Sexually dimorphic white matter geometry abnormalities in adolescent onset schizophrenia.

The normal human brain is characterized by a pattern of gross anatomical asymmetry. This pattern, known as the "torque", is associated with a sexual dimorphism: The male brain tends to be more asymmetric than that of the female. This fact, along with well-known sex differences in brain development (faster in females) and onset of psychosis (earlier with worse outcome in males), has led to the theory that schizophrenia is a disorder in which sex-dependent abnormalities in the development of brain torque, the correlate of the capacity for language, cause alterations in interhemispheric connectivity, which are causally related to psychosis (Crow TJ, Paez P, Chance SE. 2007. Callosal misconnectivity and the sex difference in psychosis. Int Rev Psychiatry. 19(4):449-457.). To provide evidence toward this theory, we analyze the geometry of interhemispheric white matter connections in adolescent-onset schizophrenia, with a particular focus on sex, using a recently introduced framework for white matter geometry computation in diffusion tensor imaging data (Savadjiev P, Kindlmann GL, Bouix S, Shenton ME, Westin CF. 2010. Local white geometry from diffusion tensor gradients. Neuroimage. 49(4):3175-3186.). Our results reveal a pattern of sex-dependent white matter geometry abnormalities that conform to the predictions of Crow's torque theory and correlate with the severity of patients' symptoms. To the best of our knowledge, this is the first study to associate geometrical differences in white matter connectivity with torque in schizophrenia.

An adapted scale to measure perceived TB and HIV stigma during household contact investigation.

Measuring stigma for TB and HIV in households undergoing contact investigation for TB is critical for understanding its impacts on health behaviours and identifying opportunities for intervention. However, standardised measurements for TB-HIV stigma in household contact investigations are limited.We adapted and validated a household stigma scale in Uganda. This involved field testing measures from another setting with 163 household contacts of newly diagnosed TB patients, conducting cognitive interviews with seven household contacts, adapting scale items using cognitive interview data, and retesting the adapted scales in a random sample of 60 contacts. We assessed inter-item covariance and performed factor analysis to select the final scale items.In whole-scale factor analysis, no cross-loading of items with scores ≥0.32 was found after the elimination of items based on covariance and symmetry. All TB items were loaded onto a single factor with scores ≥0.5, and all but one HIV item was loaded onto a second factor with scores ≥0.5. The final subscale internal consistency (Cronbach's alpha) was 0.92 for TB and 0.89 for HIV.The adapted TB-HIV stigma scale demonstrated acceptable psychometric properties and is substantially shorter and easier to administer than previous scales, making it suitable for programmatic research and evaluation..

Perceived stigma related to TB preventive therapy.

BACKGROUND: TB preventative therapy (TPT) is crucial for reducing the burden of TB in endemic settings. We assessed stigma associated with TPT and the social groups from whom stigma was anticipated.METHODS: We conducted an anonymous cross-sectional survey of community-dwelling adults in rural South Africa. Descriptive statistics, exploratory factor analysis, χ² tests, Kruskal-Wallis tests, and Poisson regression were used to identify factors associated with TPT stigma.RESULTS: The mean age of the 104 participants was 35 years, 65% were female, and 26% had completed secondary school. The vast majority perceived stigma associated with TPT (71%; mean score 1.7, SD ± 1.4). Factor analysis identified a two-factor solution that explained 61.9% of the variance. Being single (P < 0.001), previously screened for TB (P = 0.04), worried about being infected by TB (P = 0.006), and interested in taking TPT (P = 0.01) were associated with higher perceived stigma scores. TPT stigma was perceived among 8%, 16%, and 66% of their family, friends, and other community members, respectively.CONCLUSION: The prevalence of TPT-related stigma in a rural South African community was high. Community members anticipated less stigma from family members compared to other social groups. Global expansion and implementation of TPT will require novel interventions, such as engaging patients´ families to support uptake and promote adherence.

Gaps in TB preventive therapy for persons initiating antiretroviral therapy in Uganda: an explanatory sequential cascade analysis.

BACKGROUND: The WHO recommends TB symptom screening and TB preventive therapy (TPT) for latent TB infection (LTBI) in persons living with HIV (PLWH). However, TPT uptake remains limited. We aimed to characterize and contextualize gaps in the TPT care cascade among persons enrolling for antiretroviral therapy (ART).SETTING: Four PEPFAR-supported facilities in Uganda.METHODS: We studied a proportionate stratified random sample of persons registering for ART when TPT was available. Patient-level data on eligibility, initiation, and completion were obtained from registers to determine proportion of eligible patients completing each cascade step. We interviewed providers and administrators and used content analysis to identify barriers to guideline-concordant TPT practices.RESULTS: Of 399 study persons, 309 (77%) were women. Median age was 29 (IQR 25-34), CD4 count 405 cells/µL (IQR 222-573), and body mass 23 kg/m² (IQR 21-25). Of 390 (98%) screened, 372 (93%) were TPT-eligible. Only 62 (17%) eligible PLWH initiated and 36 (58%) of 62 completed TPT. Providers reported hesitating to prescribe TPT because they lacked confidence excluding TB by symptom screening alone and feared promoting drug resistance. Although isoniazid was available, past experience of irregular supply discouraged TPT initiation. Providers pointed to insufficient TB-dedicated staff, speculated that patients discounted TB risk, and worried TPT pill burden and side effects depressed ART adherence.CONCLUSIONS: While screening was nearly universal, most eligible PLWH did not initiate TPT. Only about half of those who initiated completed treatment. Providers feared promoting drug resistance, harbored uncertainty about continued availability, and worried TPT could antagonize ART adherence. Our findings suggest urgent need for stakeholder engagement in TPT provision.

Defective development of thymocytes overexpressing the costimulatory molecule, heat-stable antigen.

Heat-stable antigen (HSA) is a small, glycosyl phosphatidylinositol-anchored protein that can act as a costimulatory molecule for antigen-dependent activation of helper T cells. In addition to being expressed on antigen-presenting B cells, HSA is also expressed during the initial stages of T cell development in the thymus. HSA levels are very high on immature CD4-, CD8- double negative thymocytes, but are reduced on CD4+, CD8+ double positive cells undergoing selection in the thymus, and are entirely eliminated when these cells differentiate into immunologically competent CD4+ or CD8+ single positive T cells. To examine the potential roles of this molecule in T cell development and selection, we generated transgenic mice in which HSA was highly expressed on all classes of thymocytes. The consequence of deregulated HSA expression was a pronounced reduction in the numbers of double positive and single positive thymocytes, whereas the numbers of their double negative precursors were largely unaffected. These results demonstrate that downregulation of HSA expression at the double positive stage is a critical event in thymocyte development. The depletion of thymocytes resulting from HSA overexpression begins at the same time as the onset of negative selection, suggesting that HSA may provide signals that contribute to determining the efficiency of this process.

Cross-linking the murine heat-stable antigen induces apoptosis in B cell precursors and suppresses the anti-CD40-induced proliferation of mature resting B lymphocytes.

The murine heat-stable antigen (HSA) is a glycosyl-phosphatidylinositol-linked cell surface protein which has been implicated in cellular adhesion processes, the co-stimulation of CD4+ T cells, and B cell memory. We have recently demonstrated a significant reduction in pro-B and pre-B lymphocytes in transgenic mice that overexpress HSA. We now report that cross-linking HSA with the M1/69 monoclonal antibody induces the apoptosis of cultured B cell precursors in a stomal cell and cytokine-independent manner and that sensitivity to HSA-mediated cell death increases with developmental maturity. The cross-linking of HSA does not induce apoptosis in mature splenic B cells, but instead inhibits their ability to proliferate in response to anti-CD40 + IL-4. Taken together, these data implicate HSA as a potent negative regulator of B cell development and activation.

Social determinants of tuberculosis evaluation among household contacts: a secondary analysis.

Setting: Seven public sector tuberculosis (TB) units and surrounding communities in Kampala, Uganda. Objective: To evaluate the influence of household-level socio-economic characteristics on completion of TB evaluation during household contact investigation. Design: A cross-sectional study nested within the control arm of a randomized, controlled trial evaluating home-based sputum collection and short messaging service communications. We used generalized estimating equations to estimate the association between completion of TB evaluation and socio-economic determinants. Results: Of 116 household contacts referred to clinics for TB evaluation, 32 (28%) completed evaluation. Completing evaluation was strongly clustered by household. Controlling for individual symptoms, contacts from households earning below-median income (adjusted risk ratio [aRR] 0.28, 95%CI 0.09-0.88, P = 0.029) and contacts from households in which the head of household had no more than primary-level education (aRR 0.40, 95%CI 0.18-0.89, P = 0.025) were significantly less likely to complete evaluation for TB. Conclusion: Socio-economic factors such as low income and education increase the risk that household contacts of TB patients will experience barriers to completing TB evaluation themselves. Further research is needed to identify specific mechanisms by which these underlying social determinants modify the capability and motivation of contacts to complete contact investigation.

Contexte : Sept unités de tuberculose (TB) du secteur public et les communautés qui les entourent à Kampala, Ouganda.Objectif : Evaluer l'influence des caractéristiques socioéconomiques des foyers sur l'achèvement de la recherche de TB lors de l'investigation des contacts domiciliaires.Schéma : Une étude transversale au sein du bras témoin d'un essai randomisé, contrôlé, évaluant le recueil de crachats à domicile et les communications par messagerie SMS. Nous avons utilisé des équations d'estimations généralisées afin d'estimer l'association entre l'achèvement de l'évaluation de la TB et les déterminants socioéconomiques.Résultats : Parmi les 116 contacts domiciliaires qui ont été référés à des centres de santé pour un bilan de TB, 32 (28%) ont achevé cette évaluation. L'achèvement de l'évaluation a été fortement regroupé par foyer. En contrôlant les symptômes individuels, les contacts des foyers ayant un revenu inférieur à la médiane (ratio de risque ajusté [RRa] 0,28 ; IC95% 0,09­0,88 ; P = 0,029) et les contacts des foyers dont le niveau d'instruction du chef ne dépassait pas l'école primaire (RRa 0,40 ; IC95% 0,18­0,89 ; P = 0,025) ont été significativement moins susceptibles de terminer le bilan de TB.Conclusion : Les facteurs socioéconomiques tels qu'un faible revenu et un faible niveau d'études augmentent le risque que les contacts domiciliaires de patients TB soient confrontés à des obstacles à l'achèvement de l'évaluation de la TB. Davantage de recherche est nécessaire pour identifier les mécanismes spécifiques par lesquels des déterminants sociaux sous-jacents modifient la capacité et la motivation des contacts à terminer leur bilan.

Marco de Referencia: Siete unidades de tuberculosis (TB) del sector público y las comunidades aledañas en Kampala, Uganda.Objetivo: Evaluar la influencia de las características socioeconómicas de los hogares en la compleción de la evaluación de la TB durante la investigación de contactos domiciliarios.Método: Fue este un estudio transversal anidado en la rama de referencia de un ensayo clínico aleatorizado, que evaluaba la recogida de esputo en los hogares y las comunicaciones por servicio de SMS. Se aplicaron ecuaciones de estimación generalizadas con el fin de apreciar la asociación entre la compleción de la investigación de la TB y los determinantes socioeconómicos.Resultados: Se remitieron a los consultorios 116 contactos domiciliarios para investigación de la TB y 32 completaron la evaluación (28%). La compleción de la investigación exhibió una importante distribución en conglomerados por hogares. Al ajustar con respecto a los síntomas individuales, se observó que era mucho menos probable que se completase la investigación de la TB en los contactos de hogares con un ingreso familiar por debajo de la mediana (razón de riesgos ajustada [aRR] 0,28; IC95% 0,09­0,88; P = 0,029) y en los contactos de hogares cuya cabeza de familia no tenía un grado de instrucción superior al nivel primario (aRR 0,40; IC95% 0,18­0,89; P = 0,025).Conclusión: Los factores socioeconómicos como un bajo ingreso y un grado inferior de instrucción aumentan el riesgo de que los contactos domiciliarios encuentren obstáculos propios para completar la investigación de TB. Se precisan nuevas investigaciones que definan los mecanismos mediante los cuales estos determinantes sociales subyacentes modifican la capacidad y la motivación de las personas a finalizar la investigación de contactos.

Integrating home HIV counselling and testing into household TB contact investigation: a mixed-methods study.

Setting: Community health workers (CHWs) increasingly deliver community-based human immunodeficiency virus (HIV) counselling and testing (HCT) services. Less is known about how this strategy performs when integrated with household tuberculosis (TB) contact investigations. Objective: We conducted a prospective mixed-methods study to evaluate the feasibility and quality of CHW-facilitated, home-based HCT among household TB contacts. Design: CHWs visited households of consenting TB patients to screen household contacts for TB and HIV. They performed HIV testing using a serial enzyme-linked immunosorbent assay rapid-antibody testing algorithm. Laboratory technicians at health facilities re-tested the samples and coordinated quarterly HIV panel testing for CHWs. We conducted focus group discussions (FGDs) with CHWs on their experiences in carrying out home-based HCT. Results: Of 114 household contacts who consented to and underwent HIV testing by CHWs, 5 (4%) tested positive, 108 (95%) tested negative, and 1 (1%) had indeterminate results; 110 (96%) samples had adequate volume for re-testing. Overall agreement between CHWs and laboratory technicians was 99.1% (κ = 0.90, 95%CI 0.71-1.00, P < 0.0001). In FGDs, CHWs described context-specific social challenges to performing HCT in a household setting, but said that their confidence grew with experience. Conclusion: Home-based HCT by CHWs was feasible among household TB contacts and produced high-quality results. Strategies to address social challenges are required to optimize yield.

Contexte : Les travailleurs de santé communautaire (CHW) offrent de plus en plus de services de conseil et de test communautaires relatifs au virus de l'immunodéficience humaine (HCT). On sait moins quel est le degré de performance de cette stratégie quand elle est intégrée à des visites à domicile à la recherche de contacts de tuberculose (TB).Objectif : Nous avons réalisé une étude prospective à méthodes variées afin d'évaluer la faisabilité et la qualité de CHW à domicile, facilité par des CHW dans les foyers des contacts de TB.Schéma : Les CHW ont visité les foyers des patients TB consentants afin de dépister les contacts domiciliaires de TB et du virus de l'immunodéficience humaine (VIH). Ils ont réalisé des tests VIH grâce à un algorithme de test rapide de recherche d'anticorps en série par titrage avec immunoadsorbant lié à une enzyme. Les techniciens de laboratoire des structures de santé ont re-testé les échantillons et coordonné un test VIH en groupe trimestriel pour les CHW. Nous avons réalisé des discussions en groupe focal (FGD) avec les CHW à propos de leurs expériences de HCT à domicile.Résultats : Ont été consentants 114 contacts domiciliaires qui ont été testés à la recherche du VIH par les CHW : 5 (4%) ont eu un test positif, 108 (95%) ont eu un test négatif et 1 seul (1%) a eu des résultats indéterminés ; 110 (96%) échantillons avaient un volume suffisant pour un deuxième test. Au total, l'accord entre les CHW et les techniciens de laboratoire a été de 99,1% (κ = 0,90 ; IC95% 0,71­1,00 ; P < 0,0001). Lors des FGD, les CHW ont décrit les défis sociaux spécifiques du contexte de la réalisation du HCT dans le cadre d'un foyer, mais ont affirmé que leur confiance en eux avait augmenté avec leur expérience.Conclusion : Le HCT à domicile par les CHW s'est avéré faisable parmi les contacts domiciliaires de TB et a produit des résultats de très bonne qualité. Des stratégies visant à résoudre les défis sociaux sont requises afin d'optimiser le rendement.

Marco de referencia: Los agentes de salud comunitarios (CHW) prestan cada vez con mayor frecuencia servicios de asesoramiento y pruebas de detección del virus de la inmunodeficiencia humana (HCT) en las comunidades. Se conoce poco sobre la eficacia de esta estrategia cuando se integra en la investigación de contactos domiciliarios de los pacientes con tuberculosis (TB).Objetivo: Se llevó a cabo un estudio prospectivo con métodos mixtos, con el objeto de evaluar la factibilidad y la calidad de los servicios de HCT prestados por los CHW a los contactos de los casos de TB en los hogares.Método: Los CHW visitaron los hogares de los pacientes con TB que dieron su consentimiento, con el fin de realizar el HCT en los contactos domiciliarios. Los CHW practicaron la investigación de la infección por el virus de la inmunodeficiencia humana (VIH) mediante un algoritmo de pruebas rápidas seriadas de anticuerpos de tipo inmunoabsorbente ligado a la enzima. Los auxiliares de laboratorio en los establecimientos de salud practicaban de nuevo las pruebas en las muestras y coordinaban la realización trimestral de series de pruebas por parte de los CHW. Se realizaron sesiones de grupos de opinión (FGD) con estos profesionales, a fin de compartir sus experiencias en HCT en los hogares.Resultados: Tras recibir su consentimiento, los CHW practicaron las pruebas del VIH a 114 contactos domiciliarios. Cinco contactos obtuvieron un resultado positivo (4%), en 108 el resultado fue negativo (95%) y en un caso el resultado fue indeterminado (1%). El volumen de 110 muestras (96%) fue suficiente para repetir las pruebas. La concordancia global entre los CHW y los auxiliares de laboratorio fue 99,1% (κ = 0,90; IC95% 0,71­1,00; P < 0,0001). En las FGD, los CHW describieron las dificultades sociales específicas del contexto que tuvieron que afrontar al prestar estos servicios en los hogares, pero afirmaron que con la práctica habían adquirido mayor confianza.Conclusión: La práctica domiciliaria del HCT a los contactos de los casos de TB por parte de los CHW fue factible y se obtuvieron resultados de gran calidad. Se precisan estrategias que respondan a las dificultades sociales encontradas con el propósito de optimizar el rendimiento.

'Something so hard': a mixed-methods study of home sputum collection for tuberculosis contact investigation in Uganda.

BACKGROUND: Home sputum collection could facilitate prompt evaluation and diagnosis of tuberculosis (TB) among contacts of patients with active TB. We analyzed barriers to home-based collection as part of an enhanced intervention for household TB contact investigation in Kampala, Uganda. DESIGN: We conducted a convergent mixed-methods study to describe the outcomes of home sputum collection in 91 contacts and examine their context through 19 nested contact interviews and two focus group discussions with lay health workers (LHWs). RESULTS: LHWs collected sputum from 35 (39%) contacts. Contacts reporting cough were more likely to provide sputum than those with other symptoms or risk factors (53% vs. 15%, RR 3.6, 95%CI 1.5-2.8, P < 0.001). Males were more likely than females to provide sputum (54% vs. 32%, RR 1.7, 95%CI 1.0-2.8, P = 0.05). Contacts said support from the index patient and the convenience of the home visit facilitated collection. Missing containers and difficulty producing sputum spontaneously impeded collection. Women identified stigma as a barrier. LHWs emphasized difficulty in procuring sputum and discomfort pressing contacts to produce sputum. CONCLUSIONS: Home sputum collection by LHWs entails different challenges from sputum collection in clinical settings. More research is needed to develop interventions to mitigate stigma and increase success of home-based collection.

Patterns of usage and preferences of users for tuberculosis-related text messages and voice calls in Uganda.

BACKGROUND: Little information exists about mobile phone usage or preferences for tuberculosis (TB) related health communications in Uganda. METHODS: We surveyed household contacts of TB patients in urban Kampala, Uganda, and clinic patients in rural central Uganda. Questions addressed mobile phone access, usage, and preferences for TB-related communications. We collected qualitative data about messaging preferences. RESULTS: We enrolled 145 contacts and 203 clinic attendees. Most contacts (58%) and clinic attendees (75%) owned a mobile phone, while 42% of contacts and 10% of clinic attendees shared one; 94% of contacts and clinic attendees knew how to receive a short messaging service (SMS) message, but only 59% of contacts aged 45 years (vs. 96% of contacts aged <45 years, P = 0.0001) did so. All contacts and 99% of clinic attendees were willing and capable of receiving personal-health communications by SMS. Among contacts, 55% preferred detailed messages disclosing test results, while 45% preferred simple messages requesting a clinic visit to disclose results. CONCLUSIONS: Most urban household TB contacts and rural clinic attendees reported having access to a mobile phone and willingness to receive TB-related personal-health communications by voice call or SMS. However, frequent phone sharing and variable messaging abilities and preferences suggest a need to tailor the design and monitoring of mHealth interventions to target recipients.