BACKGROUND:Global investments to combat HIV, tuberculosis, and malaria (HTM) have delivered substantial health gains and may have reduced the burden placed by these diseases on the routine health system. We estimated the reduction in primary healthcare (PHC) utilization resulting from the scale-up of HTM services over 2000-2023 in 108 low- and middle-income countries. METHODS AND FINDINGS:For each disease, we applied established mathematical models to quantify PHC utilization (outpatient visits and inpatient bed-days provided outside of HTM programs) by individuals with symptomatic HIV, tuberculosis, or malaria unable to access HTM-specific services. For each country, we estimated averted PHC utilization by comparing a scenario describing the actual scale-up of HTM services to a counterfactual scenario holding HTM service coverage constant at year 2000 levels. We applied published unit costs to estimate the averted costs resulting from reduced PHC utilization. Over 2000-2023, scale-up of HTM services averted an estimated 6.9 (95% uncertainty interval (UI) [4.4, 10.5]) billion outpatient PHC visits and 3.9 (95% UI [2.5, 5.9]) billion inpatient bed-days, representing US$135 (95% UI [71, 250]) billion in averted costs. These reductions were greatest in sub-Saharan Africa and East Asia and Pacific regions. Across study countries, these reductions represented a median of 4.4% of hospital bed capacity and 1.6% of government health spending in 2023. These percentages were 22.9% and 5.1%, respectively, for low-income countries. Our analysis did not consider changes in PHC services beyond utilization. Also, several inputs were missing in some countries, with missing values estimated using regression imputation. CONCLUSIONS:Over recent decades, sustained investments in HTM services in high-burden settings have averted substantial PHC utilization and associated costs. These benefits should be considered when assessing investment impact.

Heterozygous familial hypercholesterolaemia is one of the most common genetic conditions leading to premature atherosclerotic cardiovascular disease. It can be diagnosed using a combination of clinical, biochemical, and genetic tools. Most guidelines recommend screening during childhood and treatment from the age of 8–10 years. However, screening remains sporadic in most countries and the majority of individuals remain undiagnosed. Registry studies have highlighted the ongoing delayed and low percentage of detection of FH in children. Universal early childhood screening models utilising a combination of biomarker-based and genetic testing have been trialled and are in practice in some countries. Newborn screening is a public health success story and one of the most effective public health measures. It offers universal screening for conditions that can result in significant morbidity or even death if left untreated. There has been renewed interest in including familial hypercholesterolaemia in newborn screening programmes. Using cord blood to identify familial hypercholesterolaemia has not yielded convincing results. However, novel screening approaches on dried blood spots that include biomarker-based lipid profile testing alone, in combination with confirmatory genetic testing, or first-line genetic testing have shown promising results. This provides the opportunity of early diagnosis and treatment of infants and their extended families. However, challenges are associated with the inclusion of familial hypercholesterolaemia in newborn screening programmes with significant impacts on the newborn, family members, and public health.

The recent withdrawal of U.S. financial support threatens essential TB service delivery, including diagnostics, treatment, TB-HIV co-infection interventions and research initiatives critical to eradicating TB. This study analyses the dependency of and potential impact of funding cuts to 26 high-burden TB countries (HBCs). We modelled three recovery scenarios: (1) minimal impact (services recover within three months), (2) moderate impact (recovery within one year), and (3) worst-case scenario (long-term service reduction). Extrapolations were made for all 26 HBCs based on representative countries from each dependency category. Across all 26 HBCs, additional TB cases between 2025 and 2030 are estimated at 0.63 million (CI 0.45-0.81) (minimal impact), 1.66 million (CI 1.2-2.1) (moderate impact), and 10.67 million (CI 7.85-13.19) (worst-case). Corresponding TB deaths are projected to increase by 99,900 (CI 65,200-130,000), 268,600 (CI 185,800-337,900), and 2,243,700 (CI 1,570,800-2,807,300), respectively. The loss of U.S. funding endangers global TB control efforts, jeopardizing progress towards End TB and SDG targets, and potentially puts millions of lives at risk. While some nations may adapt, short-term disruptions will severely impact vulnerable populations. Urgent alternative funding is needed to sustain critical TB prevention and treatment efforts.

Background: Investments to combat HIV, tuberculosis, and malaria (HTM) have delivered substantial health gains in high-burden settings. There is limited evidence on how this has affected primary health care (PHC). We estimated the changes in PHC utilization and associated cost savings resulting from scale-up of HTM interventions in 108 low- and middle-income countries over 2000-2023. Methods: For each disease, we applied validated mathematical models quantifying the incremental differences in PHC outpatient visits and inpatient bed-days by individuals with untreated symptomatic HIV, tuberculosis, or malaria. By country and year, we compared the actual scale-up of HTM services scenario against a counterfactual scenario holding HTM intervention coverage constant at year 2000 levels. We estimated the cost savings associated with these utilization reductions, and compared results to national hospital capacity and health expenditure. Findings: Over 2000-2023, scale-up of HTM services averted an estimated 6.9 (95% interval: 4.4-10.4) billion PHC outpatient visits and 3.9 (2.5-6.1) billion inpatient bed-days, equivalent to US$135 (77-225) billions in total cost savings. Reductions in utilization and cost savings were greatest in the Sub-Saharan Africa and East Asia and Pacific regions. For 2023, a median of 4.4% of hospital bed capacity and 1.6% of government health expenditures were freed-up across study countries. These percentages were 22.9% and 5.1% respectively for low-income countries. Interpretation: Sustained investments in HTM services in high-burden settings generated substantial cost savings over recent decades through reduced PHC utilization. These benefits should be considered when assessing investment impact. Funding: The Global Fund. ### Competing Interest Statement Funding for this study was provided by the Global Fund. PW acknowledges support from the Bill & Melinda Gates Foundation (INV-043624). TBH and PW acknowledge funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/X020258/1), funded by the UK Medical Research Council (MRC). This UK funded award is carried out in the frame of the Global Health EDCTP3 Joint Undertaking. NAM acknowledges support from the US National Institutes for Health, US Centers for Disease Control and Prevention, the Bill & Melinda Gates Foundation, and the European Commission. ### Funding Statement NM, TBH, CP, JS, and PW acknowledge support from the Global Fund to Fight AIDS, TB, and Malaria. PW acknowledges support from the Bill & Melinda Gates Foundation (INV-043624). TBH and PW acknowledge funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/X020258/1), funded by the UK Medical Research Council (MRC). This UK funded award is carried out in the frame of the Global Health EDCTP3 Joint Undertaking. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Hypophosphatemia occurring after ferric carboxymaltose or iron polymaltose infusion is common and has been well-characterized. Post-iron infusion hypocalcemia has been documented in case reports, but there is no data on the prevalence of hypocalcemia developing after i.v. iron infusion. In this retrospective cohort study, we sought to characterize integrated daily changes in serum phosphate and corrected calcium levels before and after iron infusion in a real-world inpatient setting. Inpatients who received i.v. iron polymaltose at the Royal Brisbane and Women's Hospital (Queensland, Australia) between January 2020 and September 2021 were included. We extracted all results for serum phosphate and corrected calcium levels for 21 d before and after iron infusion. A total of 741 patients with 8272 blood samples were included. The serum phosphate concentration reduced by an average of 30.6% (95% CI 28.2-32.9) in the 5 d following infusion. Serum phosphate reached a nadir at day 5 before incrementing, but still remained below baseline by the end of the study period. Conversely, serum corrected calcium levels increased within 1 d of iron polymaltose infusion and then dropped over the following 5 d. There was a significant increase in the prevalence of hypophosphatemia developing after iron polymaltose infusion (34% post-infusion vs 8% pre-infusion, p-value < .001). Hypophosphatemia occurred most commonly within the first week after iron infusion, whereas hypocalcemia was more frequently a later occurrence. Our results have enhanced the understanding of the day-to-day biochemical changes occurring after iron infusion as well as the prevalence and timing of post-iron infusion hypophosphatemia and hypocalcemia.

BACKGROUND:The Sustainable Development Goals (SDGs) include ending the epidemics of HIV, tuberculosis, and malaria by 2030. With 5 years remaining to meet this goal, and with the Global Fund to Fight AIDS, Tuberculosis and Malaria seeking funding for programmes in 2027-29, establishing what can be achieved through continued investment in combatting these diseases is crucial. We aimed to estimate the potential for impact by analysing the funding landscape and epidemiological situations of these three diseases, the costs of key programmes, and the extent of possible future progress in the countries eligible for Global Fund support. METHOD:In this modelling study, we developed estimates of the financial resources needed in Global Fund-supported countries to combat HIV, tuberculosis, and malaria from the global plans produced by UNAIDS, the Stop TB Partnership, and WHO. Estimates of available resources in the coming years were obtained by assuming that national expenditure on the three diseases would grow in line with general governmental expenditures, that the Global Fund would contribute an additional $18·0 billion, and that other developmental assistance would be at the same level in real terms as the average in the period 2020-22. Epidemiological and costing models for each of the three diseases were used to quantify the possible impact in Global Fund-eligible countries (including on aggregated mortality and incidence rates). The return on investment (ROI) was computed considering both the intrinsic value of health and the direct economic benefits of the reduced risk of morbidity and premature mortality. The analysis was completed at the end of 2024 with the latest available data, which pertained to the year 2023. The focus of the projection period was 2027-29, a period for which scale-up plans and funding have not yet been committed and the period when most of the resources raised by the eighth replenishment of the Global Fund would be used. FINDINGS:The total resource needs for the three diseases were estimated to be US$140·6 billion in 2027-29. We calculated that $111·3 billion (79%) of this need could be met from domestic financing ($69·7 billion), the Global Fund ($18·0 billion), and other external donors ($23·6 billion). Optimal use of these available resources could save 23 million lives and avert 400 million cases and new infections during 2027-29. The trajectory of the combined mortality rate for all diseases was projected to approach that needed to reach the SDG for 2030 (with a difference between the target in 2030 and the projection at the end of 2029 of between 1·5% and 15·5% of the normalised aggregated mortality rate), inequality in life expectancy between countries would be 7% lower by 2029, and 189 million fewer hospital days and 572 million fewer outpatient visits would be needed in 2027-29, saving $1·1 billion. For every $1·00 invested, there could be up to $19·00 in intrinsic health value created or $3·50 in direct economic benefits. INTERPRETATION:Continued investments to combat HIV, tuberculosis, and malaria could yield enormous health gains and a high return on investment. Realising these benefits will require continued growth in national expenditure and a broad maintenance of external financing for these diseases, including a successful replenishment of the Global Fund in 2025. FUNDING:The Global Fund.

Background:Tuberculosis (TB) remains one of the deadliest infectious diseases globally. Despite the World Health Organization's (WHO) End TB Strategy targets for 2035, progress has been hindered by structural, financial, and implementation barriers, including recent cuts in global funding. Strategic use of mathematical modelling is useful for prioritizing high-impact interventions and optimizing limited resources. A new global TB infection transmission model was developed to address limitations in existing tools with respect to these applications. Methods:The model includes enhanced features such as age-specific mixing, explicit representation of asymptomatic TB, stratification by drug resistance, HIV status, and new vaccine status, and inclusion of both public and private care pathways. It was calibrated to country-specific data using Bayesian adaptive Markov Chain Monte Carlo (MCMC) methods. The model was used to assess the impact of national strategic plans and the Global Plan to End TB, using a Target Population (TP) component to map interventions to WHO guidelines. Results:Model calibration showed good agreement with historical TB data from 29 high-burden countries, with case studies for Indonesia and Nigeria presented here. In Indonesia, comprehensive implementation of Global Plan interventions - including public-private mix efforts, modern diagnostics, improved treatment for drug-resistant TB, and a post-exposure vaccine - could enable the country to achieve End TB targets by 2035. In Nigeria, implementing its National Strategic Plan could reduce TB incidence by 27% and mortality by 37% by 2030, even without a vaccine. The model highlighted the additional efforts that are needed to meet the End-TB goals. Conclusions:The enhanced TB model provides a flexible, policy-relevant framework for assessing the epidemiological impact of TB interventions at both national and global levels. Its open-source design and alignment with WHO recommendations make it a valuable tool for guiding evidence-based investments amid tightening global health budgets.

Rationale:Tuberculosis (TB) remains a global health crisis, disproportionately affecting low- and middle-income countries. Strategic resource allocation is essential to achieving the WHO End TB targets. Existing TB costing tools have limitations in conducting global analyses, prompting the development of a novel model tailored to address these gaps. Methods:We developed a new, open-source TB costing model that simulates detailed TB care cascades comprising steps of screening, diagnosis, treatment, and prevention for those eligible - according to WHO guidelines for 20 distinct population groups. These include 10 groups each from patient-initiated and provider-initiated pathways, capturing variations in pulmonary status, age, HIV/ART status, and drug sensitivity. The model captures the cost of a large-scale vaccine. We demonstrate the model's functionality through a case study that informed the Global Fund's Investment Case for its 8th replenishment (2027-2029). Results:In the case study, the model was first used to estimate the cost of implementing the TB Global Plan 2023 - 2030. This scenario incorporated intervention targets, normative standards of care, and the availability of new TB tools. An optimization routine applied to 29 high-burden countries estimated maximal TB impact under constrained funding scenarios. The results were also used to assess the potential impact and contribution of innovation within the Global Fund's 8th replenishment. Discussion:This new TB costing model offers improved representation of TB care complexity across diverse populations, with enhanced transparency, flexibility, and policy relevance. Its application in global TB strategy analysis highlights its value in informing investment cases and prioritizing interventions for maximal impact under resource constraints.

BACKGROUND:The short Synacthen test (SST) is widely used to investigate adrenal insufficiency, but it can be time-consuming, costly and labour-intensive to perform and is not without risk of adverse events. AIM:To review SST requesting patterns and practices across public hospitals in Queensland. METHODS:The electronic medical records of patients who underwent a SST with Pathology Queensland between January 2020 and December 2020 were reviewed to collect data regarding the indication for the test, the requesting speciality, SST results and any adverse events. RESULTS:Six hundred and fifty-two SSTs were identified, of which 363 individual patients were included in the analysis. The majority of the tests (n = 198, 54.5%) were performed in the inpatient setting. Endocrinology most commonly ordered SSTs (n = 188, 51.8%). The suspected aetiology of adrenal insufficiency was unclear in a large proportion of requests (n = 167, 46.0%). Static testing of morning cortisol prior to SST was performed in only 249 (68.6%) patients. Of 140 inpatients data, 17.9% (n = 25) showed a robust static cortisol of ≥400 nmol/L and were treated as having normal adrenal function, suggesting SST was unnecessary in these patients. Twenty-two (6.1%) patients had a documented adverse event occurring during or after the SST. CONCLUSIONS:There was wide variability in requesting patterns and practices for SSTs across Queensland. More than one in six SSTs could have been avoided if a static morning cortisol had been performed prior. Clinician education and the adoption of a structured referral form may improve testing practices.

Despite the significant potential of protein biosensors, their construction remains a trial-and-error process. The most obvious approach for addressing this is to utilize modular biosensor architectures where specificity-conferring modalities can be readily generated to recognize new targets. Toward this goal, we established a workflow that uses mRNA display-based selection of hyper-stable monobody domains for the target of choice or ribosome display to select equally stable DARPins. These binders were integrated into a two-component allosteric biosensor architecture based on a calmodulin-reporter chimera. This workflow was tested by developing biosensors for liver toxicity markers such as cytosolic aspartate aminotransferase, mitochondrial aspartate aminotransferase, and alanine aminotransferase 1. We demonstrate that our pipeline consistently produced >10(3) unique binders for each target within a week. Our analysis revealed that the affinity of the binders for their targets was not a direct predictor of the binder's performance in a biosensor context. The interactions between the binding domains and the reporter module affect the biosensor activity and the dynamic range. We conclude that following binding domain selection, the multiplexed biosensor assembly and prototyping appear to be the most promising approach for identifying biosensors with the desired properties.

Purpose: We aimed to identify a gene signature that discriminates between sepsis and aseptic inflammation in patients administered antibiotics in the intensive care unit and compare it to commonly utilised sepsis biomarkers.Methods: 91 patients commenced on antibiotics were retrospectively diagnosed as having: (i) blood culture positive sepsis; (ii) blood culture negative sepsis; or (iii) aseptic inflammation. Bloods were collected after <24 h of antibiotic commencement for both gene expression sequencing analysis and measurement of previously identified biomarkers.Results: 53 differentially expressed genes were identified that accurately discriminated between blood culture positive sepsis and aseptic inflammation in a cohort of patients given antibiotics [aROC 0.97 (95% CI, 0.95-0.99)]. This gene signature was validated in a publicly available database. The gene signature out-performed previously identified sepsis biomarkers including C-reactive protein [aROC 0.72 (95% CI, 0.57-0.87)], NT-Pro B-type Natriuretic Peptide [aROC 0.84 (95% CI, 0.73-0.96)], and SepticyteTM LAB [aROC 0.8 (95% CI, 0.68-0.93)], but was comparable to Procalcitonin [aROC 0.96 (95% CI, 0.9-1)].Conclusions: A gene expression signature was identified that accurately discriminates between sepsis and aseptic inflammation in patients given antibiotics in the intensive care unit.

Bone turnover markers (BTM) are measures for understanding the effect of anti-resorptives upon osteoclast activity. Post-hoc trial data suggests reduction in BTM of 40% may represent a target for defining appropriate response to therapy. We modeled clinical application of this target threshold in an individual patient setting where assay measurement uncertainty and biological variation are included.Using serum C-telo-peptide (ß-CTX), we constructed hypothetical scenarios of ß-CTX measurement pre and post bisphosphonate therapy. Using typical ß-CTX assay characteristics (analytical coefficient of variation, CV 5.0%) and published intra-individual ß-CTX data for post-menopausal women (CV 18.0%), we calculated the post-therapy ß-CTX that must be seen on single repeat measure for 95% confidence that the observed result was ≥40% below baseline. Sensitivity analyses considered greater and lesser variations in the combined sources of variation.The one-tailed 95% reference change value for any detectable therapeutic decrease in ß-CTX was 22%. However, to have 95% confidence of having achieved a reduction ≥40%, an observed ß-CTX decrease of ≥56% is required. Larger decreases are needed for scenarios of greater analytical or intra-individual variation.Although population data suggest a ß-CTX decrease of 40% is commensurate with adequate therapeutic response to anti-resorptives, application to an individual patient where measurement and natural variation are present is problematic. ß-CTX decreases much >40% are required to be confident of having achieved the optimal treatment response. It is uncertain whether this is a legitimate change to be expected in all individual patients and therefore clinical application of this threshold is uncertain.

This report presents a cost–benefit analysis of increased spending on tuberculosis (TB) using impacts and costs drawn from the Global Plan to End Tuberculosis, 2023–2030. The analysis indicates that the return on TB spending is substantial with a centrally estimated benefit–cost ratio (BCR) of 46, meaning every US$ 1 invested in TB yields US$ 46 in benefits. Alternative specifications using different baselines, interventions, cost profiles, and discount rates still yield robustly high BCRs, in the range of 28–84. This report also shows that TB investment would avert substantial mortality, estimated at 27.3 million averted deaths over the 28-year period between 2023 and 2050 inclusive: almost 1 million averted deaths per year on average. Accounting for all estimated direct and indirect costs, the cost per averted death is slightly over US$ 2000. Interventions to address TB represent exceptional value-for-money.

OBJECTIVES:To (1) identify the frequency of IGF-1 elevation in a cohort of patients without clinically suspected GH excess, in a state-based reference laboratory over a 24-month period, and (2) to examine potential differences in comorbidities and relevant medications between people with an elevated IGF-1 compared to a matched control group.DESIGN:All IGF-1 measurements at Pathology Queensland between 1/12/2018-1/12/2020 were identified. The medical records of those with IGF-1 ≥1.1x the upper limit of the reference range were appraised to determine: (1) documentation of acromegalic features, (2) relevant comorbidities and medication use, and (3) further investigations to exclude pathological GH excess.PATIENTS AND MEASUREMENTS:There were 2759 IGF-1 samples measured in 1963 people ≥18 years, over the specified period. Of these, 204 had IGF-1 ≥1.1x the upper limit of the age-matched reference range; 102 cases (61M, 41F) met inclusion criteria, and were matched to 102 controls with a normal IGF-1 based on age, sex, gonadal status and pituitary anatomy on MRI.RESULTS:There were significant differences in the frequency of dopamine agonist use (19/102 cases vs. 6/102 controls, OR = 3.66, 95% confidence interval [CI]: 1.45-9.29, p = .009) and chronic kidney disease (CKD) (14/102 cases vs. 4/102 controls, OR = 3.90, 95% CI: 1.28-11.14, p = .024).CONCLUSIONS:Out of 1963 patients having IGF-1 measured, 102 (5.2%) had an elevated IGF-1 where there was no known acromegaly, GH replacement or endogenous glucocorticoid excess. Intraindividual biological variability, assay imprecision and physiological factors are known contributors to falsely elevated IGF-1, dopamine agonist therapy and CKD should also be considered.

ObjectiveEuropean and Australian guidelines for cystic fibrosis (CF) reproductive carrier screening recommend testing a small number of high frequency CF causing variants, rather than comprehensive CFTR sequencing. The study objective was to determine variant detection rates of commercially available targeted reproductive carrier screening tests in Australia. MethodsNext-generation DNA sequencing of the CFTR gene was performed on 2552 individuals from a whole population sample to identify CF causing variants. The variant detection rates of two commercially available Australian reproductive carrier screening tests, which target 50 or 175 CF causing variants, in this population were calculated. The ethnicity of individuals was determined using principal component analysis. ResultsVariant detection rates of the tests for 50 and 175 CF causing variants were 88.2% and 90.8%, respectively. No CF causing variants in individuals of East Asian ethnicity (n = 3) were detected by either test, while >86.6% (n = 69) of CF causing variants in Europeans would be identified by either test. ConclusionsReproductive carrier screening tests for a targeted set of high frequency CF variants are unable to detect approximately 10% of CF variants in a multiethnic Australian population, and individuals of East Asian ethnicity are disproportionally affected by this test limitation.

Newborn screening (NBS) assays for spinal muscular atrophy (SMA) typically use a polymerase chain reaction (PCR) based assay to identify individuals with homozygous deletion in exon 7 of the SMN1 gene. Due to high DNA sequence homology between SMN1 and SMN2, it has previously been difficult to accurately bioinformatically map short reads from next-generation DNA sequencing (NGS) to SMN1, resulting in low analytical performance and preventing NGS being used for SMA screening. Advances in bioinformatics have allowed NGS to be used in diagnostic settings, but to date these assays have not reached the scale required for high volume population newborn screening and have not been performed on the dried blood spot samples that NBS programs currently use. Here we integrate an NGS assay using hybridisation-based capture with a customised bioinformatics algorithm and purpose designed high throughput reporting software into an existing NBS program to achieve a laboratory workflow for population SMA screening. We tested the NGS assay on over 2500 newborns born over 2 weeks in a NBS program in a technical feasibility study and show high sensitivity and specificity. Our results suggest NGS may be an alternate method for SMA screening by NBS programs, providing a multiplex testing platform on which potentially hundreds of inherited conditions could be simultaneously tested.

The 2018 United Nations High-Level Meeting on Tuberculosis (UNHLM) set targets for case detection and TB preventive treatment (TPT) by 2022. However, by the start of 2022, about 13.7 million TB patients still needed to be detected and treated, and 21.8 million household contacts needed to be given TPT globally. To inform future target setting, we examined how the 2018 UNHLM targets could have been achieved using WHO-recommended interventions for TB detection and TPT in 33 high-TB burden countries in the final year of the period covered by the UNHLM targets. We used OneHealth-TIME model outputs combined with the unit cost of interventions to derive the total costs of health services. Our model estimated that, in order to achieve UNHLM targets, >45 million people attending health facilities with symptoms would have needed to be evaluated for TB. An additional 23.1 million people with HIV, 19.4 million household TB contacts, and 303 million individuals from high-risk groups would have required systematic screening for TB. The estimated total costs amounted to ~USD 6.7 billion, of which ~15% was required for passive case finding, ~10% for screening people with HIV, ~4% for screening household contacts, ~65% for screening other risk groups, and ~6% for providing TPT to household contacts. Significant mobilization of additional domestic and international investments in TB healthcare services will be needed to reach such targets in the future.

IntroductionDespite antiretroviral therapy (ART) scale-up among people living with HIV (PLHIV), those with advanced HIV disease (AHD) (defined in adults as CD4 count <200 cells/mm(3) or clinical stage 3 or 4), remain at high risk of death from opportunistic infections. The shift from routine baseline CD4 testing towards viral load testing in conjunction with "Test and Treat" has limited AHD identification. MethodsWe used official estimates and existing epidemiological data to project deaths from tuberculosis (TB) and cryptococcal meningitis (CM) among PLHIV-initiating ART with CD4 <200 cells/mm(3), in the absence of select World Health Organization recommended diagnostic or therapeutic protocols for patients with AHD. We modelled the reduction in deaths, based on the performance of screening/diagnostic testing and the coverage and efficacy of treatment/preventive therapies for TB and CM. We compared projected TB and CM deaths in the first year of ART from 2019 to 2024, with and without CD4 testing. The analysis was performed for nine countries: South Africa, Kenya, Lesotho, Mozambique, Nigeria, Uganda, Zambia, Zimbabwe and the Democratic Republic of Congo. ResultsThe effect of CD4 testing comes through increased identification of AHD and consequent eligibility for protocols for AHD prevention, diagnosis and management; algorithms for CD4 testing avert between 31% and 38% of deaths from TB and CM in the first year of ART. The number of CD4 tests required per death averted varies widely by country from approximately 101 for South Africa to 917 for Kenya. ConclusionsThis analysis supports retaining baseline CD4 testing to avert deaths from TB and CM, the two most deadly opportunistic infections among patients with AHD. However, national programmes will need to weigh the cost of increasing CD4 access against other HIV-related priorities and allocate resources accordingly.

Tuberculosis (TB) killed more people globally than any other single pathogen over the past decade. Where surveillance is weak, estimating TB burden estimates uses modeling. In many African countries, increases in HIV prevalence and antiretroviral therapy have driven dynamic TB epidemics, complicating estimation of burden, trends, and potential intervention impact. We therefore develop a novel age-structured TB transmission model incorporating evolving demographic, HIV and antiretroviral therapy effects, and calibrate to TB prevalence and notification data from 12 African countries. We use Bayesian methods to include uncertainty for all TB model parameters, and estimate age-specific annual risks of TB infection, finding up to 16.0%/year in adults, and the proportion of TB incidence from recent (re)infection, finding a mean across countries of 34%. Rapid reduction of the unacceptably high burden of TB in high HIV prevalence settings will require interventions addressing progression as well as transmission.

Objectives: We tested the hypothesis that the free-beta subunit (beta hCG) is diagnostically more sensitive with total hCG assays (hCGt) not detecting all tumours secreting beta hCG. The effects of sex, age, and renal failure were investigated as secondary objectives. Methods: We compared beta hCG with hCGt in 204 testicular cancer patients (99 seminomas, 105 non-seminonatous germ cell tumours). The effects of sex and age were determined in 125 male and 138 female controls and that of renal failure was investigated in 119 haemodialysis patients. Biochemical assessment of gonadal status was performed with LH, FSH, oestradiol and testosterone. Results: Discordant results were common with isolated increases of hCGt observed in 32 (15.7 %) and beta hCG in 14 (6.9 %) patients. Primary hypogonadism was the most common cause of isolated hCGt increases. After therapeutic interventions beta hCG decreased below its upper reference more rapidly than hCGt. We observed unequivocal false negative results in two patients with non-seminomatous germ cell tumours. Both occurred in patients with clinical tumour recurrences; in one instance we observed a false negative hCGt while in the second false negative beta hCG's were documented in serial samples. Conclusions: The similar false negative rates did not support the hypothesis that beta hCG will detect more patients with testicular cancer than hCGt. In contrast to hCGt, beta hCG was unaffected by primary hypogonadism which is a predictably frequent complication in testicular cancer patients. We therefore recommend beta hCG as the preferred biomarker in testicular cancer.