Adaptation and validation of a TB stigma scale for adolescents in Lima, Peru.

BACKGROUND: TB-related stigma contributes to poor clinical outcomes and reduced wellbeing for affected individuals. Adolescents may be particularly susceptible to TB-related stigma due to their heightened sensitivity to peer acceptance, yet few studies have evaluated TB-related stigma in this group. Without a validated scale, it remains challenging to measure TB-related stigma in adolescents.METHODS: We adapted and validated the Van Rie TB Stigma Scale (VTSS) for adolescents on treatment for rifampicin-susceptible TB in Lima, Peru. The modified stigma scale was administered within a larger survey, which measured other psychosocial factors, including depression, adverse childhood experiences (ACEs), and social support. Data analysis included factor analysis, internal consistency, and convergent validity.RESULTS: From October 2020 to September 2021, 249 adolescents (individuals aged 10-19 years) completed the survey. Preliminary confirmatory factor analysis led to removal of two items. The final 10-item scale demonstrated good internal consistency (Cronbach's α = 0.82) and adequate model fit (χ²/df = 2.0; root mean square error of approximation: 0.06; comparative fit index: 0.94; Tucker-Lewis Index: 0.92: standardized root mean square residual: 0.05). Stigma was positively correlated with ACEs (γ = 0.13), depression (γ = 0.39), and suicidal ideation (γ = 0.27), and negatively correlated with social support (γ = -0.19).CONCLUSION: This adolescent TB stigma scale may serve as a practical tool to measure TB-related stigma and evaluate the impact of stigma-reduction interventions in adolescents.

Outcomes of WHO-conforming, longer, all-oral multidrug-resistant TB regimens and analysis implications.

BACKGROUND: Evidence of the effectiveness of the WHO-recommended design of longer individualized regimens for multidrug- or rifampicin-resistant TB (MDR/RR-TB) is limited.OBJECTIVES: To report end-of-treatment outcomes for MDR/RR-TB patients from a 2015-2018 multi-country cohort that received a regimen consistent with current 2022 WHO updated recommendations and describe the complexities of comparing regimens.METHODS: We analyzed a subset of participants from the endTB Observational Study who initiated a longer MDR/RR-TB regimen that was consistent with subsequent 2022 WHO guidance on regimen design for longer treatments. We excluded individuals who received an injectable agent or who received fewer than four likely effective drugs.RESULTS: Of the 759 participants analyzed, 607 (80.0%, 95% CI 77.0-82.7) experienced successful end-of-treatment outcomes. The frequency of success was high across groups, whether stratified on number of Group A drugs or fluoroquinolone resistance, and ranged from 72.1% to 90.0%. Regimens were highly variable regarding composition and the duration of individual drugs.CONCLUSIONS: Longer, all-oral, individualized regimens that were consistent with 2022 WHO guidance on regimen design had high frequencies of treatment success. Heterogeneous regimen compositions and drug durations precluded meaningful comparisons. Future research should examine which combinations of drugs maximize safety/tolerability and effectiveness.

Concordance of three approaches for operationalizing outcome definitions for multidrug-resistant TB.

BACKGROUND: The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).METHODS: Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.RESULTS: Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.CONCLUSION: High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.

Facilitators and barriers to TB care during the COVID-19 pandemic.

BACKGROUND: Knowledge about factors influencing access and adherence to TB care, and on the impact of the COVID-19 pandemic on TB care in resource-restricted settings is scarce. We conducted this study in Atsimo-Andrefana, a rural region in southern Madagascar where TB prevalence, poverty and food insecurity rates are high. We aimed to determine facilitators and barriers to access to and provision of TB care in rural Madagascar during the COVID-19 pandemic. METHODS: We conducted qualitative focus group discussions (FGDs) and in-depth interviews (IDIs) with patients with TB, community health workers, facility-based health workers, public health officials and non-governmental organisation staff. We analysed interviews using thematic analysis. RESULTS: We conducted 11 FGDs and 23 IDIs. We identified three main barriers to access and adherence to TB care: 1) stigma, 2) indirect treatment costs, and 3) food insecurity. The facilitator perceived as most influential was high health worker motivation. The effects of the COVID-19 pandemic on TB care varied between stake-holders; some health workers described delays in TB diagnosis and increased workload. CONCLUSIONS: To improve access and adherence to TB care, both indirect treatment costs and stigma need to be reduced; undernourished patients with TB should receive food support.

CONTEXTE: Les connaissances sur les facteurs influençant l'accès et l'adhésion aux soins antituberculeux, ainsi que sur l'impact de la pandémie de COVID-19 sur les soins antituberculeux dans les milieux à ressources limitées sont rares. Nous avons mené cette étude à Atsimo-Andrefana, une région rurale du sud de Madagascar où la prévalence de la TB et les taux de pauvreté et d'insécurité alimentaire sont élevés. Nous avons cherché à déterminer les facilitateurs et les obstacles à l'accès et à la fourniture de soins antituberculeux dans les zones rurales de Madagascar pendant la pandémie de COVID-19. MÉTHODES: Nous avons mené des discussions qualitatives en groupe (FGD) et des entretiens approfondis (IDI) avec des patients atteints de tuberculose, des agents de santé communautaires, des agents de santé en établissement, des responsables de la santé publique et des membres d'organisations non gouvernementales. Nous avons analysé les entretiens en utilisant l'analyse thématique. RÉSULTATS: Nous avons mené 11 FGD et 23 IDI. Nous avons identifié trois principaux obstacles à l'accès et à l'observance des soins antituberculeux : 1) la stigmatisation, 2) les coûts indirects du traitement et 3) l'insécurité alimentaire. Le facilitateur perçu comme le plus influent était la forte motivation des agents de santé. Les effets de la pandémie de COVID-19 sur les soins antituberculeux varient selon les parties prenantes ; certains agents de santé ont décrit des retards dans le diagnostic de la TB et une augmentation de la charge de travail. CONCLUSIONS: Pour améliorer l'accès et l'adhésion aux soins antituberculeux, il faut réduire à la fois les coûts indirects du traitement et la stigmatisation ; les patients tuberculeux sousalimentés devraient recevoir une aide alimentaire.

Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Uncovering reasons for treatment initiation delays among children with TB in Lima, Peru.

BACKGROUND: Timely diagnosis and treatment of pediatric tuberculosis (TB) is critical to reducing mortality but remains challenging in the absence of adequate diagnostic tools. Even once a TB diagnosis is made, delays in treatment initiation are common, but for reasons that are not well understood.METHODS: To examine reasons for delay post-diagnosis, we conducted semi-structured interviews with Ministry of Health (MoH) physicians and field workers affiliated with a pediatric TB diagnostic study, and caregivers of children aged 0-14 years who were diagnosed with pulmonary TB in Lima, Peru. Interviews were analyzed using systematic comparative and descriptive content analysis.RESULTS: We interviewed five physicians, five field workers and 26 caregivers with children who initiated TB treatment < 7 days after diagnosis (n = 15) or who experienced a delay of ≥7 days (n = 11). Median time in delay from diagnosis to treatment initiation was 26 days (range 7-117). Reasons for delay included: health systems challenges (administrative hurdles, medication stock, clinic hours), burden of care on families and caregiver perceptions of disease severity.CONCLUSION: Reasons for delay in treatment initiation are complex. Interventions to streamline administrative processes and tools to identify and support families at risk for delays in treatment initiation are urgently needed.

Time for a change: considering regimen changes in analyses of observational drug-resistant TB treatment cohort data.

Randomized clinical trials represent the gold standard in therapeutic research. Nevertheless, observational cohorts of patients treated for multidrug-resistant TB (MDR-TB) or rifampin-resistant TB (RR-TB) also play an important role in generating evidence to guide drug-resistant TB care. Generally, summary exposure classifications (e.g., 'ever vs. never´, 'exposed at baseline´) have been used to characterize drug exposure in the absence of detailed longitudinal data on MDR-TB regimen changes. These summary classifications, along with an absence of data on covariates that change throughout the course of treatment, constrain researchers´ ability to answer the most relevant questions while accounting for known biases. In this paper, we highlight the importance of regimen changes in improving inference from observational studies of longer MDR-TB treatment regimens, and offer an overview of the data and analytic strategies required to do so.

Introducing new and repurposed TB drugs: the endTB experience.

In 2015, the initiative Expand New Drug Markets for TB (endTB) began, with the objective of reducing barriers to access to the new and repurposed TB drugs. Here we describe the major implementation challenges encountered in 17 endTB countries. We provide insights on how national TB programmes and other stakeholders can scale-up the programmatic use of new and repurposed TB drugs, while building scientific evidence about their safety and efficacy. For any new drug or diagnostic, multiple market barriers can slow the pace of scale-up. During 2015-2019, endTB was successful in increasing the number of patients receiving new and repurposed TB drugs in 17 countries. The endTB experience has many lessons, which are relevant to country level introduction of new TB drugs, as well as non-TB drugs and diagnostics. For example: the importation of TB drugs is possible even in the absence of registration; emphasis on good clinical monitoring is more important than pharmacovigilance reporting; national guidelines and expert committees can both facilitate and hinder innovative practice; clinicians use new and repurposed TB drugs when they are available; data collection to generate scientific evidence requires financial and human resources; pilot projects can drive national scale-up.

Surfactant-Mediated Epitaxial Growth of Single-Layer Graphene in an Unconventional Orientation on SiC.

We report the use of a surfactant molecule during the epitaxy of graphene on SiC(0001) that leads to the growth in an unconventional orientation, namely R0° rotation with respect to the SiC lattice. It yields a very high-quality single-layer graphene with a uniform orientation with respect to the substrate, on the wafer scale. We find an increased quality and homogeneity compared to the approach based on the use of a preoriented template to induce the unconventional orientation. Using spot profile analysis low-energy electron diffraction, angle-resolved photoelectron spectroscopy, and the normal incidence x-ray standing wave technique, we assess the crystalline quality and coverage of the graphene layer. Combined with the presence of a covalently bound graphene layer in the conventional orientation underneath, our surfactant-mediated growth offers an ideal platform to prepare epitaxial twisted bilayer graphene via intercalation.

Dielectric Elastomer Actuator Driven Soft Robotic Structures With Bioinspired Skeletal and Muscular Reinforcement.

Natural motion types found in skeletal and muscular systems of vertebrate animals inspire researchers to transfer this ability into engineered motion, which is highly desired in robotic systems. Dielectric elastomer actuators (DEAs) have shown promising capabilities as artificial muscles for driving such structures, as they are soft, lightweight, and can generate large strokes. For maximum performance, dielectric elastomer membranes need to be sufficiently pre-stretched. This fact is challenging, because it is difficult to integrate pre-stretched membranes into entirely soft systems, since the stored strain energy can significantly deform soft elements. Here, we present a soft robotic structure, possessing a bioinspired skeleton integrated into a soft body element, driven by an antagonistic pair of DEA artificial muscles, that enable the robot bending. In its equilibrium state, the setup maintains optimum isotropic pre-stretch. The robot itself has a length of 60 mm and is based on a flexible silicone body, possessing embedded transverse 3D printed struts. These rigid bone-like elements lead to an anisotropic bending stiffness, which only allows bending in one plane while maintaining the DEA's necessary pre-stretch in the other planes. The bones, therefore, define the degrees of freedom and stabilize the system. The DEAs are manufactured by aerosol deposition of a carbon-silicone-composite ink onto a stretchable membrane that is heat cured. Afterwards, the actuators are bonded to the top and bottom of the silicone body. The robotic structure shows large and defined bimorph bending curvature and operates in static as well as dynamic motion. Our experiments describe the influence of membrane pre-stretch and varied stiffness of the silicone body on the static and dynamic bending displacement, resonance frequencies and blocking forces. We also present an analytical model based on the Classical Laminate Theory for the identification of the main influencing parameters. Due to the simple design and processing, our new concept of a bioinspired DEA based robotic structure, with skeletal and muscular reinforcement, offers a wide range of robotic application.

Performance of a household tuberculosis exposure survey among children in a Latin American setting.

OBJECTIVE: To evaluate the performance of a survey that quantifies the intensity of household tuberculosis (TB) exposure among children.METHODS: Children aged 0-14 years in Lima, Peru, with ≥1 signs and/or symptoms of TB and a history of contact with an adult TB patient were included. The 10-question survey was administered to caregivers and addressed sleep proximity, frequency of exposure, and infectiousness of the contact. Infection status was determined using tuberculin skin tests (TSTs). The exposure scale was evaluated for association with TST positivity using mixed-effects regression analyses.RESULTS: The exposure score was significantly associated with TST positivity (age-adjusted odds ratio [aOR] 1.14, 95%CI 1.02-1.28). We observed a stronger association with TST positivity in children aged ≤5 years; (aOR 1.23, 95%CI 1.07-1.41) and no association in children 6-14 years of age (aOR 0.99, 95%CI 0.82-1.20).CONCLUSION: This survey was easy to use and modestly successful in predicting TST positivity in children aged ≤5 years. It may be a useful resource for clinicians for diagnosing TB in children, and for national TB programs aiming to scale up preventive therapy initiatives.

Living apart together-bacterial volatiles influence methanotrophic growth and activity.

Volatile organic compounds play an important role in microbial interactions. However, little is known about how volatile-mediated interactions modulate biogeochemical processes. In this study, we show the effect of volatile-mediated interaction on growth and functioning of aerobic methane-oxidizing bacteria, grown in co-culture with five different heterotrophs. Both growth and methane oxidation of Methylobacter luteus were stimulated by interaction with specific heterotrophs. In Methylocystis parvus, we observed significant growth promotion, while methane oxidation was inhibited. Volatolomics of the interaction of each of the methanotrophs with Pseudomonas mandelii, revealed presence of a complex blend of volatiles, including dimethylsulfide, dimethyldisulfide, and bicyclic sesquiterpenes. Although the ecological role of the detected compounds remains to be elucidated, our results provide unprecedented insights into interspecific relations and associated volatiles for stimulating methanotroph functioning, which is of substantial environmental and biotechnological significance.

[Body weight and mental disorders : Results from a clinical psychiatric cross-sectional study of people with intellectual disabilities]. / Körpergewicht und psychische Erkrankungen : Ergebnisse einer klinisch-psychiatrischen Querschnittsanalyse bei Menschen mit Intelligenzminderung.

BACKGROUND: People with intellectual disabilities (ID) have a shorter life expectancy and higher mortality rate and more often suffer from various physical and mental disorders (WHO: 3-4 times more often than the general population). Obesity is an important risk factor for various disorders. This cross-sectional study examined the body weight and its risk factors in a clinical population of adults with ID. METHODS: The prevalence of underweight, normal weight, and overweight was determined using the body mass index (BMI) for 633 patients of an outpatient clinic for people with ID and mental disorders. A multiple logistic regression analysis was used to assess factors for alterations in body weight. RESULTS: Approximately one out of two men and two out of three women with ID and mental disorders were overweight. Adults with mild and moderate ID, female gender, increasing age, Down's syndrome, behavioral disorders, and a less supported living situation were associated with a higher rate of obesity. People with dementia and autism spectrum disorders showed a lower rate of obesity. CONCLUSION: Young women with ID and mental disorders were particularly at risk for obesity. The respective factors may support the development of specific prevention programs to reduce the risk of overweight and thereby lead to better mental and physical health in people with ID.

Gadolinium deposition in the paediatric brain: T1-weighted hyperintensity within the dentate nucleus following repeated gadolinium-based contrast agent administration.

AIM: To determine whether repeated gadolinium-based contrast agent administration (GBCA) in children is associated with the development of increased T1-weighted signal intensity within the cerebellar dentate nucleus. MATERIALS AND METHODS: With institutional review board approval for this The Health Insurance Portability and Accountability Act-compliant retrospective study, a cohort of 41 patients under the age of 18 years who underwent at least four contrast-enhanced magnetic resonance imaging (MR) examinations of the brain from 2005 to 2015 were identified. For each examination, both dentate nuclei were manually contoured, and the mean dentate nucleus-to-pons signal intensity (DN-P SI) ratio was calculated. The DN-P SI ratios from the last to first MRI examination were compared, and the correlation between DN-P SI ratio and cumulative gadolinium dose was calculated using a linear mixed effect model to control for potentially confounding variables. RESULTS: For the 41 patients in the cohort, there was a significant increase in the mean DN-P SI ratio from the first MRI to the last MRI examination (1.05 versus 1.11, p=0.004). After controlling for patient diagnosis, history of chemotherapy or radiation, sex, and age, there was a significant positive association between DN-P SI ratio and cumulative gadolinium dose (coefficient=0.401, p=0.032). CONCLUSION: Repeated GBCA administration in children is associated with increased T1-weighted signal intensity within the dentate nucleus.

Increasing isoniazid preventive therapy uptake in an HIV program in rural Papua New Guinea.

Setting: Tuberculosis (TB) is the leading cause of death among people living with the human immunodeficiency virus (PLHIV) in Papua New Guinea. Despite a policy for isoniazid preventive therapy (IPT) among PLHIV, implementation has been slow. Objective: We prospectively evaluated a standardized guided screening process, including TB diagnostic support, to increase IPT initiation in adult PLHIV on antiretro-viral treatment. Design: The guided process included a paper-based IPT screening tool that prompted review of patient history and TB symptoms and sputum analysis by smear microscopy and Xpert® MTB/RIF. Chest X-ray was performed at the provider's discretion. We quantified the yield of this guided process on IPT initiation and detection of TB and rifampicin resistance, and examined the contributions of each diagnostic modality. Results: Among 532 patients, TB was ruled out and IPT initiated in 450 (84%). TB was diagnosed and treatment was started in 82 (15%) patients. Xpert detected rifampicin resistance in one of 21 patients (5%, 95%CI 0.24-21.3) with a positive Xpert result. All TB cases were diagnosed by chest X-ray and/or Xpert. No cases were diagnosed by sputum smear alone. Conclusion: A standardized guided process, including TB diagnostic support, successfully enabled IPT initiation and identified a large burden of undetected TB.

Contexte : La tuberculose (TB) est la première cause de décès parmi les personnes vivant avec le VIH (PVVIH) en Papouasie Nouvelle Guinée. En dépit d'une politique en faveur du traitement préventif par isoniazide (TPI) parmi les PVVIH, la mise en oeuvre a été lente.Objectif : Nous avons prospectivement évalué un processus de dépistage standardisé guidé, incluant le soutien au diagnostic de la TB, pour augmenter la mise en route du TPI chez les adultes PVVIH sous traitement antirétroviral.Schéma : Le processus guidé a inclus un outil de dépistage sur support papier du TPI qui a suscité la revue des antécédents des patients, les symptômes de TB et l'analyse des crachats par microscopie de frottis et Xpert® MTB/RIF. Une radiographie pulmonaire a été réalisée à la discrétion du prestataire de soins. Nous avons quantifié le rendement de ce processus guidé relatif à la mise en route du TPI et à la détection de la TB et de la résistance à la rifampicine et examiné les contributions de chaque modalité de diagnostic.Résultats : Parmi 532 patients, la TB a été éliminée et le TPI a été initié chez 450 (84%) patients. Une TB a été diagnostiquée et le traitement a été mis en œuvre chez 82 (15%) patients. L'Xpert a détecté la résistance à la rifampicine chez un des 21 patients (5% ; IC95% 0,24­21,3) avec un résultat d'Xpert positif. Tous les cas de TB ont été diagnostiqués par radiographie pulmonaire et/ou Xpert. Aucun cas n'a été diagnostiqué par frottis de crachats seul.Conclusion : Un processus guidé standardisé, incluant la soutien au diagnostic de la TB, a permis la mise en route du TPI et identifié une large charge de TB non détectée.

Marco de referencia: La tuberculosis (TB) es la principal causa de muerte en las personas infectadas por el virus de la inmunodeficiencia humana (VIH) en Papua Nueva Guinea. Pese a las políticas vigentes en materia de tratamiento preventivo con isoniazida (TPI) en las personas afectadas por el VIH, su aplicación ha sido lenta.Objetivo: Se evaluó de manera prospectiva un procedimiento normalizado dirigido de detección sistemática, que comprendía el apoyo al diagnóstico de la TB, con el objeto de aumentar la tasa de iniciación del TPI en los adultos aquejados de infección por el VIH que recibían tratamiento antirretrovírico.Método: El procedimiento dirigido comportaba un instrumento impreso de detección para el TPI, que incitaba la evaluación de los antecedentes del paciente, los síntomas de TB y un análisis del esputo mediante la baciloscopia y la prueba Xpert® MTB/RIF. La radiografía de tórax se practicó según el criterio del profesional de salud. Se cuantificó el efecto de este método dirigido sobre la iniciación del TPI, la detección de la TB y la resistencia a rifampicina y se examinaron además las contribuciones de cada modalidad diagnóstica.Resultados: De los 532 pacientes, en 450 se descartó el diagnóstico de TB y se inició el TPI (84%). Se diagnosticó la TB y se inició el tratamiento a 82 personas (15%). Mediante la prueba Xpert se detectó la resistencia a rifampicina en uno de los 21 pacientes con resultado positivo a esta prueba (5%; intervalo de confianza del 95% de 0,24 a 21,3). Todos los casos de TB se diagnosticaron mediante la radiografía de tórax, la prueba Xpert o ambas. La baciloscopia por sí sola no permitió el diagnostico de ningún caso.Conclusión: Un procedimiento normalizado dirigido, que comportaba apoyo al diagnóstico de la TB, hizo posible la iniciación del TPI y favoreció el reconocimiento de una gran carga de morbilidad por TB no detectada.