Background: One major challenge in the implementation of household contact investigation (HCI) for tuberculosis (TB) in high burden settings is finding contact persons in the home for screening. Conducting HCI during evenings, weekends, or holidays, particularly in settings with high levels of poverty, may improve effectiveness and implementation.
Methods: We conducted a pragmatic, individually randomized controlled trial of HCI for TB at two sites in South Africa, comparing the effectiveness of two novel strategies for timing (during evenings and weekends in an urban area and during three annual holiday periods in a rural area) to weekday working hours. The primary outcome was the number of secondary cases identified and started on TB treatment per index participant, comparing novel versus standard timing at each site. Clinicaltrials.gov registration: NCT04520113.
Findings: From September 2020 to August 2023, we randomized 1335 index participants with TB in Limpopo to receive standard HCI and 666 to receive holiday = based HCI, and 1616 to receive standard HCI and 805 to receive evening/weekend HCI in Soshanguve. In Limpopo, standard HCI and holidy-based HCI and resulted in 0.6 and 0.7 secondary TB diagnoses started on treatment per 100 index participants, respectively (difference: 0.1 [95% CI: -0.7, 0.8, p = 0.84]). In Soshanguve, evening/weekend-based HCI and standard HCI generated 0.4 and 0.6 diagnoses started on TB treatment per 100 index participants, respectively (difference 0.3 [95% CI: -0.8, 0.4, p = 0.54]).
Interpretation: HCI conducted either during evenings/weekends or during holiday did not increase effectiveness compared to HCI conducted during weekday working hours.
Funding: Funding was provided by the United States National Institute of Allergy and Infectious Diseases (Grant # 5R01AI147681).
Background: Individuals with type 2 diabetes mellitus are treated with a growing variety of medications targeting multiple metabolic pathways. In recent years, incretins such as the GLP-1 receptor agonists have proven effective in the control of hyperglycemia but also in weight loss, where they are now separately approved as a treatment for obesity. Given the importance of obesity and metabolic syndrome as risk factors for malignancy, the impact of GLP-1 receptor agonists on cancer risk is of increasing interest. Here, we performed an analysis of the impact of GLP-1 receptor agonists and SGLT2 inhibitors on cancer risk and mortality.
Methods: We performed a multicenter retrospective cohort study using the TriNetX database of electronic health records between 2019 and 2024, including patients with a diagnosis of type 2 diabetes mellitus. Individuals prescribed GLP-1 receptor agonists, SGLT2 inhibitors, or neither were compared for the incidence of four obesity-related hematologic malignancies using a Cox proportional hazards model. Similar analysis was applied to mortality associated with these medication classes in individuals with type 2 diabetes mellitus and the hematologic malignancies under study.
Findings: GLP-1 receptor agonist use is associated with a significantly decreased risk of multiple myeloma (HR 0.64, p = 0.01), but not chronic myeloid leukemia (HR 1.06, p = 0.857), acute myeloid leukemia (HR 0.81, p = 0.354), or myelodysplastic syndrome (HR 0.98, p = 0.996). This effect was preserved in subgroups with BMI >30 and HbA1c >8%. Further, we find that in patients with multiple myeloma and acute myeloid leukemia, SGLT2 inhibitor use is associated with a significantly increased risk of mortality, independent of heart or kidney failure (MM HR 2.27, p < 0.001, AML HR 2.00, p = 0.006).
Interpretation: Our results strengthen the association between metabolic disease and multiple myeloma yet call for prospective investigation into the use of SGTL2 inhibitors in patients with specific hematologic neoplasms.
Funding: National Institutes of Health.
Background: Individuals with Lynch syndrome (LS) are advised to undergo pancreatic ductal adenocarcinoma (PDAC) surveillance if their lifetime risk is ≥5%, however, evidence is limited. This study quantifies lifetime risk and survival of three cancers relevant to PDAC surveillance, including PDAC, ampullary carcinoma (AC) and distal cholangiocarcinoma (dCC), to evaluate whether surveillance is justified.
Methods: This retrospective nationwide Dutch cohort study included individuals with LS pathogenic variants (PVs) in MLH1, MSH2, MSH6, PMS2 or EpCAM (identified between 1985 and 2024) and compared them to sporadic cases from the general population (diagnosed between 2000 and 2022). Cumulative incidence (CI) of PDAC, AC and dCC was estimated using Fine-and-Gray models for LS and a CI formula for sporadic cases. Relative risks (RRs) were calculated by comparing CIs. Survival of the cancers was compared between both cohorts using 1:10 matched analyses by age at diagnosis, sex, stage, and year of diagnosis.
Findings: In total, 2605 individuals with LS were included (median age 63.9 years; IQR 53.7-74.0), of whom 1515 (58.2%) were female. PVs were identified in MLH1 (723, 27.8%), MSH2 (895, 34.4%), MSH6 (731, 28.1%), PMS2 (233, 8.9%) and EpCAM (23, 0.9%). By age 75, the combined CI of PDAC, AC and dCC was 3.0% (95% CIs, 1.5-5.8) in MLH1, 3.4% (95% CIs, 2.0-5.8) in MSH2/EpCAM, 1.0% (95% CIs, 0.3-2.7) in MSH6 and 0% in PMS2. No familial-clustering of cancers was observed. Matched survival did not differ between PDACs in LS and sporadic cases. In contrast, survival was better for AC in LS (34.3 months; 95% CIs, 3.2-Inf) compared to sporadic cases (15.5 months; 95% CIs, 9.9-19.3).
Interpretation: In LS, the combined lifetime risk of PDAC, AC and dCC ranged from 0 to 3.4% across different genes, remaining below the 5% risk threshold for PDAC surveillance. Additionally, having an affected relative did not appear to increase risk. These findings suggest that current surveillance recommendations for individuals with LS should be re-evaluated.
Funding: Lynch-Polyposis.
Background: Data on cancer incidence and associated risk factors among women with HIV are limited. We investigated cancer burden among women with HIV.
Methods: We included all women ≥18 years from the two large multicentre observational cohort collaborations (D:A:D and RESPOND). The primary outcomes were incidence of all cancers, HPV-related and common individual cancers including breast cancer, lung cancer, and non-Hodgkin lymphoma (NHL) from 2006 to 2021. Baseline was defined as the latest date of entry into local cohort enrolment and 1st January 2006 for D:A:D and 1st January 2012 for RESPOND. Participants were followed from baseline until the date of first cancer, final follow-up or administrative censoring-whichever occurred first. We assessed risk factors using multivariable Poisson regression by applying robust standard errors and determined a population attributable fraction (PAF) for key risk factors for cancers.
Findings: Among 17,512 women included, median age at baseline was 39.5 years (interquartile range, IQR 32.5-46.0). Over 141,404 person-years (PYS) and a median 9.2 (5.5-10.1) years of follow-up, 832 women were diagnosed with any cancer; incidence rate 5.9 (95% CI 5.5-6.4)/1000 PYS, 163 HPV-related cancers (1.1 [1.0-1.3]/1000 PYS), 150 breast cancers (1.1 [0.9-1.2]/1000 PYS), 94 lung cancers (0.7 [0.5-0.8]/1000 PYS) and 72 NHL (0.5 [0.4-0.6]/1000 PYS). Older age (≥45 vs. <45 years), Southern Europe (vs. Western Europe) and smoking were associated with an increased risk of overall cancers. Lower pre-ART nadir CD4, time-updated CD4, and a prior AIDS diagnosis were associated with lung- and HPV-related cancer. In PAF analysis, smoking and HIV-related factors such as lower current CD4, nadir CD4 and HIV viremia significantly contributed to cancer risk.
Interpretation: Our findings suggest that women with HIV older than 45 years, past or current immunosuppressed or current smokers could be candidates for intensified cancer screening and prevention.
Funding: The Highly Active Antiretroviral Therapy Oversight Committee, The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The Brighton HIV Cohort, The National Croatian HIV Cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The Isabel Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort, The University of Cologne HIV Cohort, Merck Life Sciences, ViiV Healthcare, and Gilead Sciences.
Background: Machine Learning (ML) can contribute to reducing child mortality and morbidity in low- and middle-income countries (LMICs), yet its development and clinical adoption remain unclear. This systematic review provides an overview of ML for hospitalised children in LMICs.
Methods: In June 2025, searches in five scientific databases and one scholarly search engine identified 26 eligible peer-reviewed studies using ML on hospitalised children under 18. Studies using only conventional statistics and perinatal data were excluded. Study quality and bias were assessed using PROBAST + AI. Descriptive statistics were used for data analysis. PRISMA reporting guideline was followed.
Findings: These studies were conducted in Asia (58%) and Sub-Saharan Africa (38%), mostly retrospective (62%), and predominantly used patient files (62%). The median sample size was 1291. Prognostic models dominated (69%), primarily targeting mortality (50%). Ensemble methods were most common (50%). The median AUROC was 0.81 (IQR 0.78-0.83). Most models were at a clinical Readiness Level 3-4 (81%). Barriers and facilitators related to data (65%, 34% respectively), implementation (50%, 77%), technology (31%, 42%), and human (19%, 35%) were reported.
Interpretation: We provided evidence of ML's promising performance for LMICs. Mortality prediction was the main focus. Arriving at clinical applications that benefit LMICs, requires investment in high-quality data and alignment to local (clinical) needs.
Funding: This project is part of the EDCTP2 programme (grant number RIA2020I-3294 IMPALA) supported by the European Union.
Background: Understanding experiences of diagnostic investigation for any new screening modality is important to inform the development of pathways for future implementation. We explored experience of diagnostic work-up within the NHS in people with a cancer signal detected result from a blood-based multi-cancer early detection (MCED) screening test in the NHS-Galleri trial (NCT05611632).
Methods: A subset of 41 participants with a cancer signal detected result (with/without a cancer diagnosis), were interviewed 6-months after their result. Participants described their experiences of diagnostic investigation within the NHS. Reflexive Thematic Analysis was used.
Findings: The journey through the period of diagnostic investigation was extremely varied since this was dependent on the predicted cancer site(s). Participant narratives demonstrated wide variation in the required tests, number of contacts with healthcare staff and duration of the whole process. Five themes were interpreted from participants' narratives: i) Feeling prepared for procedures; ii) Needing to advocate; iii) Needing to self-navigate: iv) Speed of the diagnostic process and having to wait; v) Reaching 'the end' of diagnostic work-up.
Interpretation: If MCED screening is implemented in future, it will be important to carefully consider implementation of appropriate diagnostic investigation for patients who have a cancer signal detected. We recommend minimising the length of the diagnostic testing period, offering patient navigation and formulating clear plans for what happens at the end of the patient journey. While our findings highlight important considerations to support positive experiences for those having follow-up tests after a cancer signal detected result, they also have broader application for improvement of cancer diagnostic pathways more generally.
Funding: This work was funded and sponsored by GRAIL Bio UK, Ltd. as a sub-study within the NHS-Galleri trial. GRAIL funded the costs of the data collection as well as staff salaries through a contract with King's College London/Queen Mary University of London.
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