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Individuals with compromised immune systems are particularly vulnerable to COVID-19. Although several studies have assessed factors associated with COVID-19-related hospitalisation and mortality in the general population, few studies have focused specifically on immunocompromised populations. With the approval of NHS England, we conducted a cohort study using the OpenSAFELY platform covering successive waves of COVID-19 (wave 1, alpha, delta, omicron BA.1/BA.2, JN.1). In each wave, we included adults in five hierarchically assigned immunocompromised subgroups: solid organ transplant (SOT); bone marrow compromise (BMC); active radio- or chemo-therapy (RCT); active immunosuppressive medication (IMM); and primary or acquired immunodeficiency (IMD). In each subgroup, we estimated wave-specific rates of severe COVID-19-related outcomes and relative hazards according to vaccination status, sociodemography (age, ethnicity, deprivation), and comorbidities, as determined at the start of the wave. We included between 475,360 (BA.1/BA.2 wave) and 508,545 (JN.1 wave) immunocompromised individuals per wave. Across successive waves, individuals with SOT, BMC, or RCT exhibited higher rates of severe COVID-19 than those with IMM or IMD. Compared with being unvaccinated in the past 26 weeks, vaccination in the 12 weeks preceding the start of a wave was associated with a consistent reduction in severe COVID-19, albeit with a smaller effect size among SOT recipients relative to other subgroups. Though attenuated compared to earlier waves, this association persisted during JN.1 dominance (adjusted hazard ratios of 0.88 [95% CI 0.60-1.30] for SOT, 0.64 [95% CI 0.53-0.77] for BMC, 0.68 [95% CI 0.44-1.03] for RCT, 0.68 [95% CI 0.52-0.88] for IMM, and 0.68 [95% CI 0.55-0.82] for IMD). Older age and increased comorbidity count were strongly associated with increased risk of severe COVID-19 across subgroups and waves. The risk of COVID-19 varies substantially within and across immunocompromised subgroups. The presence of other comorbidities was strongly associated with the risk of severe COVID-19 across successive waves. Primary vaccination and successive booster doses were associated with a consistent reduction in severe COVID-19 in this high-risk population, including during the JN.1 wave. National Institute for Health and Care Research (NIHR) Health Protection Research Unit in Vaccines and Immunisation (NIHR200929/NIHR207408).

The Alzheimer's Disease Neuroimaging Initiative (ADNI) recently celebrated its 20th anniversary, reflecting two decades of major contributions to Alzheimer's research through open data sharing and longitudinal multimodal assessments. This review synthesizes 122 high-impact studies using ADNI data or biospecimens from 2023 to mid-2025 to clarify mechanisms of Alzheimer's disease (AD) progression. Studies describe impairment of glymphatic clearance and the impact of cerebral small vessel disease, trajectories of amyloid beta and tau deposition, inflammation, metabolic disturbances, synaptic dysfunction, and neurodegeneration, leading to cognitive impairment and neuropsychiatric symptoms. Multifactorial contributions from genetic and epigenetic influences, co-pathologies and comorbidities, and mechanisms of resilience modulate disease progression. Finally, heterogeneity of clinical presentation and disease course is described in the context of multiple contributing factors, highlighting the complexity of AD. By integrating imaging, fluid biomarkers, genetics, and clinical measures, ADNI provides a comprehensive research dataset for unraveling mechanisms underlying AD progression.

The need for detailed built-up area data for applications such as population modelling, urban planning, and environmental research is growing due to the pace of global population changes, particularly in the Global South, where existing datasets have limitations. Here, we processed the Google Open Buildings Temporal (OBT) dataset to derive six 100-m spatial resolution datasets per year on building characteristics. The characteristics include building count, total perimeter, total area, total volume, height variance, and mean distance to the nearest building edges. These were calculated using arithmetic operations, convolutions, and spatial aggregation. The derived data was validated against a set of existing largescale open spatial datasets on buildings and human settlement extents for single timepoints. Additionally, temporal consistency was assessed, with polynomial fitting explored to test suitability for smoothing the data where significant fluctuations were seen. The new dataset strongly correlated with the Google Open Buildings Polygons dataset (e.g., building count: r = 0.88; building area: r = 0.90) but showed systematic perimeter underestimation in dense areas due to blending effects. Weaker correlations were found with other datasets due to methodological differences. Internally, building height variance correlated moderately with total volume ( r = 0.47). A strong positive correlation ( r > 0.8) existed between building count, area, volume, and population. Temporal analysis revealed significant fluctuations in most characteristics, especially height-related metrics, with second-order polynomial fitting proving optimal for smoothing. A validated 100-m resolution building characteristics dataset for the Global South, covering each year from 2016 to 2023, derived from Google OBT, was produced. While showing consistency with similar largescale spatial datasets, temporal fluctuations indicate a need for further processing for time-series applications.

Combined therapy with delamanid, bedaquiline, and quabodepistat (DBQ) showed potent early bactericidal activity and was well tolerated in a phase 2a, 14-day early bactericidal activity trial in participants with drug-susceptible pulmonary tuberculosis. This subsequent proof-of-concept trial evaluated the efficacy and safety of a 4-month, three-dose level regimen of DBQ in participants with drug-susceptible pulmonary tuberculosis compared with 6 months of the standard of care. This open-label, randomised, proof-of-concept, non-inferiority, phase 2b/c trial was conducted at six clinical research sites in South Africa. Adults aged 18-65 years with newly diagnosed, drug-susceptible pulmonary tuberculosis were recruited by research sites from community tuberculosis clinics. Participants were randomly assigned (1:2:2:1) by balanced block randomisation (block size six) to receive oral delamanid (300 mg once a day) and bedaquiline (400 mg once a day for 2 weeks then 200 mg three times a week) plus quabodepistat at once-daily doses of 10 mg (DBQ10 group), 30 mg (DBQ30 group), or 90 mg (DBQ90 group) for 4 months; or 6 months of RHEZ (rifampicin, isoniazid, ethambutol, and pyrazinamide for 8 weeks followed by 18 weeks of rifampin and isoniazid). All drugs were administered orally. Masking procedures were not used, although microbiology laboratory staff were masked to treatment assignment. The primary endpoints were the proportion of participants reaching sputum culture conversion by the end of the treatment period in the modified intention-to-treat (mITT) analysis set and safety in the safety analysis set. Non-inferiority, with a margin of 12%, was assessed for the primary endpoint in the mITT analysis set, comparing the pooled DBQ group and the RHEZ group using a two-sided 80% CI. This study was registered at ClinicalTrials.gov, NCT05221502, and is complete. Between April 12, 2022, and May 19, 2024, 306 individuals were screened, of whom 122 were enrolled and randomly assigned: 20 to the DBQ10 group, 42 to the DBQ30 group, 39 to the DBQ90 group, and 21 to the RHEZ group. 121 participants received at least one dose of study drug and comprised the mITT analysis set. At the end of the treatment period, the proportion of participants with sputum culture conversion was 100·0% (95% CI 83·2-100·0, all 20 participants) in the DBQ10 group, 92·9% (80·5-98·5, 39 of 42 participants) in the DBQ30 group, 97·4% (86·2-99·9, 37 of 38 participants) in the DBQ90 group, 96·0% (90·1-98·9, 96 of 100 participants) in the pooled DBQ group, and 100·0% (83·9-100·0, all 21 participants) in the RHEZ group. The comparison between the pooled DBQ group and the RHEZ group met non-inferiority for the primary endpoint (difference -4·0% [80% CI -7·4 to 3·4]). Adverse events were mostly mild to moderate, with no serious adverse events or discontinuations attributed to trial medications. Rates of adverse events of grade 3 or higher were 20% (four of 20 participants) in the DBQ10 group, 14% (six of 42 participants) in the DBQ30 group, 11% (four of 38 participants) in the DBQ90 group, and 5% (one of 21 participants) in the RHEZ group. One participant (in the DBQ90 group) died after worsening pulmonary tuberculosis with pneumonia, which was assessed as not related to study treatment. 105 (87%) of 121 participants had at least one treatment-emergent adverse event: 17 (85%) of 20 in the DBQ10 group, 37 (88%) of 42 in the DBQ30 group, 30 (79%) of 38 in the DBQ90 group, and all 21 (100%) participants in the RHEZ group. The most common treatment-emergent adverse events in the total population of 121 participants were upper respiratory tract infection (n=36, 30%), headache (n=24, 20%), and diarrhoea (n=12, 10%). In this proof-of-concept study, 4 months of DBQ showed a promising end-of-treatment non-inferiority signal versus 6 months of RHEZ and was generally well tolerated. Our results support further studies of quabodepistat as a potential component of new treatment-shortening regimens for tuberculosis. Otsuka Pharmaceutical Development & Commercialization, with partial funding from the Gates Foundation.

This paper presents a participatory method for conducing a collaborative and culturally appropriate dialogue process between gene drive researchers and Indigenous Peoples and local communities. Coordinated by the Outreach Network for Gene Drive Research and representatives of the International Indigenous Forum on Biodiversity (IIFB), this dialogue aimed to build trust and facilitate mutual understanding and create a safe space for sharing traditional knowledge, rather than to reach decisions on the research or implementation of gene drive technology. Over a three-year period, the dialogue evolved through multiple formats, recognising the specific needs to establish a meaningful and culturally appropriate dialogue between these two groups, while ensuring that Indigenous Peoples and local communities could share their traditional knowledge, traditions and innovations in a safe and trusted environment. The method integrates key engagement principles - such as good faith, reciprocity, inclusivity, and respect for Indigenous Peoples and local communities' knowledge systems - and describes how they were operationalised in practice. It provides a concrete example of applied engagement methodology in the context of gene drive and explores how these principles have influenced the dialogue's format and the journey of both groups throughout this process, while also sharing some of the challenges they encountered. This is not a theoretical review, but a joint account from practitioners from diverse backgrounds and interests, on how engagement methods can be implemented in real-world settings. The approach offers practical insights for designing sustained and scalable engagement strategies between scientists and Indigenous Peoples on complex and emerging science topics.

Neglected Tropical Diseases disproportionately affect populations in Africa and other low- and middle-income countries. Machine learning has potential to improve disease prediction, detection and control, but its use in neglected tropical disease research remains poorly characterized. This scoping review examines the current landscape of machine learning applications for neglected tropical diseases in Africa, identifying trends, gaps and opportunities for future research and implementation. We conducted a scoping review using Joanna Briggs Institute methodology. PubMed and cited references were searched for studies applying machine learning to neglected tropical diseases in Africa. After screening and eligibility assessment, 77 studies were included in the qualitative synthesis. Here we show that most studies focus on schistosomiasis, leishmaniasis, lymphatic filariasis, and soil-transmitted helminthiases. Geo-risk prediction is the most common application while a few studies address disease detection and none focus on drug discovery or intervention optimization. Tree-based and Maximum Entropy models are the most frequently used and commonly reported as best performing. Most studies use small datasets. African institutional leadership, open sharing of data and source code, engagement of programmatic and policy stakeholders, and deployment of models in real-world settings remain limited. Machine learning research for neglected tropical diseases in Africa remains concentrated in a few diseases and applications, with limited translation into practice. Greater investment in local capacity building, equitable collaborations, open data sharing, transfer learning, deployment-focused research, and standardized machine learning workflows could enhance the real-world impact of machine learning for neglected tropical diseases control and elimination. Neglected tropical diseases (NTDs) affect millions of people, especially in Africa and other low- and middle-income countries (LMICs). Machine learning (ML), a form of artificial intelligence, can help prevent and control these diseases. We reviewed published studies to understand how ML is being used for NTDs in Africa. We identified 77 studies, most of which focused on predicting where diseases are likely to occur. Few studies developed tools for diagnosis, treatment planning, or real-world healthcare use. We also found limited involvement of African research institutions and low sharing of data and computer code. Our findings show that ML could improve NTD control, but stronger collaborations, better data sharing and local capacity building, are needed to ensure impact in affected communities.

Recent mpox outbreaks highlight the need for novel, effective, and scalable vaccines against monkeypox virus (MPXV). The quadrivalent mRNA vaccine candidate BNT166a encoding MPXV antigens A35, B6, M1, and H3 was selected for clinical development based on evidence of immunogenicity and protective efficacy against multiple orthopoxviruses in preclinical models. We aimed to investigate the safety and immunogenicity of BNT166a in healthy adults. In this open-label, uncontrolled, non-randomised, dose-escalation, first-in-human, phase 1 trial, we included healthy adults with no history of mpox, smallpox, or vaccinia virus (VACV) infection. We assigned VACV-naive participants (ie, individuals with no history of smallpox or mpox vaccination) to receive two intramuscular injections of 10 μg, 30 μg, or 60 μg BNT166a 4 weeks apart, and we assigned VACV-experienced participants (ie, individuals with a history of smallpox vaccination and no other orthopoxvirus vaccination) to receive two 30 μg BNT166a injections 4 weeks apart. The primary endpoints were solicited reactions within 7 days and unsolicited adverse events within 28 days after vaccination in participants who received at least one BNT166a vaccination. Exploratory endpoints of binding and neutralising antibody titres were assessed until 12 months after the second dose in participants who received both BNT166a vaccinations. This trial is registered with ClinicalTrials.gov, NCT05988203, and is ongoing. Of 159 individuals screened for eligibility between Sept 21, 2023, and March 14, 2024, 48 VACV-naive participants (median age 35 years [IQR 24·0-39·0], 24 [50%] men, and 24 [50%] women) and 16 VACV-experienced participants (median age 58 years [54·5-60·5], five [31%] men, and 11 [69%] women) were enrolled, all of whom received at least one BNT166a vaccination. Among VACV-naive participants, local reactions (grade ≥1) were reported in eight (50%) of 16 participants in the 10-μg group, 13 (81%) of 16 in the 30-μg group, and 14 (88%) of 16 in the 60-μg group after the first dose, and in nine (60%) of 15 participants in the 10-μg group, 12 (86%) of 14 in the 30-μg group, and 13 (93%) of 14 in the 60-μg group after the second dose. Local reactions were reported in 11 (69%) of 16 VACV-experienced participants after the first dose and 14 (88%) of 16 after the second dose. Among VACV-naive participants, systemic events were reported in ten (63%) of 16 participants in the 10-μg group, seven (44%) of 16 in the 30-μg group, and 11 (69%) of 16 in the 60-μg group after the first dose, and in 11 (73%) of 15 participants in the 10-μg group, 13 (93%) of 14 in the 30-μg group, and 14 (100%) of 14 in the 60-μg group after the second dose. Systemic adverse events were reported in seven (44%) of 16 VACV-experienced participants after the first dose and in 13 (81%) of 16 after the second. Most events were mild to moderate in severity; two participants in the 60-μg group reported systemic events of grade 3 or worse after the second dose (one reported grade 3 fatigue and grade 3 fever and the other reported grade 4 fever). Adverse events considered BNT166a-related within 28 days of either vaccination were experienced by 18 (28%) participants; all but one (grade 3 neutropenia in a 60-μg dose recipient) were mild to moderate in severity. Three participants (two 10-μg dose recipients and one VACV-experienced participant) had serious adverse events, none of which were considered related to vaccination. BNT166a induced binding antibodies against all four mRNA-encoded antigens in all participants, with a 100% seroresponse rate 2 weeks after the second dose; titres persisted until 12 months after the second dose. MPXV clade IIb neutralising antibodies were detected in eight (62%) of 13 VACV-naive participants in the 10-μg group, ten (71%) of 14 in the 30-μg group, and 11 (92%) of 12 in the 60-μg group, and in 14 (93%) of 15 VACV-experienced participants. VACV neutralising antibodies were detected in six (46%) of 13 VACV-naive participants in the 10-μg group, 11 (79%) of 14 in the 30-μg group, and 12 (100%) of 12 in the 60-μg group, and in 14 (93%) of 15 VACV-experienced participants. MPXV and VACV neutralising titres peaked at 2 weeks after the second dose in the VACV-naive groups and at 1 month after the second dose in the VACV-experienced group and declined towards baseline concentrations in all groups over 12 months after the second dose. In both VACV-naive and VACV-experienced participants, BNT166a was well tolerated, with local and systemic reactogenicity events occurring more frequently after the second dose than the first. BNT166a efficiently induced multiantigen-directed MPXV antibodies, which persisted until 12 months. MPXV clade IIb and VACV neutralising capacity was shown but with waning long-term responses. The overall safety and immunogenicity profile supported BNT166a's advancement to phase 2 trials. BioNTech and the Coalition for Epidemic Preparedness Innovations.

This analysis evaluated the effects of olokizumab (OKZ) on patient-reported outcomes (PROs) after up to 106&#xa0;weeks of treatment in patients with active rheumatoid arthritis (RA) refractory to methotrexate (MTX; MTX-inadequate response [MTX-IR]) or refractory to tumor necrosis factor inhibitor (TNFi; TNFi-inadequate response [TNFi-IR]). Post-hoc analysis was performed of pooled PROs from phase III, double-blind, placebo-controlled trials (CREDO1/2 MTX-IR; CREDO3 TNFi-IR; NCT02760368/ NCT02760407/NCT03225932) and their open-label extension (OLE; up to 106&#xa0;weeks) in adults with active RA despite treatment with MTX or TNFi. Patients were treated with OKZ 64&#xa0;mg every 2 weeks (q2w) or every 4 weeks (q4w)&#x2009;+&#x2009;MTX versus MTX&#x2009;+&#x2009;placebo (weeks 0-24) or active comparator (CREDO2), followed by an OLE (all OKZ). The PROs analyzed were patient global assessment; pain (visual analog scale); Health Assessment Questionnaire Disability Index (HAQ-DI); 36-Item Short Form Health Survey (SF-36); Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (FACIT-F); Work Productivity Survey Rheumatoid Arthritis (WPS-RA) and the European Quality of Life-Five-Dimension Questionnaire (EQ-5D). Changes from baseline at weeks 12, 24 and 106 were analyzed using a mixed model for repeated measures; analyses included percentages of patients reporting improvements &#x2265; minimal clinically important difference (MCID). By week 12, treatment with OKZ compared to placebo (PBO) resulted in greater numerical and clinically meaningfully changes from baseline in all PROs for patients refractory to MTX: the HAQ-DI was -&#x2009;0.60 for OKZ q2w, -&#x2009;0.58 for OKZ q4w and -&#x2009;0.34 for PBO; pain VAS was -&#x2009;33.26, -&#x2009;32.51, -&#x2009;18.39, respectively; and the FACIT-F was 8.47, 8.42 and 4.69, respectively (p&#x2009;<&#x2009;0.0001). Similar but less prominent improvements were noted in the patients with TNFi-IR. Post hoc analyses demonstrated a higher proportion of patients receiving OKZ reported improvements&#x2009;&#x2265;&#x2009;MCID versus those receiving PBO (p&#x2009;<&#x2009;0.05) in all PROs in both groups at week 12. For patients treated with OKZ, the observed improvements from baseline were maintained and increased in magnitude through week 106. Treatment with OKZ over 106&#xa0;weeks resulted in sustained numerically greater and clinically meaningful improvements in PROs compared to baseline in both RA patients with MTX-IR and those with TNFi-IR. These findings support the long-term benefit of OKZ on PROs. ClinicalTrials.gov identifiers NCT02760368, NCT02760407, NCT02760433, NCT03120949.

Combination therapy of glucokinase activators and sodium-glucose cotransporter-2 inhibitors may exhibit potent glucose-lowering effects and improvement of &#x3b2;-cell function and insulin sensitivity in patients with type 2 diabetes mellitus, given their complementary mechanisms of action. However, the safety, pharmacokinetic interactions and pharmacodynamic effects of such combinations remain unexplored. To address this gap, we conduct an open-label, sequential phase I trial (ClinicalTrials.gov, NCT03790787 ) evaluating the dorzagliatin and the sodium-glucose cotransporter-2 inhibitor empagliflozin in patients with type 2 diabetes mellitus and obesity in the US. After strict screening against the inclusion/exclusion criteria, 16 participants are deemed eligible. Participants receive sequential treatments-empagliflozin alone, empagliflozin plus dorzagliatin, and dorzagliatin alone-five days for each regimen, followed by a comprehensive assessment of pharmacokinetic profiles and safety. The primary outcomes included GMR for Cmax and AUC0-24h of empagliflozin and dorzagliatin of pharmacokinetic parameters and the incidence of adverse events, abnormal vital signs, abnormal clinical laboratory findings, and 12-lead electrocardiogram abnormalities of safety profile. A total of 27 adverse events occurs in 9 participants (56.3%), the majority of which are mild, with the exception of one case of moderate constipation. No clinically significant findings or changes attributable to study drug treatment were found in clinical chemistry, hematology and urinary analyses, and observed in vital signs, 12-lead electrocardiogram and physical examination. The geomean ratio and their associated 90% confidence intervals for both maximum plasma concentration (empagliflozin: 98.43% (84.07%, 115.25%); dorzagliatin: 103.94% (90.45%, 119.44%)) and area under the concentration-time curve from 0 to 24&#x2009;h (empagliflozin: 97.53% (94.35%, 100.82%); dorzagliatin: 99.65% (95.25%, 104.25%)) of empagliflozin and dorzagliatin fall entirely within the conventional bioequivalence range of 80.00% to 125.00%. No pharmacokinetic drug-drug interaction is observed, and the treatment exhibits a favorable safety profile with good overall tolerability.

With an estimated 41.1B digital devices, the term "digital biomarkers" has been increasingly bandied about in the research literature. There is, however, a significant disconnect between the presumption of digital biomarkers and the reality of digital biomarkers. The research literature embraces the concept of digital biomarkers without concomitant evidence for validation of digital measures as biomarkers. Unlike imaging or blood-based biomarkers, there is a woeful lack of research dedicated to validating digital measures as biomarkers. This gap also presents an opportunity. Regulatory agencies worldwide have long-standing protocols used by pharmaceutical and biotech companies to stand up quality management systems (QMS) that track research from inception to regulatory approved submissions. The recent United States (US) Food and Drug Administration (FDA) approval of Alzheimer's disease (AD) plasma biomarkers is another example where successful QMS implementation provided the processes and transparency necessary to obtain approval. Regulatory guidelines for digital technology validation are more circumspect on validation pathways of AD digital biomarkers, but FDA provides a framework for building a QMS that could potentially do so. Building an open source QMS for AD digital biomarker validation will be a critical breakthrough for harnessing the potential of digital technologies for detection, monitoring and treatment of AD and related disorders.

The homotetrameric thermosensitive transient receptor potential vanilloid 2 (TRPV2) channel is a biological macromolecule with unique high temperature threshold and sensitivity. However, the underlying thermodynamic basis has not been well understood. In this computational study, the 3D cryo-EM structures of rat TRPV2 in response to various chemical perturbations at different sites at low temperatures were quantified at the tertiary and quaternary levels using a highly sensitive thermoring model. The results indicated that a putative stable pre-open closed state without a lipid at the well-known active vanilloid site exhibited at least three weakest tertiary noncovalent bridges on the protein surface as primary thermal sensors with matched thresholds for initial heat activation. Any chemical perturbation away from these sensors activated the channel but with lower cold sensitivity. In contrast, when the sensors were simultaneously exposed to a mild detergent, together with hydrolysis of nearby charged residues at the membrane surface, the channel could be opened with the unique high cold sensitivity similarly to mirror the initial heat sensation. Further, disrupting intersubunit interactions near the heat sensors was required for full channel opening at both upper and lower gates. Therefore, the heat capacity mechanism, once cross-examined, could be applied to elucidate the unique thermoring basis for the sharp heat response of thermosensitive TRPV2 above body temperature.

Current research suggests that post-treatment HIV control may be possible for some people following antiretroviral treatment (ART) interruption. Although closely monitored analytic treatment interruption (ATI) studies can be performed safely and are crucial to determine who may no longer require ART, currently it is unknown how acceptable these studies will be in Botswana. To determine the knowledge, attitudes and acceptability of ATI-inclusive studies in Botswana. We employed a non-randomized purposive design to recruit study participants. We conducted face-to-face open-ended interviews with 12 young people living with HIV and 8 caregivers, 8 healthcare providers and 4 community advocates in Gaborone and Palapye. Thirty-two (32) participants consented to be interviewed. The median age of young people living with HIV was 29 years. All young people living with HIV indicated that they were on ART and acknowledged the benefits of being on ART. All young people living with HIV were unaware of ATIs, whereas 6 out of 8 caregivers, 6 out of 8 healthcare providers and 2 out of 4 community advocates had never heard of ATIs. Most participants found ATI research to be acceptable and believed that it would be beneficial provided there were adequate risk mitigations in place. ATI studies were acceptable to both young people living with HIV and their caregivers. There was limited knowledge about ATI, highlighting a need to inform communities and health care providers on the scientific aspects of ATI and HIV cure research.

BACKGROUND: Alzheimer&#x2019;s disease and related disorders (ADRD) pose a growing global health challenge, with cases expected to nearly triple by 2050. Early detection is critical for improving outcomes, yet most cases remain undiagnosed. Integrating routine cognitive assessments into primary care can provide timely access to treatments, and improve disease management and patient outcomes. The Davos Alzheimer&#x2019;s Collaborative Healthcare System Preparedness (DAC-SP) program created an Early Detection Blueprint (dacblueprint.org), a digital, open-access microsite which translates evidence-based implementation strategies and resources into a practical operational guide for healthcare systems to establish early detection programs in primary care. METHODS: To help bridge the gap between research and real-world practice, DAC-SP launched the US Early Detection of Cognitive Impairment Program in September 2024. This program supports 10 diverse healthcare systems across the United States through grant funding and a core curriculum including self-directed, peer and expert learning to design, implement, and sustain routine cognitive assessment programs in primary care settings. Informed by the Consolidated Framework for Implementation Research (CFIR), program evaluation data will be collected via surveys, monthly implementation reports, and semi-structured qualitative interviews. Using a concurrent mixed-methods program evaluation, this study will assess the implementation outcomes of adoption, implementation, and sustainability of the routine cognitive assessment programs across sites. RESULTS: The US Early Detection Program is expected to conclude in July of 2026, with sustainability assessments completed by December 2026 and results by March 2027. Findings will include cross-site changes in the number of routine cognitive assessments completed over time and changes in healthcare provider attitudes towards early detection and implementation of adapted clinical workflows. Additional learnings from the US Early Detection Program will include barriers and facilitators to the early detection of cognitive impairment in primary care, and site-specific factors that influenced adoption of routine cognitive assessments across diverse practice settings. Cross-site learnings and feedback will inform revisions to a US-specific version of the Early Detection Blueprint for future US healthcare systems. CONCLUSION: The DAC-SP US Early Detection Program aims to modernize detection, diagnosis, and care of Alzheimer&#x2019;s disease and related disorders by expanding the routine use of cognitive assessments in primary care and generating actionable insights to drive improvements across the US healthcare landscape.

Alzheimer's disease (AD) continues to pose a major public health challenge. Since its launch in 2004, the Alzheimer's Disease Neuroimaging Initiative (ADNI) has played a pivotal role in advancing the field by providing a comprehensive, open-access, longitudinal dataset that integrates neuroimaging, biomarker, genetic, and clinical data related to AD. We used standard literature search methods to identify &#x223c;1830 publications from 2023 to mid-2025 that used ADNI data or samples. This review highlights key ADNI studies with direct clinical applications. We describe how these have impacted the development and validation of plasma biomarkers, improved clinical trials, assessed AD therapies, and developed methods for diagnosis and prediction using clinical, fluid, and imaging biomarkers. These contributions are underlain by an improved understanding of biological mechanisms of disease progression in AD and highlight ADNI's central role in advancing translational research and accelerating progress toward more effective, individualized care for patients with AD.

Adjustable-volume prosthetic sockets are designed to address residual limb volume fluctuations that temporarily alter socket fit. These systems are relatively new to the market and their global use, and the type of patient they work best for, remains unclear. This study explored global experiences and perspectives on fitting different styles of commercially available adjustable-volume prosthetic sockets. An online survey was distributed globally to prosthetists. The survey asked about experiences with adjustable sockets, including successes, challenges, and barriers faced when fitting, and the impact of amputation level on success. Responses were statistically compared between United States (US) and non-US respondents. Of 195 valid responses, 66.7% were from the US. Eighty-five percent of respondents had fit an adjustable socket, with those in the US more likely to fit them than those outside of the US (p = 0.001). Reported success rates ranged from 40.0% to 75.1% depending on the socket style, with no significant differences between US and non-US respondents or between amputation levels. Open-ended feedback highlighted the importance of patient selection, the timing of use, and differing views on the implications of prefabricated designs for clinical practice and access to care. Globally, prosthetists report moderate success in fitting a variety of lower limb adjustable-volume sockets at different levels of amputation. As the market for adjustable-volume sockets continues to expand, further research is warranted to evaluate long-term outcomes across styles and amputation levels to better inform global prescription practices.

Ultra-low-field (ULF) MRI facilitates neuroimaging access, yet its application in early infancy is constrained by low resolution and contrast, and the limited suitability of existing segmentation tools. In this work we introduce and validate miniMORPH, an open-source pipeline for automated brain volumetry from 0.064T T2-weighted MRI acquired across infancy and toddlerhood. ULF scans were acquired from infants aged 2 to 27 months across two cohorts in South Africa and Uganda. Age-specific templates and priors were used to segment major brain tissues and substructures. Validation used two high-field (HF) references: (i) expert manual HF segmentations for key ROIs across ages, and (ii) automated HF segmentations from SuperSynth on paired HF-ULF scans. We quantified (a) between-subject ordering across modalities using Pearson's correlation (r) and (b) systematic scaling differences using percentage error (PE) and time-corrected percentage error (CPE), stratifying performance by cohort and age. Face validity was also tested via mixed-effects models of age, sex, and birthweight. miniMORPH generated anatomically plausible segmentations of major brain regions across infancy. In paired HF-ULF comparisons, between-subject ordering was generally preserved across many ROIs, with stronger correspondence in the South African cohort than in the Ugandan cohort at 12 months. Systematic scaling offsets were most evident in CSF-rich or boundary-sensitive compartments, with consistently negative CPE for ventricles and cerebellum. Performance varied with age, showing the greatest variability at 3 months. miniMORPH successfully captured regional age-related growth trajectories. Sex-dependent volumetric differences were widespread but attenuated after intracranial volume correction. Low birthweight infants exhibited reduced regional volumes and altered growth trajectories. Taken together, these findings indicate that miniMORPH enables volumetric analysis of ULF infant MRI and preserves between-subject variation suitable for developmental and group analyses. ROI- and cohort-specific offsets, particularly in CSF-rich regions, may require calibration when absolute volumes are needed. The pipeline is openly available at https://github.com/UNITY-Physics/fw-minimorph.

Cooperative nanoparticle (NP) internalization offers a powerful route for drug delivery, yet whether its efficiency can be amplified by receptor-targeting of cargo remains a critical open question. Here, we demonstrate that modifying cargo NPs with a receptor-targeting ligand (RPARPAR for neuropilin-1) dramatically amplifies their bystander uptake initiated by TAT-functionalized NPs (T-NPs). The internalization of targeted silver NPs surged from &#x223c;10 to &#x223c;70 units per cell, compared to that of their nonfunctionalized counterparts from &#x223c;2 to &#x223c;20 units. Combining receptor perturbation experiments with coarse-grained molecular dynamics simulations, we reveal that ligand-receptor binding does not constitute an independent pathway but instead synergizes with membrane mechanics. It amplifies cooperative capture by tethering cargo to the cell surface, enhancing its susceptibility to engulfment within curvature-driven, low-free energy zones. Furthermore, we identify extracellular cysteine as a crucial metabolic checkpoint; its continuous availability is required to maintain cellular redox homeostasis, which gates the underlying macropinocytic machinery. Together, our findings establish an integrated, multilevel mechanism where receptor engagement, membrane mechanics, and cellular metabolism converge to drive highly efficient cooperative internalization. This framework provides rational design principles for engineering next-generation cooperative nanodelivery systems and offers fundamental insights into collective endocytic processes.

Group antenatal care (G-ANC) is an alternative model of antenatal care that incorporates clinical assessment and care, participatory learning, and peer support. It gives expectant mothers the opportunity to discuss and share experiences with a group of women of similar gestational age throughout the pregnancy. This pilot study aimed to explore the feasibility of introducing a six-meeting G-ANC model in health posts, the most basic level of the health system in Ethiopia. A qualitative study of G-ANC was conducted at five purposively selected health posts in two zones in the Amhara region of Ethiopia, involving 54 pregnant women aged 15&#xa0;years and older with a gestational age of less than 20&#xa0;weeks. Trained research staff moderated 13 in-depth and 7 key informant interviews that were conducted after the second of the six G-ANC meetings. All interviews and discussions were recorded with consent from participants. Transcribed interviews were translated and thematically analyzed using a framework with open code qualitative data analysis software aiding in data sorting, categorization, and coding. An adequate number of pregnant women were identified early in pregnancy and recruited to form G-ANC groups for this study. Pregnant women were willing to be enrolled and participate in G-ANC meetings and indicated interest in attending future meetings. Health extension workers (HEWs) demonstrated the ability to facilitate G-ANC meetings effectively. Introduction of G-ANC at the health post level appears feasible. None of the major anticipated feasibility challenges, adequate enrollment of eligible women, women's willingness to participate in successive meetings, and HEW capacity to facilitate, were encountered. Existing community structures were instrumental in achieving adequate enrollment. The training and G-ANC meeting guides enabled HEWs to effectively facilitate the meetings. Preliminary results from this pilot study informed the design of a stepped-wedge cluster randomized trial to evaluate the acceptability and effectiveness of G-ANC at the health post level on increased coverage of antenatal care and facility-based delivery.

Evidence linking household air pollution exposure and blood hemoglobin concentration is lacking. We examine the effect of a liquefied petroleum gas cookstove and fuel intervention on hemoglobin concentration, along with associations between household air pollution exposures and hemoglobin concentration, among pregnant women. We enroll 800 pregnant women each in Guatemala, Peru, India, and Rwanda in an open-label randomized controlled trial (NCT02944682). In 3178 women (intervention=1585; control=1593), we measure hemoglobin concentration and 24-hour personal exposure to particulate matter with an aerodynamic diameter &#x2264;2.5&#x3bc;m (PM2.5), black carbon (BC), and carbon monoxide (CO) at three timepoints (9-20, 24-28, and 32-36 weeks gestation). We evaluate the effects of the intervention on hemoglobin concentration and conduct exposure-response analyses to examine associations between 24-hour personal exposure to measured pollutants and hemoglobin concentration. We identify a significant increase in hemoglobin in the intervention group (0.074&#x2009;g/dL, 95% CI: 0.002, 0.145) compared to the control group. In exposure-response analyses, each 1ppm increase in CO exposure is associated with a 0.015&#x2009;g/dL (95% CI: 0.008, 0.023) increase in hemoglobin. In our analyses, neither PM2.5 nor BC are associated with hemoglobin concentration. Further research may be needed to examine the biological mechanisms underlying our findings.