Geographic distribution and predictors of diagnostic delays among possible TB patients in Uganda.

BACKGROUND: Understanding the geographic distribution and factors associated with delayed TB diagnosis may help target interventions to reduce delays and improve patient outcomes. METHODS: We conducted a secondary analysis of adults undergoing TB evaluation within a public health demonstration project in Uganda. Using Global Moran's I (GMI) and Getis-Ord GI* statistics, we evaluated for residential clustering and hotspots associated with patient-related and health system-related delays. We performed multivariate logistic regression to identify individual predictors of both types of delays. RESULTS: Of 996 adults undergoing TB evaluation (median age: 37 years, IQR 28-49), 333 (33%) experienced patient delays, and 568 (57%) experienced health system delays. Participants were clustered (GMI 0.47-0.64, P ⩽ 0.001) at the sub-county level, but there were no statistically significant hotspots for patient or health system delays. Married individuals were less likely to experience patient delays (OR 0.6, 95% CI 0.48-0.75; P < 0.001). Those aged 38-57 years (OR 1.2, 95% CI 1.07-1.38; P = 0.002) were more likely than those aged ⩾58 years to experience patient delays. Knowledge about TB (OR 0.8, 95% CI 0.63-0.98; P = 0.03) protected against health system delays. CONCLUSIONS: We did not identify geographic hotspots for TB diagnostic delays. Instead, delays were associated with individual factors such as age, marital status and TB knowledge.

CONTEXTE: Comprendre la distribution géographique et les facteurs associés aux retards de diagnostic de la TB peut aider à cibler les interventions visant à réduire les retards et à améliorer les résultats pour les patients. MÉTHODES: Nous avons effectué une analyse secondaire des adultes soumis à une évaluation de la TB dans le cadre d'un projet de démonstration de santé publique en Ouganda. À l'aide des statistiques Global Moran's I (GMI) et Getis-Ord GI*, nous avons évalué les regroupements résidentiels et les points critiques associés aux retards liés aux patients et au système de santé. Nous avons effectué une régression logistique multivariée pour identifier les prédicteurs individuels des deux types de retards. RÉSULTATS: Sur les 996 adultes soumis à une évaluation de la TB (âge médian : 37 ans, IQR 28­49), 333 (33%) ont subi des retards liés aux patients et 568 (57%) ont subi des retards liés au système de santé. Les participants étaient regroupés (GMI 0,47­0,64 ; P ⩽ 0,001) au niveau du sous-comté, mais il n'y avait pas de points critiques statistiquement significatifs pour les retards des patients ou du système de santé. Les personnes mariées étaient moins susceptibles de subir des retards de la part des patients (OR 0,6 ; 95% CI 0,48­0,75 ; P < 0,001). Les personnes âgées de 38 à 57 ans (OR 1,2 ; 95% CI 1,07­1,38 ; P = 0,002) étaient plus susceptibles que celles âgées de ⩾58 ans de subir des retards. Les connaissances sur la TB (OR 0,8 ; 95% CI 0,63­0,98 ; P = 0,03) protégeaient contre les retards du système de santé. CONCLUSIONS: Nous n'avons pas identifié de points critiques géographiques pour les retards de diagnostic de la TB. Les retards étaient plutôt associés à des facteurs individuels tels que l'âge, la situation matrimoniale et les connaissances sur la TB.

Assessing a norming intervention to promote acceptance of HIV testing and reduce stigma during household tuberculosis contact investigation: protocol for a cluster-randomised trial.

INTRODUCTION: HIV status awareness is important for household contacts of patients with tuberculosis (TB). Home HIV testing during TB contact investigation increases HIV status awareness. Social interactions during home visits may influence perceived stigma and uptake of HIV testing. We designed an intervention to normalise and facilitate uptake of home HIV testing with five components: guided selection of first tester; prosocial invitation scripts; opt-out framing; optional sharing of decisions to test; and masking of decisions not to test. METHODS AND ANALYSIS: We will evaluate the intervention effect in a household-randomised controlled trial. The primary aim is to assess whether contacts offered HIV testing using the norming strategy will accept HIV testing more often than those offered testing using standard strategies. Approximately 198 households will be enrolled through three public health facilities in Kampala, Uganda. Households will be randomised to receive the norming or standard strategy and visited by a community health worker (CHW) assigned to that strategy. Eligible contacts ≥15 years will be offered optional, free, home HIV testing. The primary outcome, proportion of contacts accepting HIV testing, will be assessed by CHWs and analysed using an intention-to-treat approach. Secondary outcomes will be changes in perceived HIV stigma, changes in perceived TB stigma, effects of perceived HIV stigma on HIV test uptake, effects of perceived TB stigma on HIV test uptake and proportions of first-invited contacts who accept HIV testing. Results will inform new, scalable strategies for delivering HIV testing. ETHICS AND DISSEMINATION: This study was approved by the Yale Human Investigation Committee (2000024852), Makerere University School of Public Health Institutional Review Board (661) and Uganda National Council on Science and Technology (HS2567). All participants, including patients and their household contacts, will provide verbal informed consent. Results will be submitted to a peer-reviewed journal and disseminated to national stakeholders, including policy-makers and representatives of affected communities. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT05124665.

Perceptions, preferences, and experiences of tuberculosis education and counselling among patients and providers in Kampala, Uganda: A qualitative study.

Tuberculosis (TB) education seeks to increase patient knowledge about TB, while TB counselling seeks to offer tailored advice and support for medication adherence. While universally recommended, little is known about how to provide effective, efficient, patient-centred TB education and counselling (TEC) in low-income, high HIV-TB burden settings. We sought to characterise stakeholder perceptions of TEC in a public, primary care facility in Kampala, Uganda, by conducting focus group discussions with health workers and TB patients in the TB and HIV clinics. Participants valued TEC but reported that high-quality TEC is rarely provided, because of a lack of time, space, staff, planning, and prioritisation given to TEC. To improve TEC, they recommended adopting practices that have proven effective in the HIV clinic, including better specifying educational content, and employing peer educators focused on TEC. Patients and health workers suggested that TEC should not only improve TB patient knowledge and adherence, but should also empower and assist all those undergoing evaluation for TB, whether confirmed or not, to educate their households and communities about TB. Community-engaged research with patients and front-line providers identified opportunities to streamline and standardise the delivery of TEC using a patient-centred, peer-educator model.

Pharmacokinetics and safety of repeated oral dosing of acetaminophen in adult horses.

BACKGROUND: There are no published studies on the pharmacokinetics of acetaminophen at the dosage used clinically (20 mg/kg), nor has the safety of multiple doses in horses been investigated. OBJECTIVE: Define the pharmacokinetic parameters of oral acetaminophen at 20 mg/kg in adult horses as a single dose, and twice daily for 14 days to assess the safety of multiple dosing. STUDY DESIGN: Pharmacokinetic study, multiple dose safety study. METHODS: Eight healthy Thoroughbred geldings were given acetaminophen (20 mg/kg; 500 mg tablets) orally as a single dose followed by doses every 12 h for 14 days. Serial blood samples were collected for determination of plasma acetaminophen concentrations using high performance liquid chromatography with ultraviolet detection. Serum biochemical analysis, gastroscopy and liver biopsy were examined during the safety study. RESULTS: Following a single dose, mean maximum concentration (Cmax ) was 16.61 µg/mL at 1.35 h (Tmax ), and drug concentration was below the lower limit of detection in most horses by 24 h. Elimination half-life (T1/2 ) was 2.78 h. No significant accumulation was noted following multiple doses. Average Cmax of acetaminophen following multiple oral dosing was 15.85 µg/mL, with a Tmax of 0.99 h and T1/2 of 4 h. Serum activities of sorbitol dehydrogenase were significantly decreased and total bilirubin concentrations were significantly increased following the last dose. No statistically significant changes were noted in gastroscopy scores. MAIN LIMITATIONS: Only one dose level (20 mg/kg) was studied, sample size was small and only a single breed and sex was used, with no pretreatment liver biopsies. CONCLUSION: This study described the pharmacokinetics of acetaminophen following single and multiple 20 mg/kg oral doses in adult horses and demonstrated the safety of acetaminophen with multiple oral dosing over 14 days. The summary is available in Portuguese - see Supporting information.

Multicentre, blinded, randomised clinical trial comparing the use of flunixin meglumine with firocoxib in horses with small intestinal strangulating obstruction.

BACKGROUND: Small intestinal strangulating obstruction (SISO) is associated with endotoxaemia which leads to an increased risk of death. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat signs of endotoxaemia by inhibiting cyclo-oxygenases (COX). COX-1 is expressed constitutively and promotes gut barrier function, whereas COX-2 is inducible and contributes to the signs of endotoxaemia. In preclinical SISO trials, intestinal barrier recovery was more complete with reductions in endotoxin permeability in horses treated with COX-2 selective NSAIDs as compared with horses treated with flunixin meglumine. OBJECTIVES: We hypothesised that treatment of post-surgical SISO horses with firocoxib (COX-2 selective) would reduce the signs of endotoxaemia to a greater extent than flunixin meglumine (nonselective COX inhibitor) while continuing to provide similar levels of pain control. STUDY DESIGN: Blinded randomised clinical trial. METHODS: In addition to clinical monitoring, preoperative and 12-, 24- and 48-h post-operative plasma samples were assessed for prostaglandin E2 (PGE2 ), thromboxane B2 (TXB2 ), TNF⍺ and soluble CD14 (sCD14). RESULTS: In 56 recruited SISO horses, either flunixin meglumine (1.1 mg/kg, i.v., q12h) or firocoxib (0.3 mg/kg, i.v. loading dose; 0.1 mg/kg, i.v., q24h) was given in the post-operative period in three university hospitals from 2015 to 2017. COX-2 selectivity was confirmed by a relative lack of inhibition of the COX-1 prostanoid TXB2 by firocoxib and significant inhibition by flunixin meglumine (P = 0.014). Both drugs inhibited the COX-2 prostanoid PGE2 . There were no significant differences in pain scores between groups (P = 0.2). However, there was a 3.23-fold increased risk (P = 0.04) of increased plasma sCD14 in horses treated with flunixin meglumine, a validated biomarker of equine endotoxaemia. MAIN LIMITATIONS: Horses were all treated with flunixin meglumine prior to referral. In addition, many horses were treated with lidocaine, which has been shown to mitigate the deleterious effects of flunixin meglumine. CONCLUSIONS: In SISO cases, firocoxib reduced a biomarker of endotoxaemia as compared with flunixin meglumine while continuing to provide similar levels of pain control.

Pharmacokinetics and ex vivo anti-inflammatory effects of oral misoprostol in horses.

BACKGROUND: Misoprostol is an E prostanoid (EP) 2, 3 and 4 receptor agonist that is anecdotally used to treat and prevent NSAID-induced GI injury in horses. Misoprostol elicits anti-inflammatory effects in vivo in men and rodents, and inhibits TNFα production in equine leucocytes in vitro. OBJECTIVE: Define the pharmacokinetic parameters of oral misoprostol in horses, and determine the inhibitory effect of oral misoprostol administration on equine leucocyte TNFα production in an ex vivo inflammation model. STUDY DESIGN: Pharmacokinetic study, ex vivo experimental study. METHODS: Six healthy adult horses of mixed breeds were used. In phase one, horses were given 5 µg/kg misoprostol orally, and blood was collected at predetermined times for determination of misoprostol free acid (MFA) by UHPLC-MS/MS. Pharmacokinetic parameters were calculated. In phase two, horses were dosed as in phase one, and blood was collected at T0, 0.5, 1 and 4 h following misoprostol administration for leucocyte isolation. Leucocytes were stimulated with 100 ng/mL LPS, and TNFα mRNA concentrations were determined via quantitative real-time PCR. RESULTS: About 5 µg/kg oral misoprostol produced a rapid time to maximum concentration (Tmax ) of 23.4 ± 2.4 min, with a maximum concentration (Cmax ) of 0.29 ± 0.07 ng/mL and area under the curve (AUC0-∞ ) of 0.4 ± 0.12 h ng/mL. LPS stimulation of equine leucocytes ex vivo significantly increased TNFα mRNA concentrations, and there was no significant effect of misoprostol even at the Tmax . MAIN LIMITATIONS: Only a single dose was used, and sample size was small. CONCLUSIONS: Misoprostol is rapidly absorbed following oral administration in horses, and a single 5 µg/kg dose had no significant inhibitory effect on ex vivo LPS-stimulated TNFα mRNA production in leucocytes. Further studies analysing different dosing strategies, including repeat administration or combination with other anti-inflammatory drugs, are warranted.

Oral reserpine administration in horses results in low plasma concentrations that alter platelet biology.

BACKGROUND: Reserpine is a popular drug in the equine industry for long-term tranquilisation. Clinical observations revealed that blood from horses receiving oral reserpine was hypercoagulable. No studies have documented the pharmacokinetics of orally administered reserpine nor the effects of reserpine on platelets in horses. OBJECTIVES: To evaluate the pharmacokinetics of oral reserpine in horses and the effects of clinically relevant concentrations of reserpine on platelet functionality in vitro. STUDY DESIGN: Experimental controlled study. METHODS: The pharmacokinetics of oral reserpine (2.5 mg/horse, once) were determined in six healthy adult horses. Plasma samples were collected and concentrations of reserpine were determined by UPLC-MS/MS. Using this data, the in vitro effects of reserpine on platelets were examined. Aggregation, adhesion and releasate assays for serotonin and thromboxane B2 were performed on platelets exposed to varying concentrations of reserpine (0.01-10 ng/mL), aspirin (negative control) and saline (unexposed control). RESULTS: Oral reserpine administration demonstrated low plasma concentrations with a Cmax of 0.2 ± 0.06 ng/mL and a prolonged half-life of 23.6 ± 6.24 h. Simulations over a dose range of 2-8 µg/kg predicted Cmax at steady state between 0.06-0.9 ng/mL. Platelets exposed to these reserpine concentrations in vitro displayed increased aggregation and adhesion compared to unexposed or aspirin-exposed platelets as well as compared to higher concentrations of reserpine. These functional changes correlated with lower concentrations of serotonin and higher concentrations of thromboxane B2 in the platelet suspension supernatant. MAIN LIMITATIONS: This study used a small number of horses and only in vitro platelet experiments. CONCLUSIONS: Oral reserpine demonstrates low plasma concentrations and a prolonged half-life in horses. At these concentrations, reserpine causes significant changes in platelet function, most likely due to serotonin release and re-uptake which primes platelets for activation and thromboxane B2 release. These findings suggest that clinicians should harvest blood for biological processing prior to the onset of reserpine administration.

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.

'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.

Quality of care in childhood tuberculosis diagnosis at primary care clinics in Kampala, Uganda.

OBJECTIVE: To assess the quality of routine childhood tuberculosis (TB) evaluation in Kampala, Uganda. SETTING AND DESIGN: This was a cross-sectional study of children aged <15 years attending six government-run clinics from November 2015 to December 2016. Clinicians completed a standardized patient record form for all child visits. We assessed the following performance indicators of TB evaluation developed based on the Desk Guide of the International Union Against Tuberculosis and Lung Disease, an evidence-based decision aid on childhood TB diagnosis and management for clinicians: proportion screened for TB symptoms or contact history, proportion referred for laboratory evaluation if screen-positive, and proportion treated for TB if test-positive or meeting clinical criteria. RESULTS: Of 24 566 consecutive children enrolled, 11 614 (47%) were fully screened for TB symptoms. Of 1747 (15%) children who screened positive, 360 (21%) had sputum examined, including 159 (44%) using smear microscopy, 244 (67%) using Xpert® MTB/RIF, and 52 (14%) using both techniques. Treatment was initiated in 18/20 (80%) children who tested positive. An additional 65 screen-positive children met the clinical criteria for TB; none were initiated on treatment. CONCLUSIONS: Large gaps exist along the pathway to diagnosis and treatment of childhood TB. There is an urgent need for enhanced implementation of evidence-based approaches to TB diagnosis to improve outcomes in childhood TB.

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.

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.

Pharmacokinetics, pharmacodynamics and clinical use of trazodone and its active metabolite m-chlorophenylpiperazine in the horse.

Trazodone is a serotonin receptor antagonist and reuptake inhibitor used extensively as an anxiolytic in human and small animal veterinary medicine. The aims of this study were to determine the pharmacokinetics of oral trazodone in experimental horses and to evaluate the effect of oral trazodone in clinical horses. Six experimental horses were administered trazodone at 7.5 or 10 mg/kg. Plasma concentrations of trazodone and its metabolite (m-CPP) were determined via UPLC-MS/MS. Noncompartmental pharmacokinetic analysis, sedation and ataxia scores were determined. Trazodone was rapidly absorbed after oral administration with a maximum concentration of 2.5-4.1 µg/ml and half-life of the terminal phase of approximately 7 hr. The metabolite was present at low levels in all horses, representing only 2.5% of the total area under the curve. In experimental horses, concentration-dependent sedation and ataxia were noted, lasting up to 12 hr. For clinical cases, medical records of horses treated with trazodone for various abnormal behaviours were reviewed and data were summarized. Trazodone was successful in modifying behavioural problems to some degree in 17 of 18 clinical cases. Tolerance and subsequent lack of drug effect occurred in two of 18 clinical cases following 14 or 21 days of use. In both populations of horses, adverse effects attributed to trazodone include oversedation, muscle fasciculations and transient arrhythmias.

Pharmacokinetics of the anticonvulsant levetiracetam in neonatal foals.

BACKGROUND: Seizures are a common manifestation of neurological disease in the neonatal foal and are an important cause of morbidity and mortality in this population. Current antiepileptic options are effective, but often have undesirable adverse effects, short duration of action and high cost. Levetiracetam has an ideal safety and pharmacokinetic profile in multiple species, including the adult horse, and may be a safe and cost-effective alternative anticonvulsant in neonatal foals. Due to differences in drug disposition and clearance dosages in neonates, dosing recommendations in other species or adult horses cannot be extrapolated to foals. OBJECTIVE: To establish the pharmacokinetic profile of single-dose i.v. and intragastric administration of levetiracetam in healthy neonatal foals. STUDY DESIGN: Randomised crossover experimental study. METHODS: Levetiracetam was administered as a single dose to six healthy foals (ages 1-10 days) at a dose of 32 mg/kg bwt i.v. or intragastrically. Plasma levetiracetam concentrations were measured using a validated HPLC protocol. RESULTS: After i.v. administration to healthy foals, levetiracetam had a mean (±s.d.) elimination half-life of 7.76 ± 0.51 h, a mean systemic clearance of 61.67 ± 10.96 (mL/h/kg) and a mean apparent volume of distribution at steady state of 0.670 ± 0.124 (L/kg). Following intragastric administration, levetiracetam had a peak concentration of 38.34 ± 7.42 mg/L and time to achieve peak concentration was 0.875 (0.5-1.5) h. Mean bioavailability for IG administration was excellent (103.04 ± 14.51%). No significant differences in pharmacokinetic variables between routes and order of administration were observed. MAIN LIMITATIONS: Small sample size and single-dose administration. CONCLUSIONS: Levetiracetam has excellent intragastric bioavailability in foals and is predicted to maintain plasma concentrations at or above the proposed target concentration with twice daily i.v. or oral administration. Once-daily administration may be possible in some foals based on the therapeutic range recommended in other species.

Bioavailability and tolerability of nebulised dexamethasone sodium phosphate in adult horses.

BACKGROUND: Nebulisation of the injectable dexamethasone sodium phosphate (DSP) would offer an inexpensive way of delivering a potent corticosteroid directly to the lungs of horses with asthma. However, this approach would be advantageous only if systemic absorption is minimal and if the preservatives present in the formulation do not induce airway inflammation. OBJECTIVE: To investigate the bioavailability of nebulised DSP and determine whether it induces airway inflammation or hypothalamic-pituitary-adrenal (HPA) axis suppression in healthy adult horses. STUDY DESIGN: Randomised crossover experiment. METHODS: Dexamethasone sodium phosphate was administered to six healthy adult horses at a dose of 5 mg q. 24 h for 5 days via nebulised, or intravenous (i.v.) routes. Plasma dexamethasone concentrations were measured by UPLC/MS-MS to calculate bioavailability. Cytological examination of bronchoalveolar fluid was performed at baseline and after the last dose of DSP. A validated chemiluminescent immunoassay was used to measure basal serum cortisol concentrations. RESULTS: After nebulisation to adult horses, dexamethasone had a mean (±s.d.) maximum plasma concentration of 0.774 ± 0.215 ng/mL and systemic bioavailability of 4.3 ± 1.2%. Regardless of route of administration, there was a significant decrease in the percentage of neutrophils in bronchoalveolar lavage fluid over time. During i.v. administration, basal serum cortisol concentration decreased significantly from baseline to Day 3 and remained low on Day 5. In contrast, basal serum cortisol concentration did not change significantly during administration via nebulisation. MAIN LIMITATIONS: Small sample size and short period of drug administration. CONCLUSIONS: Dexamethasone sodium phosphate administered via nebulisation had minimal systemic bioavailability and did not induce lower airway inflammation or HPA axis suppression in healthy horses.

Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial.

More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers with baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1ß, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study.

Feasibility of a streamlined tuberculosis diagnosis and treatment initiation strategy.

OBJECTIVE: To assess the feasibility of a streamlined strategy for improving tuberculosis (TB) diagnostic evaluation and treatment initiation among patients with presumed TB. DESIGN: Single-arm interventional pilot study at five primary care health centers of a streamlined, SIngle-saMPLE (SIMPLE) TB diagnostic evaluation strategy: 1) examination of two smear results from a single spot sputum specimen using light-emitting diode fluorescence microscopy, and 2) daily transportation of smear-negative sputum samples to Xpert® MTB/RIF testing sites. RESULTS: Of 1212 adults who underwent sputum testing for TB, 99.6% had two smears examined from the spot sputum specimen. Sputum was transported for Xpert testing within 1 clinic day for 83% (907/1091) of the smear-negative patients. Of 157 (13%) patients with bacteriologically positive TB, 116 (74%) were identified using sputum smear microscopy and 41 (26%) using Xpert testing of smear-negative samples. Anti-tuberculosis treatment was initiated in 142 (90%) patients with bacteriologically positive TB, with a median time to treatment of 1 day for smear-positive patients and 6 days for smear-negative, Xpert-positive patients. CONCLUSION: The SIMPLE TB strategy led to successful incorporation of Xpert testing and rapid treatment initiation in the majority of patients with bacteriologically confirmed TB in a resource-limited setting.