted prevalence ratio in mobile units = 2.63, 95% CI 1.37–5.03). CONCLUSION: We observed a high yield of new HIV diagnoses among adults identified by active application of a broad symptom screen. Use of integrated tuberculosis and HIV screening could help close the detection gap for both conditions.

Although Kenya has a high burden of tuberculosis (TB), only 46% of cases were diagnosed in 2016.To identify strategies for increasing attendance at community-based mobile screening units.We analysed operational data from a cluster-randomised trial, which included community-based mobile screening implemented during February 2015-April 2016. Community health volunteers (CHVs) recruited individuals with symptoms from the community, who were offered testing for human immunodeficiency virus (HIV) and sputum collection for XpertA total of 1424 adults with symptoms were screened at 25 mobile unit sites. The median total attendance among sites was 54 (range 6-134, interquartile range [IQR] 24-84). The median yields of TB diagnoses and new HIV diagnoses were respectively 2.4% (range 0.0-16.7, IQR 0.0-5.3) and 2.5% (range 0.0-33.3, IQR 1.2-4.2). Attendance at urban sites was variable; attendance at rural sites where CHVs were paid a daily minimum wage was significantly higher than at rural sites where CHVs were paid a nominal monthly stipend (Mobile units were most effective and efficient when implemented as a single event with community health workers who are paid a daily wage.Bien que le Kenya soit lourdement affecté par la tuberculose (TB), seulement 46% des cas ont été diagnostiqués en 2016.Identifier les stratégies visant à augmenter la fréquentation des unités mobiles de dépistage en communauté.Nous avons analysé les données opérationnelles d'un essai randomisé en grappes, qui a inclus les unités mobiles de dépistage dans les communautés mises en œuvre entre février 2015 et avril 2016. Les travailleurs de santé communautaire (CHV) ont recruté des individus symptomatiques de la communauté, à qui ont été proposés un test de virus de l'immunodéficience humaine (VIH) et un recueil de crachats pour un test XpertAu total, 1424 adultes symptomatiques ont été dépistés dans 25 sites d'unités mobiles. La fréquentation médiane totale dans les sites a été de 54 (fourchette : 6–134; intervalle interquartile [IQR]: 24–84). Le rendement médian de diagnostic de TB et de nouveaux diagnostics de VIH a été de 2,4% (fourchette 0,0–16,7 ; IQR 0,0–5,3) et de 2,5% (fourchette 0,0–33,3 ; IQR 1,2–4,2), respectivement. La fréquentation dans les sites urbains a été variable ; la fréquentation dans les sites ruraux où les CHV ont reçu un salaire minimum journalier a été significativement plus élevée que dans les sites ruraux où les CHV ont reçu une compensation mensuelle modeste (Les unités mobiles ont été les plus efficaces et rentables quand elles ont été mises en œuvre sous forme d'un évènement unique avec les CHV qui sont payés chaque jour.A pesar de que Kenya tenga una carga de morbilidad por tuberculosis (TB) alta, en el 2016 solo se diagnosticaron 46% de los casos.Definir estrategias que aumenten la asistencia a las unidades móviles comunitarias de detección sistemática.Se analizaron los datos operativos de un ensayo clínico aleatorizado en conglomerados, que incluyó unidades móviles comunitarias de detección activa de la TB de febrero del 2015 a abril del 2016. Los agentes de salud comunitarios voluntarios (CHV) incorporaron a las personas sintomáticas de la comunidad, a quienes se ofreció la prueba diagnóstica del virus de la inmunodeficiencia humana (VIH) y el examen de muestras de esputo con la prueba XpertSe examinaron 1424 adultos sintomáticos en 25 puestos de unidades móviles. La mediana de la asistencia global en todos los puestos fue 54 (entre 6 y 134; amplitud intercuartil [IQR] 24–84). La mediana del rendimiento diagnóstico de TB fue 2,4% (entre 0,0 y 16,7; IQR 0,0–5,3) y la de diagnósticos nuevos de infección por el VIH fue 2,5% (entre 0,0 y 33,3; IQR 1,2–4,2). La asistencia a los puestos urbanos fue variable; en los puestos rurales, donde los CHV recibían un salario mínimo diario, la asistencia fue significativamente más alta que en los puestos donde los voluntarios recibían una remuneración nominal mensual (Las unidades móviles fueron más eficaces y eficientes cuando los CHV operaban en un evento único, con remuneración diaria.

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.

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.

Background: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis blood stream infection (MTB-BSI) is incompletely understood. We hypothesised that MTB-BSI prevalence has been underestimated, that MTB-BSI independently predicts death, and sputum Xpert has suboptimal diagnostic yield for MTB-BSI. Methods: We conducted a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood-culture (TBBC), including HIV-positive adults aged ≥13-years with suspected tuberculosis. Predicted probabilities of MTB-BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum (Xpert or culture if Xpert unavailable) and urinelipoarabinomannan for MTB-BSI were obtained by two-level random-effect meta-analysis, mortality hazard of MTB-BSI by mixed-effect Cox proportional-hazard modelling, and effect of treatment delay with propensity-score analysis. Findings 5751 patients met inclusion criteria. Predicted probability of MTB-BSI was 45% (95%CI 38-52%) for danger-sign positive tuberculosis inpatients with cohort median CD4 count of 76 cells/μL. Diagnostic yield of sputum was 77% (95%CI 63–87%), rising to 89% (95%CI 80-94%) when combined with urinelipoarabinomannan testing. MTB-BSI increased hazard of death before 30-days (aHR2·5, 95%CI 2·1–3·1). In a propensity-score matched cohort (n=630), mortality increased with treatment delay >4 days in MTB-BSI (OR 3·2, 95%CI 1·1–10·3). Interpretation: In critically-ill adults with HIV-tuberculosis, MTB-BSI is a very frequent manifestation of tuberculosis and strongly predicts mortality. Better diagnostic yield in patients with MTB-BSI can be achieved by parallel use of sputum-Xpert and urine-LAM. Treatment delay may increase mortality hazard. Funding Statement: This study was supported by Wellcome fellowships 109105z/15/a, 105165/Z14/A. Charlotte Schutz was funded by the South African Medical Research Council under the National Health Scholars Programme. Moshi, Tanzania research was supported by an International Studies on AIDS Associated Co-infections (ISAAC) award, a program funded by the US National Institutes of Health (NIH) (U01 AI062563). John A. Crump receives support from US NIH R01AI121378. Elizabeth L. Corbett is supported by a Wellcome trust senior fellowship in clinical science (WT200901). Gary Maartens was supported in part by National Research Fund incentive funding (UID: 85810). Susan E. Dorman was supported by contract #HHSN2722000900050C and grant K24AI104830 (to SED), both from the US National Institutes of Health. Douglas Wilson was supported by BMS Secure the Future. Graeme Meintjes was supported by the Wellcome Trust (098316 and 203135/Z/16/Z), the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787), NRF incentive funding (UID: 85858) and the South African Medical Research Council through its TB and HIV Collaborating Centres Programme with funds received from the National Department of Health (RFA# SAMRC-RFA-CC: TB/HIV/AIDS-01-2014). Declaration of Interests: David Alland is on the Scientific Advisory Board of Specific Technologies and receives a portion of the licensing income paid by Cepheid to Rutgers University for sales of the Xpert Ultra assay. Neil Martinson has received institutional grants for collection of specimens for Roche and Becton Dickinson, and from Pfizer for assessing incident pneumonia. All other authors declare no competing interests. Ethics Approval Statement: PROSPERO registration: CRD42016050022.

Introduction Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen. Methods/Design S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority. Discussion This phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels. Trial registration: NCT02410772 . Registered 8 April 2015, https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1

Objective To better define and automate biosurveillance syndrome categorization using modern unsupervised vector embedding techniques. Introduction Comprehensive medical syndrome definitions are critical for outbreak investigation, disease trend monitoring, and public health surveillance. However, because current definitions are based on keyword string-matching, they may miss important distributional information in free text and medical codes that could be used to build a more general classifier. Here, we explore the idea that individual ICD codes can be categorized by examining their contextual relationships across all other ICD codes. We extend previous work in representation learning with medical data [1] by generating dense vector embeddings of these ICD codes found in emergency department (ED) visit records. The resulting representations capture information about disease co-occurrence that would typically require SME involvement and support the development of more robust syndrome definitions. Methods We evaluate our method on anonymized ED visit records obtained from the New York City Department of Health and Mental Hygiene. The data set consists of approximately 3 million records spanning January 2016 to December 2016, each containing from one to ten ICD-9 or ICD-10 codes. We use these data to embed each ICD code into a high-dimensional vector space following techniques described in Mikolov, et al. [2], colloquially known as word2vec. We define an individual code’s context window as the entirety of its current health record. Final vector embeddings are generated using the gensim machine learning library in Python. We generate 300-dimensional embeddings using a skip-gram network for qualitative evaluation. We use the TensorFlow Embedding Projector to visualize the resulting embedding space. We generate a three-dimensional t-SNE visualization with a perplexity of 32 and a learning rate of 10, run for 1,000 iterations (Figure 1). Finally, we use cosine distance to measure the nearest neighbors of common ICD-10 codes to evaluate the consistency of the generated vector embeddings (Table 1). Results T-SNE visualization of the generated vector embeddings confirms our hypothesis that ICD codes can be contextually grouped into distinct syndrome clusters (Figure 1). Manual examination of the resulting embeddings confirms consistency across codes from the same top-level category but also reveals cross-category relationships that would be missed from a strictly hierarchical analysis (Table 1). For example, not only does the method appropriately discover the close relationship between influenza codes J10.1 and A49.2, it also reveals a link between asthma code J45.20 and obesity code E66.09. We believe these learned relationships will be useful both for refining existing syndrome categories and developing new ones. Conclusions The embedding structure supports the hypothesis of distinct syndrome clusters, and nearest-neighbor results expose relationships between categorically unrelated codes (appropriate upon examination). The method works automatically without the need for SME analysis and it provides an objective, data-driven baseline for the development of syndrome definitions and their refinement. References [1] Choi Y, Chiu CY-I, Sontag D. Learning Low-Dimensional Representations of Medical Concepts. AMIA Summits on Translational Science Proceedings. 2016;2016:41-50. [2] Mikolov T, Sutskever I, Chen K, Corrado GS, Dean J. Distributed representations of words and phrases and their compositionality. InAdvances in neural information processing systems 2013 (pp. 3111-3119).

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 (pINTERPRETATION: 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.

SETTING Drug susceptibility testing (DST) is recommended in Kenya to identify multidrug-resistant tuberculosis (MDR-TB) in persons registered for tuberculosis (TB) retreatment. DST is performed at a central laboratory with a two-step growth-based process and a regional laboratory with a simultaneous molecular- and growth-based process. OBJECTIVE To compare proportions of retreatment cases who underwent DST and turnaround times for hospitals referring to the central vs. regional laboratory. DESIGN Cases were persons registered for TB retreatment from 1 January 2012 to 31 December 2013. Records of 11 hospitals and 7 hospitals referring patients to the regional and central laboratories, respectively, were reviewed. RESULTS Respectively 238/432 (55%) and 88/355 (25%) cases from hospitals referring to the regional and central laboratories underwent DST. The mean time from case registration to receipt of DST results and initiation of MDR-TB treatment was quicker in hospitals referring to the regional laboratory. The time required for the transportation of specimens, specimen testing and receipt of DST results at hospitals was shorter for the regional laboratory (P < 0.05). CONCLUSION Testing was faster and more complete at hospitals referring to the regional laboratory. A comprehensive review of MDR-TB detection in Kenya is required to increase the proportion of cases receiving DST.

Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown.We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment.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.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).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).

Phase 2 clinical trials for tuberculosis (TB) treatment require reliable culture methods to determine presence or absence of Mycobacterium tuberculosis (Mtb) over the course of therapy, as these trials are based primarily on bacteriological endpoints. We evaluate which of 5 solid media is most reliable: Lowenstein-Jensen (LJ) egg-based medium and 4 Middlebrook agar media (nonselective 7H10 and 7H11 and selective 7H10 and 7H11). We analyze 393 specimens from 50 HIV-negative Ugandan adults with newly-diagnosed, pulmonary TB and high acid-fast bacillus smear grade. Specimens were collected every 2–4 weeks during the first 12 weeks of therapy. We compare the results for each culture to 2 composite reference standards—one that was deemed positive if any solid culture was positive for Mtb and another based on latent class analysis. Both reference standards established that the 2 selective Middlebrook media most reliably determine the presence or absence of Mtb (P

Setting Twenty tuberculosis (TB) clinics in the United States and Canada. Objective To evaluate the efficacy and safety of a 6-month intermittent regimen of rifampin (RMP), pyrazinamide (PZA) and ethambutol (EMB) in human immunodeficiency virus (HIV) negative patients with culture-confirmed pulmonary or extra-pulmonary tuberculosis and either isoniazid (INH) resistance or INH intolerance. Design Patients were enrolled in a single-arm clinical trial to receive intermittent dosing after at least 14 initial daily doses of RMP+PZA+EMB. Treatment was continued twice (BIW) or thrice weekly (TIW) per physician/patient preference for a total of 6 months, with 2 years of follow-up for relapse after treatment. Results From 1999 to 2004, 98 patients were enrolled, 78 with reported INH resistance and 20 with INH intolerance. BIW dosing was used in 77 and TIW in 21. Study treatment was completed in 73 (74%). Reasons for discontinuation were hepatic adverse events (n= 12), other adverse effects (n= 3) and other reasons (n= 10). Failure (n= 1) and relapse (n= 2) occurred in 3 (3.5%, 95%CI 1.2-9.8) of 86 patients eligible for efficacy analysis, all occurring in patients with cavitary, acid-fast bacilli smear-positive pulmonary TB. Conclusions Intermittent RMP+PZA+EMB appears to be effective in HIV-negative patients, but the regimen is poorly tolerated, possibly due to the prolonged use of PZA. Alternative regimens of lower toxicity are needed.

Zusammenfassung Ziel der Studie war, die Zink(Zn)- und Eisen(Fe)-Konzentrationen sowie Beziehungen zu Stoffwechselparametern bei festliegenden Kühen zu analysieren. Material und Methoden: Festliegende und klinisch gesunde Fleckviehkühe wurden in fünf Gruppen eingeteilt: a) Kontrollgruppe (KG, n = 21), b) Gebärparese(GP)-Kühe gesamt (n = 174), c) GP-Kühe ohne Zusatzkrankheiten (n = 145), d) GP-Kühe mit Mastitis (n = 10), e) GP-Kühe mit Retentio secundinarum oder postpartaler Endometritis (n = 19). Die Blutserumanalyse umfasste folgende Parameter: Selen (Se), Zn, Fe, Mangan (Mn), Kupfer (Cu), Kalzium (Ca), anorganisches Phosphat (Pi), Magnesium (Mg), Kalium (K), Tumornekrosefaktor α (TNFα), Haptoglobin (Hp), Antioxidanzien (Trolox Equivalent Antioxidative Capacity, TEAC), Protein, Albumin, freie Fettsäuren (FFS), Beta-Hydroxybutyrat (BHB), Bilirubin, Harnstoff, Kreatinin, Glukose, Cholesterol, Gamma-Glutamyltransferase (GGT) und alkalische Phosphatase (AP). Ergebnisse: Die Konzentrationen von Zn, Fe, Ca, Pi und TEAC waren bei allen festliegenden Kühen niedriger, die von Hp höher als in der KG (p 0,05). In Gruppe c) lagen Ca- und Pi-Konzentration niedriger als in den Gruppen d) und e) (p 0,05). In Gruppe e) wurde eine signifikant geringere Zn-Konzentration bestimmt als in Gruppe c) (p 0,05). Zn korrelierte negativ mit K (KG), positiv mit TEAC, Cu, Mn und Fe (Gruppe b und c) und Mn (Gruppe e) (p 0,05). Fe korrelierte gesichert positiv mit Ca (Gruppe c), mit Pi (Gruppe c), mit K (Gruppe b und c), mit Mg (Gruppen b–d) sowie mit Zn, Cu und Se (Gruppe b und c) (p 0,05). TNFα war in den Gruppen b) und c) erhöht und korrelierte negativ mit Fe (p 0,05). Die Aktivität der AP war in den Gruppen b) und e) niedriger als in der KG (p 0,05). Schlussfolgerung: Die Resultate und Literaturberichte befürworten die Hypothese, dass Zn und Fe unmittelbar den Knochenstoffwechsel beeinflussen und in die Pathogenese der GP involviert sein können. Die Hp- und TEAC-Konzentrationen unterstützen diese Interpretation. Die Kontrolle des Zn- und des Fe-Status der Kühe und die Supplementation von Zn sollten in die Prävention und erweiterte Therapie der GP eingeschlossen werden.

Zusammenfassung Gegenstand und Ziel: Häufiges Auftreten der Gebärparese (GP) sowie zum Teil unbefriedigende Behandlungserfolge zwingen zur Frage, inwieweit neben den bekannten Ursachen weitere Faktoren Inzidenz und Therapieerfolg bei GP beeinflussen. Spurenelemente, wie Selen (Se), sind in den Knochenstoffwechsel involviert, doch gibt es wenige Kenntnisse über fördernde Einflüsse von Se bei der Entstehung der GP. Ziel der Studie war deshalb, die Konzentration von Se und statistische Beziehungen zu unter Se-Einflüssen stehenden Parametern bei festliegenden Kühen zu analysieren. Material und Methoden: Festliegende und klinisch gesunde Fleckviehkühe wurden in fünf Gruppen eingeteilt: a) Kontrollgruppe (KG, n = 21) b) GP-Kühe gesamt (n = 174), c) GP-Kühe ohne Zusatzkrankheiten (n = 145), d) GP-Kühe mit Mastitis (n = 10) sowie e) GP-Kühe mit Retentio secundinarum oder puerperaler Metritis (n = 19). Die Blutserumanalysen umfassten Selen (Se), Kalzium (Ca), anorganisches Phosphat (Pi), Tumornekrosefaktor α (TNFα), Haptoglobin (Hp), Antioxidanzien (Trolox Equivalent Antioxidative Capacity) sowie weitere metabolische Parameter. Ergebnisse: Die Serumkonzentrationen von Se, Ca, Pi und TEAC waren in den Gruppen b) bis e) signifikant niedriger bzw. Hp höher als in der KG (p 0,05). Se korrelierte in der KG positiv mit Pi, in den Gruppen b) und c) mit Ca, Pi, K, Mg und in Gruppe c) mit Hp (p 0,05). Die Ca- und Pi-Konzentrationen lagen in Gruppe c) signifikant niedriger als in Gruppe d) (p 0,05). Die TNFα-Konzentration zeigte sich in den Gruppen b) und c) gegenüber a) erhöht und korrelierte in der Gruppe e) mit Se (p 0,05). Die Aktivität der alkalischen Phosphatase war in den Gruppen b) und e) niedriger als in der KG und korrelierte in der Gruppe a) mit Se (p 0,05). Schlussfolgerung: In Übereinstimmung mit Literaturangaben unterstützen die Resultate die Hypothese, dass Se unmittelbar in den Knochenstoffwechsel eingreift und damit in der Pathogenese der GP involviert sein könnte. Se wirkt über Zytokine auf die Ca-Mobilisierbarkeit aus dem Knochen. Die gemessenen Konzentrationen von Hp und TEAC unterstützen diese Interpretation. Die Kontrolle des Se-Status und die Se-Supplementation der Kühe sollten bei der Prävention und erweiterten Therapie der GP berücksichtigt werden.

Setting A large randomized controlled trial recently showed that for treating latent tuberculous infection (LTBI) in persons at high risk of progression to tuberculosis (TB) disease, a 12-dose regimen of weekly rifapentine plus isoniazid (3HP) administered as directly observed treatment (DOT) can be as effective as 9 months of daily self-administered isoniazid (9H). Objectives To assess the cost-effectiveness of 3HP compared to 9H. Design A computational model was designed to simulate individuals with LTBI treated with 9H or 3HP. Costs and health outcomes were estimated to determine the incremental costs per active TB case prevented and per quality-adjusted life year (QALY) gained by 3HP compared to 9H. Results Over a 20-year period, treatment of LTBI with 3HP rather than 9H resulted in 5.2 fewer cases of TB and 25 fewer lost QALYs per 1000 individuals treated. From the health system and societal perspectives, 3HP would cost respectively US$21,525 and $4294 more per TB case prevented, and respectively $4565 and $911 more per QALY gained. Conclusions 3HP may be a cost-effective alternative to 9H, particularly if the cost of rifapentine decreases, the effectiveness of 3HP can be maintained without DOT, and 3HP treatment is limited to those with a high risk of progression to TB disease.

BACKGROUND Delayed diagnosis of tuberculosis (TB) increases mortality. OBJECTIVE To evaluate whether stool culture improves the diagnosis of TB in people living with the human immunodeficiency virus (PLHIV). DESIGN We analysed cross-sectional data of TB diagnosis in PLHIV in Cambodia, Thailand and Viet Nam. Logistic regression was used to assess the association between positive stool culture and TB, and to calculate the incremental yield of stool culture. RESULTS A total of 1693 PLHIV were enrolled with a stool culture result. Of 228 PLHIV with culture-confirmed TB from any site, 101 (44%) had a positive stool culture; of these, 91 (90%) had pulmonary TB (PTB). After adjusting for confounding factors, a positive stool culture was associated with smear-negative (odds ratio [OR] 26, 95% confidence interval [CI] 12-58), moderately smear-positive (OR 60, 95%CI 23-159) and highly smear-positive (OR 179, 95%CI 59-546) PTB compared with no PTB. No statistically significant association existed with extra-pulmonary TB compared with no extra-pulmonary TB (OR 2, 95%CI 1-5). The incremental yield of one stool culture above two sputum cultures (5%, 95%CI 3-8) was comparable to an additional sputum culture (7%, 95%CI 4-11). CONCLUSION Nearly half of the PLHIV with TB had a positive stool culture that was strongly associated with PTB. Stool cultures may be used to diagnose TB in PLHIV.

Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555. © 2017 AGA Institute

The lack of consistent associations between clinical outcomes and microbiological responses to therapy for some infectious diseases has raised questions about the adequacy of microbiological endpoints for tuberculosis treatment trials.To evaluate the association between symptoms and microbiological response to tuberculosis treatment.We performed a retrospective analysis of four clinical trials in which participants had culture-positive tuberculosis, standardized symptom assessment, and follow-up mycobacterial cultures. Two trials (studies 22 and 23) followed participants to identify recurrent tuberculosis; participants in studies 27 and 28 were only followed to treatment completion.This analysis included 1,978 participants; 39 (2.0%) had culture-confirmed treatment failure, and 75 (3.9%) had culture-confirmed recurrence. Productive cough was associated with indices of increased mycobacterial burden at diagnosis (acid-fast smear grade, severity of radiographic abnormalities). Fever and sweats improved rapidly with treatment, whereas productive cough decreased more slowly and was present in 20% of visits after treatment completion. During treatment, study participants with productive cough more often had concurrent culture positivity compared with those without productive cough (studies 22 and 23: adjusted odds ratio, 1.80; 95% confidence interval [CI], 1.33-2.44). Finally, symptoms during the latter part of treatment and follow-up were associated with culture-confirmed treatment failure and recurrence in studies 22 and 23 (for cough: adjusted hazard ratio, 2.07; 95% CI, 1.23-3.49; for fever: adjusted hazard ratio, 5.05; 95% CI, 2.76-9.19).There are consistent relationships between symptoms and microbiological indices of tuberculosis, including measures of mycobacterial burden at baseline, culture positivity during treatment, and time to culture-confirmed treatment failure and recurrence.

The IFN-γ release assays and tuberculin skin tests are used to support the diagnosis of both latent and active tuberculosis. However, we previously demonstrated that a negative tuberculin test in active tuberculosis is associated with disseminated disease and death. It is unknown whether the same associations exist for IFN-γ release assays.To determine the association between these tests and site of tuberculosis and death among persons with active tuberculosis.We analyzed IFN-γ release assays and tuberculin test results for all persons with culture-confirmed tuberculosis reported to the U.S. National Tuberculosis Surveillance System from 2010 to 2014. We used logistic regression to calculate the association between these tests and site of disease and death.A total of 24,803 persons with culture-confirmed tuberculosis had either of these test results available for analysis. Persons with a positive tuberculin test had lower odds of disseminated disease (i.e., miliary or combined pulmonary and extrapulmonary disease), but there was no difference in the odds of disseminated disease with a positive IFN-γ release assay. However, persons who were positive to either of these tests had lower odds of death. An indeterminate IFN-γ release assay result was associated with greater odds of both disseminated disease and death.Despite perceived equivalence in clinical practice, IFN-γ release assays and tuberculin test results have different associations with tuberculosis site, yet similar associations with the risk of death. Furthermore, an indeterminate IFN-γ release assay result in a person with active tuberculosis is not unimportant, and rather carries greater odds of disseminated disease and death. Prospective study may improve our understanding of the underlying mechanisms by which these tests are associated with disease localization and death.

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.

Summary 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.

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.

Transmembrane proteins are gatekeepers of the cells; controlling the transport of substrates as well as communicating signals among cells and between the organelles and cytosol. Solute carriers (SLC) and G protein-coupled receptors (GPCR) are the largest family of membrane transporters and membrane receptors respectively. The overall aim of this thesis was to provide a basic understanding of some of the novel SLCs and GPCRs with emphasis on expression, transport property, evolution and probable function. The first part of the thesis directs towards the study of some novel solute carriers. In an initial study, we provided an overall picture of the sequence relationship and tissue expression of 14 diverse atypical SLCs confirming some of their evolutionary conservation and highly specific expression pattern. The focus then was on the SLC17 family (mainly vesicular proteins) and a novel member named Slc17a9. This study revealed that SLC17 family could be divided into four main phylogenetic clades which were all present before the divergence of the insect lineage with Slc17a9 having the most restricted evolutionary history. Detailed expression study of Slc17a9 in the mouse brain suggests that it is also expressed in some regions important for purinergic neurotransmission. Further, we deorphanised an aminoacid transporter Slc38a7 which was expressed in a majority of neurons in the CNS and showed that it preferably mediate transport of L–glutamine and L–histidine. The second part of the thesis focuses on the study of two GPCRs belonging to the Rhodopsin superfamily, Gpr162 and Gpr153. A phylogenetic analysis revealed that both Gpr153 and Gpr162 originated from a common ancestor before the radiation of the mammalian lineage. Expression study revealed that Gpr162 had a predominant expression in the CNS and relatively lower expression in the other tissue tested whereas Gpr153 had a more widespread and similar expression pattern in both CNS and peripheral tissues. The functional studies of the two GPCRs were done using the antisense oligodeoxynucleotide knockdown rat model. These studies provided evidence linking the orphan Gpr162 gene with the regulation of food intake– related behaviour whereas Gpr153 gene caused only a slight reduction in food intake.

The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists.This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method.Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (θ(0)) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0-17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0-17.0 mg/kg) and L-703,606 (1.0-17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1-1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 min before morphine (1.0-10.0 mg/kg) or saline.Morphine dose-dependently decreased θ(0) (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ(0); 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ(0) or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine, and 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect θ(0) or MAX.The decrease in θ(0) by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids.

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.