Cost-effectiveness analysis of interventions to improve diagnosis and preventive therapy for paediatric tuberculosis in 9 sub-Saharan African countries: A modelling study.

BACKGROUND: Over 1 million children aged 0 to 14 years were estimated to develop tuberculosis in 2021, resulting in over 200,000 deaths. Practical interventions are urgently needed to improve diagnosis and antituberculosis treatment (ATT) initiation in children aged 0 to 14 years and to increase coverage of tuberculosis preventive therapy (TPT) in children at high risk of developing tuberculosis disease. The multicountry CaP-TB intervention scaled up facility-based intensified case finding and strengthened household contact management and TPT provision at HIV clinics. To add to the limited health-economic evidence on interventions to improve ATT and TPT in children, we evaluated the cost-effectiveness of the CaP-TB intervention. METHODS AND FINDINGS: We analysed clinic-level pre/post data to quantify the impact of the CaP-TB intervention on ATT and TPT initiation across 9 sub-Saharan African countries. Data on tuberculosis diagnosis and ATT/TPT initiation counts with corresponding follow-up time were available for 146 sites across the 9 countries prior to and post project implementation, stratified by 0 to 4 and 5 to 14 year age-groups. Preintervention data were retrospectively collected from facility registers for a 12-month period, and intervention data were prospectively collected from December 2018 to June 2021 using project-specific forms. Bayesian generalised linear mixed-effects models were used to estimate country-level rate ratios for tuberculosis diagnosis and ATT/TPT initiation. We analysed project expenditure and cascade data to determine unit costs of intervention components and used mathematical modelling to project health impact, health system costs, and cost-effectiveness. Overall, ATT and TPT initiation increased, with country-level incidence rate ratios varying between 0.8 (95% uncertainty interval [UI], 0.7 to 1.0) and 2.9 (95% UI, 2.3 to 3.6) for ATT and between 1.6 (95% UI, 1.5 to 1.8) and 9.8 (95% UI, 8.1 to 11.8) for TPT. We projected that for every 100 children starting either ATT or TPT at baseline, the intervention package translated to between 1 (95% UI, -1 to 3) and 38 (95% UI, 24 to 58) deaths averted, with a median incremental cost-effectiveness ratio (ICER) of US$634 per disability-adjusted life year (DALY) averted. ICERs ranged between US$135/DALY averted in Democratic of the Congo and US$6,804/DALY averted in Cameroon. The main limitation of our study is that the impact is based on pre/post comparisons, which could be confounded. CONCLUSIONS: In most countries, the CaP-TB intervention package improved tuberculosis treatment and prevention services for children aged under 15 years, but large variation in estimated impact and ICERs highlights the importance of local context. TRIAL REGISTRATION: This evaluation is part of the TIPPI study, registered with ClinicalTrials.gov (NCT03948698).

Improving TB detection among children in routine clinical care through intensified case finding in facility-based child health entry points and decentralized management: A before-and-after study in Nine Sub-Saharan African Countries.

In 2022, an estimated 1.25 million children <15 years of age developed tuberculosis (TB) worldwide, but >50% remained undiagnosed or unreported. WHO recently recommended integrated and decentralized models of care as an approach to improve access to TB services for children, but evidence remains limited. The Catalyzing Paediatric TB Innovation project (CaP-TB) implemented a multi-pronged intervention to improve TB case finding in children in nine sub-Saharan African countries. The intervention introduced systematic TB screening in different facility-based child-health entry-points, decentralisation of TB diagnosis and management, improved sample collection with access to Xpert® MTB/RIF or MTB/RIF Ultra testing, and implementation of contact investigation. Pre-intervention records were compared with those during intervention to assess effect on paediatric TB cascade of care. The intervention screened 1 991 401 children <15 years of age for TB across 144 health care facilities. The monthly paediatric TB case detection rate increased significantly during intervention versus pre-intervention (+46.0%, 95% CI 36.2-55.8%; p<0.0001), with variability across countries. The increase was greater in the <5 years old compared to the 5-14 years old (+53.4%, 95% CI 35.2-71.9%; p<0.0001 versus +39.9%, 95% CI 27.6-52.2%; p<0.0001). Relative contribution of lower-tier facilities to total case detection rate increased from 37% (71.8/191.8) pre-intervention to 50% (139.9/280.2) during intervention. The majority (89.5%) of children with TB were identified through facility-based intensified case-finding and primarily accessed care through outpatient and inpatient departments. In this multi-country study implemented under real-life conditions, the implementation of integrated and decentralized interventions increased paediatric TB case detection. The increase was driven by lower-tier facilities that serve as the primary point of healthcare contact for most patients. The effect was greater in children < 5 years compared to 5-14 years old, representing an important achievement as the TB detection gap is higher in this subpopulation. (Study number NCT03948698).

Impact of Routine Point-of-Care Versus Laboratory Testing for Early Infant Diagnosis of HIV: Results From a Multicountry Stepped-Wedge Cluster-Randomized Controlled Trial.

BACKGROUND: Although the World Health Organization recommends HIV-exposed infants receive a 6-week diagnostic test, few receive results by 12 weeks. Point-of-care (POC) early infant diagnosis (EID) may improve timely diagnosis and treatment. This study assesses the impact of routine POC versus laboratory-based EID on return of results by 12 weeks of age. METHODS: This was a cluster-randomized stepped-wedge trial in Kenya and Zimbabwe. In each country, 18 health facilities were randomly selected for inclusion and randomized to timing of POC implementation. FINDINGS: Nine thousand five hundred thirty-nine infants received tests: 5115 laboratory-based and 4424 POC. In Kenya and Zimbabwe, respectively, caregivers were 1.29 times [95% confidence interval (CI): 1.27 to 1.30, P < 0.001] and 4.56 times (95% CI: 4.50 to 4.60, P < 0.001) more likely to receive EID results by 12 weeks of age with POC versus laboratory-based EID. POC significantly reduced the time between sample collection and return of results to caregiver by an average of 23.03 days (95% CI: 4.85 to 21.21, P < 0.001) in Kenya and 62.37 days (95% CI: 58.94 to 65.80, P < 0.001) in Zimbabwe. For HIV-infected infants, POC significantly increased the percentage initiated on treatment, from 43.2% to 79.6% in Zimbabwe, and resulted in a nonsignificant increase in Kenya from 91.7% to 100%. The introduction of POC EID also significantly reduced the time to antiretroviral therapy initiation by an average of 17.01 days (95% CI: 9.38 to 24.64, P < 0.001) in Kenya and 56.00 days (95% CI: 25.13 to 153.76, P < 0.001) in Zimbabwe. CONCLUSIONS: POC confers significant advantage on the proportion of caregivers receiving timely EID results, and improves time to results receipt and treatment initiation for infected infants. Where laboratory-based EID systems are unable to deliver results to caregivers rapidly, POC should be implemented as part of an integrated testing system.

HIV Mother-to-Child Transmission in Cameroon: EID Positivity Yields and Key Risk Factors by Health Service Points After Usage of POC EID Systems.

BACKGROUND: Most HIV-exposed infants access early infant diagnosis (EID) through the prevention of mother-to-child transmission (PMTCT) service points. However, there are limited data on HIV positivity in non-PMTCT health care settings (pediatric wards, emergency departments, outpatient departments, tuberculosis clinics, etc.). The introduction of point-of-care testing provided an opportunity to describe HIV positivity at alternative health service points and associated risk factors. METHODS: We performed a cross-sectional subanalysis with data from 58 health facilities in Cameroon. The risk of a child being HIV positive at a health service point was considered as a dependent variable, and exploratory variables were assessed using multivariate models with a significance level of 0.05. RESULTS: Overall, 2254 HIV-exposed infants identified by clinical or biological screening were tested by polymerase chain reaction using point-of-care EID. Approximately 74.3% of the infants were tested at a PMTCT entry point, whereas 25.7% were tested at non-PMTCT service points. The positivity yield was 5.7% (95 of the 1674) at the PMTCT service point and 17.6% (102 of the 580) at non-PMTCT service points. Non-PMTCT service points [adjusted odds ratio (aOR): 1.95; 95% confidence interval (CI): 1.36 to 2.80] and vaginal delivery (aOR: 2.56; 95% CI: 1.25 to 5.25) were independently associated with HIV positivity. In a separate analysis (infants aged 0-6 months), mixed feeding mode (aOR: 3.68; 95% CI: 2.00 to 6.77) was also associated with HIV positivity. CONCLUSIONS: More than half of children newly identified as HIV-positive were tested at non-PMTCT service points. The highest EID positivity yields were found in non-PMTCT service points. Strengthening HIV testing in non-PMTCT service points may help to identify additional infected children and improve timely initiation of treatment and care.

Use of Point-of-Care Nucleic Acid Tests Beyond Early Infant Diagnosis of HIV: A Retrospective Case Review in Lesotho.

BACKGROUND: Rapid diagnostic tests (RDTs) for HIV antibodies remain the primary method of diagnosis of HIV in individuals over age 18 months in Lesotho. Although antibody tests have high sensitivity and specificity, up to 2.3% of serial two-test algorithms can have discrepant results between RDTs. In the case of inconclusive RDT results, Lesotho guidelines at the time of this study recommended either repeat testing with the same RDT algorithm after 14 days or immediately collect a blood sample to be sent for laboratory-based polymerase chain reaction testing. Point-of-care qualitative nucleic acid tests (POC qual NAT) may have benefits in rapidly resolving these inconclusive results, particularly when compared with repeating RDTs later or conventional polymerase chain reaction testing at the National Reference Laboratory. SETTING: Hospitals and clinics at 29 locations throughout Lesotho that had access to point-of-care nucleic acid testing. METHODS: Retrospective case review. RESULTS: We identified 100 testing records where POC qual NAT was used to resolve inconclusive RDTs per Lesotho guidelines. Eighty-nine percent of patients received their results in a median of one day from their inconclusive RDT result (interquartile range 0-7 days). Sixty-eight patients (68%) were determined to be HIV positive based on POC nucleic acid tests (NATs), of which 54 (79%) were started on antiretroviral therapy (ART). Median time from inconclusive RDT result to initiation of ART therapy was 2 days (interquartile range 0-14 days). Three patients in this review were pregnant at the time of testing; one was HIV positive by POC qual NAT and was started on ART therapy the same day. CONCLUSION: As the availability of POC qual NAT platforms increases, they may serve as feasible options for rapid resolution of inconclusive results and initiation of ART, particularly in populations with high risk of imminent transmission.

Evaluation of a routine point-of-care intervention for early infant diagnosis of HIV: an observational study in eight African countries.

BACKGROUND: In 2017, there were 180 000 estimated new HIV infections in children aged 0-14 years. Without early diagnosis and treatment, half of infants with HIV die by age 2 years, with peak mortality around age 8-10 weeks. Conventional early infant diagnosis (EID) systems have not consistently returned results in a timely manner. However, point-of-care (POC) EID devices, which are new to market, could improve outcomes. In December, 2016, POC EID testing was introduced in eight sub-Saharan African countries as part of routine service delivery. We aimed to compare key service delivery and clinical outcomes and costs of POC versus conventional EID. METHODS: In our observational study, we compared service delivery and clinical outcomes in eight countries (Cameroon, Côte d'Ivoire, Kenya, Lesotho, Mozambique, Rwanda, Swaziland, and Zimbabwe), before and after a POC intervention was introduced for EID of HIV. For the baseline, pre-intervention sample, we sampled 30 consecutive tests for HIV-exposed infants who had a documented date of blood collection for EID within Ministry of Health registers in a subset of Elizabeth Glaser Pediatric AIDS Foundation (EGPAF)-supported sites that would be enrolled in POC. For the post-intervention sample, all infants who were tested with POC EID for HIV at an EGPAF site were included in the sample. For both conventional and POC EID testing, we did not specify an age range, but used national EID guidelines for EID eligibility. A range of sites for conventional data collection were selected to represent both primary testing sites (where POC EID instruments would be placed) and spoke sites, rural and urban environment, and high throughput and low throughput sites. In all countries, except Mozambique, we developed a POC EID test request form in conjunction with the Ministry of Health. In Mozambique, EGPAF-trained staff extracted data from health facility registers and other sources using a data collection form. Certain specific indicators were required for all countries, but countries could collect additional variables, as the POC EID test request form was used for patient management for the duration of the project. These forms were filled in by health-care providers at the facility. Once the form was completed it was collected by EGPAF staff and entered into a project-specific database. The cost per test result returned was approximated by use of the Global Fund's total cost of ownership estimates. FINDINGS: Retrospective collection of data on clinical and service delivery outcomes of conventional testing began on Nov 14, 2016, and was completed on Nov 26, 2017, for tests done between March 3, 2014, and March 30, 2017, at 96 health-care facilities using conventional testing. POC tests were done at 339 health-care facilities between Dec 1, 2016, and Dec 31, 2017. We evaluated data from 2875 infants exposed to HIV who were tested with conventional testing methods (2899 tests) and 18 220 infants tested with POC testing (19 071 tests). Several EID outcomes were significantly improved with POC testing relative to conventional testing. The return of results to caregivers within 30 days (in 18 737 [98·3%] of 19 058 infants receiving POC testing vs 542 [18·7%] of 2898 infants receiving conventional testing; p<0·0001), the median time from sample collection to return of results to caregivers (0 vs 55 days; p<0·0001), the number of infants with HIV initiating antiretroviral therapy (ART) within 60 days of sample collection (639 [92·3%] of 692 infants vs 42 [43·3%] of 97 infants; p<0·0001), the median time from sample collection to ART initiation among infants with HIV (0 vs 49 days; p<0·0001), and the median age at ART initiation among infants with HIV who were tested at 6-8 weeks (1·6 vs 3·3 months; p<0·0001) were all improved with POC testing compared with conventional testing. The cost per test result returned within 30 days was less for POC (US$27·24, range 21·39-33·10) than conventional testing ($131·02, 96·26-165·76). INTERPRETATION: POC EID improves the speed of return of HIV test results and enables earlier ART initiation; this approach could potentially reduce morbidity and mortality in infants with HIV. National programmes, funders, and implementing partners should consider POC EID as a preferred testing strategy for implementation. FUNDING: Unitaid.

HIV Testing After a First Positive Rapid Diagnostic Test: A Role for Nucleic Acid Testing?

We developed an open-access, Excel-based model simulating currently recommended and alternative algorithms for adult HIV testing as a preliminary investigation of trade-offs between accuracy and costs. Despite higher costs, simpler HIV testing algorithms incorporating point of care nucleic acid testing may improve outcomes and thus merit additional research and field testing.

Binding of Vac14 to neuronal nitric oxide synthase: Characterisation of a new internal PDZ-recognition motif.

PDZ domains mediate protein interactions primarily through either classical recognition of carboxyl-terminal motifs or PDZ/PDZ domain associations. Several studies have also described internal modes of PDZ recognition, most of which depend on beta-finger structures. Here, we describe a novel interaction between the PDZ domain of nNOS and Vac14, the activator of the PtdIns(3)P 5-kinase PIKfyve. Binding assays using various Vac14 deletion constructs revealed a beta-finger independent interaction that is based on a novel internal motif. Mutational analyses reveal essential residues within the motif allowing us to define a new type of PDZ domain interaction.

[The difficulty in assessing the wounds of the officers of the Napoleonic armies]. / De la difficulté d'apprécier les blessures des officiers des armées napoléoniennes.

About any difficulties of assessment of the injuries of Napoleonic army officers. A gravely injured military was often injured again a few days later so doubt can occur about the reality of the firts injury. Then through the different cases the remark is frequent without satisfactory explanation.

[The Law of 19 Ventôse, year 21 (10 March 1803): fundamental text and provisional expedient]. / La Loi du 19 Ventôse an XI, texte fondateur et expédient provisoire.

During the last years of the Ancien Régime, Fourcroy established the link between Vicq d'Azyr and Colombier who both wore themselves out in order to reform the medical profession, fallen into a state of turmoil. But both died, and henceforth everything was handled by Fourcroy. On 10 March 1803 (19 Ventose an XI) he arranged for the passage of a fundamental law--today is its bi-centennial--reorganising the profession. Henceforth no one could exercise that profession without having been received as a doctor, except in underdeveloped regions where "health officers" (less qualified practitioners) would be accepted.

[Napoleon facing the experts (1795-2001)]. / Napoléon face aux experts (1795-2001).

After the autopsy in 1821 had concluded that stomach cancer was the cause of Napoleon's death other diagnoses have been suggested with mixed success. In 1913, the scientific community inclined to favour an amoebic attack as the cause of death but returned to the stomach cancer diagnosis in 1978. At the beginning of this century, the arsenic poisoning hypothesis has been given media coverage but it lacks any real scientific basis.

New diagnostics for tuberculosis: fulfilling patient needs first.

BACKGROUND: An effective tuberculosis (TB) control programme requires early diagnosis and immediate initiation of treatment. Any delays in diagnosing TB not only impair a patient's prognosis, but also increase the risks of transmitting the disease within the community. Unfortunately, the most recent TB diagnostic tools still depend on high-infrastructure laboratories, making them poorly adapted for use in resource-limited settings. Additionally, existing tests show poor performance in diagnosing TB in children, people living with HIV/AIDS, and extrapulmonary forms of the disease. As a consequence, TB patients are still to date left with either fair access to poor diagnostics or poor access to fair diagnostics. DISCUSSION: This article discusses recent efforts to identify the minimal test specifications for a new TB point-of-care diagnostic test through an approach based on medical and patient needs. As a first step, survey interviews with field practitioners were designed in order to identify the top-priority medical needs in resource-limited settings concerning new TB diagnostics. Subsequently, an expert meeting convening field practitioners, laboratory experts, diagnostic test developers and researchers was held with the objective of defining the minimal test specifications for a new TB point-of-care test that would meet the identified medical needs. Finally, gaps in, as well as potential solutions for, enabling the development of adequate, patient needs-driven, low-cost new TB diagnostic tests specifically designed for vulnerable populations are discussed. SUMMARY: Any new TB point-of-care diagnostic test should be designed to meet minimal specifications satisfying the most urgent medical needs in resource-poor settings. The major gaps for developing a new TB point-of-care test include identification of new biomarkers, simplification of technological platforms, development of adequate and accessible specimen banks, and identification and definition of reference standards for diagnosis of childhood TB. Innovative research and development funding ensuring de-linkage of research and development costs from the price of the new product, such as a prize fund mechanism, could help focus these efforts towards the delivery of a much-needed point-of-care diagnostic test for TB.

Huntingtin interacting protein 1 (HIP1) regulates clathrin assembly through direct binding to the regulatory region of the clathrin light chain.

Huntingtin interacting protein 1 (HIP1) is a component of clathrin coats. We previously demonstrated that HIP1 promotes clathrin assembly through its central helical domain, which binds directly to clathrin light chains (CLCs). To better understand the relationship between CLC binding and clathrin assembly we sought to dissect this interaction. Using C-terminal deletion constructs of the HIP1 helical domain, we identified a region between residues 450 and 456 that is required for CLC binding. Within this region, point mutations showed the importance of residues Leu-451, Leu-452, and Arg-453. Mutants that fail to bind CLC are unable to promote clathrin assembly in vitro but still mediate HIP1 homodimerization and heterodimerization with the family member HIP12/HIP1R. Moreover, HIP1 binding to CLC is necessary for HIP1 targeting to clathrin-coated pits and clathrin-coated vesicles. Interestingly, HIP1 binds to a highly conserved region of CLC previously demonstrated to regulate clathrin assembly. These results suggest a role for HIP1/CLC interactions in the regulation of clathrin assembly.