To identify early-occurring healthcare and sociodemographic risk factors associated with lower extremity amputation (LEA) by analysing health trajectories up to 10 years before amputation.

A national, observational, registry-based matched case–control study.

The Danish universal healthcare system, using national health registers.

We included 2551 individuals who underwent first-time LEA in 2017–2018 and matched each to two control groups: (1) The Community Controls Group representing the average population who were matched on age, sex and municipality (n=12 748) and (2) a Diabetes Mellitus/Peripheral Arterial Disease (DM/PAD) Control Group matched on age, sex and DM or PAD duration (n=12 478) representing a high-risk population.

Presence of healthcare, sociodemographic and medication-related risk factors associated with LEA was evaluated across three time periods leading up to amputation: the Immediate (0–2 years prior), Early (2–5 years prior) and Long-term (5–10 years prior) risk period.

Polypharmacy and antibiotic use—particularly dicloxacillin targeting Staphylococcus aureus—were strongly associated with LEA across all time periods. Dicloxacillin was prescribed on average 7.8 years prior to major amputation, with long-term ORs of 2.99 (95% CI 2.51 to 3.56) and 2.07 (95% CI 1.75 to 2.46) compared with community and DM/PAD controls. Opioid and paracetamol use also showed strong associations. Individuals with LEA were more likely to live alone and have lower educational attainment. Frequent dental visits were inversely associated with risk.

This study identifies characteristics associated with LEA, including long-term exposure to dicloxacillin and opioid analgesics, alongside polypharmacy and socioeconomic disadvantage. These factors were detectable up to 10 years before amputation and may serve as early indicators for risk identification and guide targeted general practitioner interventions.

Tuberculosis (TB) remains a significant public health challenge in many African communities, where underreporting and underdiagnosis are prevalent due to barriers in accessing care and inadequate diagnostic tools. This is particularly concerning in hard-to-reach areas with a high burden of TB/HIV co-infection, where missed or delayed diagnoses exacerbate disease transmission, increase mortality and lead to severe economic and health consequences. To address these challenges, it is crucial to evaluate innovative, cost-effective, community-based screening strategies that can improve early detection and linkage to care.

We conduct a prospective, community-based, diagnostic, pragmatic trial in communities of the Butha Buthe District in Lesotho and the Greater Edendale area of Msunduzi Municipality, KwaZulu-Natal in South Africa to compare two strategies for population-based TB screening: computer-aided detection (CAD) technology alone (CAD4TBv7 approach) versus CAD combined with point-of-care C reactive protein (CRP) testing (CAD4TBv7-CRP approach). Following a chest X-ray, CAD produces an abnormality score, which indicates the likelihood of TB. Score thresholds informing the screening logic for both approaches were determined based on the WHO’s target product profile for a TB screening test. CAD scores above a threshold prespecified for the CAD4TBv7 approach indicate confirmatory testing for TB (Xpert MTB/RIF Ultra). For the CAD4TBv7-CRP approach, a CAD score within a predefined window requires the conduct of the second screening test, CRP, while a score above the respective upper threshold is followed by Xpert MTB/RIF Ultra. A CRP result above the selected cut-off also requires a confirmatory TB test. Participants with CAD scores below the (lower) threshold and those with CRP levels below the cut-off are considered screen-negative. The trial aims to compare the yield of detected TB cases and cost-effectiveness between two screening approaches by applying a paired screen-positive design. 20 000 adult participants will be enrolled and will receive a posterior anterior digital chest X-ray which is analysed by CAD software.

The protocol was approved by National Health Research Ethics Committee in Lesotho (NH-REC, ID52-2022), the Human Sciences Research Council Research Ethics Committee (HSRC REC, REC 2/23/09/20) and the Provincial Health Research Committee of the Department of Health of KwaZulu-Natal (KZ_202209_022) in South Africa and from the Swiss Ethics Committee Northwest and Central Switzerland (EKNZ, AO_2022–00044). This manuscript is based on protocol V.4.0, 19 January 2024. Trial findings will be disseminated through peer-reviewed publications, conference presentations and through communication offices of the consortium partners and the project’s website (https://tbtriage.com/).

ClinicalTrials.gov (NCT05526885), South African National Clinical Trials Register (SANCTR; DOH-27-092022-8096).