Faculty Bibliography

BACKGROUND:Oral pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) provision via online pharmacies (henceforth online PrEP and PEP) offers promise in increasing biomedical HIV prevention coverage. In this study, we aimed to estimate the cost-effectiveness of online PrEP and PEP scale-up in western Kenya. METHODS:We adapted a network-based model, EMOD-HIV, to simulate online PrEP and PEP implementation from 2026 to 2036; costs and use of online PrEP and PEP and client characteristics were informed by the ePrEP Kenya pilot study, which evaluated online PrEP and PEP provision in Nairobi and Mombasa, Kenya. Other parameters were obtained from surveillance data and published literature. Eligible clients were aged 15-49 years reporting condomless sex with non-marital partners. We assumed online PrEP and PEP provision was implemented through public-private partnership, with the Kenya Ministry of Health providing PrEP and PEP drugs and service delivery costs paid by the online pharmacy (and charged to clients). We estimated HIV infections, HIV-related deaths, and disability-adjusted life-years (DALYs) averted compared with the baseline scenario of background oral PrEP only. We calculated incremental cost-effectiveness ratios (ICERs) assessing only costs incurred by the Kenya Ministry of Health over 35 years and used a supply-side threshold of US$500 per DALY averted. We calculated 95% uncertainty intervals (UIs) across 100 parameter sets. FINDINGS/RESULTS:Online PrEP and PEP was projected to reach population coverage of 0·7% (95% UI 0·7-0·8) for PEP and 0·3% (0·2-0·3) for PrEP and avert 13·9% (10·1-17·1) of HIV infections over 10 years. HIV-related deaths were reduced by 4·3% (95% UI 2·0-6·9) over the 35-year time horizon. The intervention was cost-effective from the Kenya Ministry of Health perspective (ICER $212 [95% UI 15-1409] per DALY averted). In a scenario assuming only online PEP availability (to isolate the effect of PEP), 11·6% (95% UI 8·6-15·2) of HIV infections were averted (ICER $210 [95% UI 41-3798] per DALY averted). The intervention remained cost-effective when varying PrEP and PEP effectiveness and assuming HIV testing and treatment disruptions. INTERPRETATION/CONCLUSIONS:Online PrEP and PEP can avert substantial HIV infections, even with low population coverage. PEP was responsible for most intervention health benefits, likely due to high observed demand for PEP compared with PrEP in the pilot study. Leveraging private retailers can be efficient for scaling up HIV prevention in an era of shrinking donor funding. FUNDING/BACKGROUND:Gates Foundation.

BACKGROUND:Road injuries are a leading cause of mortality and morbidity worldwide. Years of international efforts have aimed to strengthen policy engagement, including the 2020 UN General Assembly's proclamation of the Second Decade of Action for Road Safety (2021-30), targeting a 50% reduction in road traffic deaths and serious injuries by 2030. The aim of this study is to provide estimates to monitor progress and identify intervention gaps. METHODS:As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2023, we estimated incidence, mortality, and morbidity of road injuries for 204 countries and territories from 1990 to 2023. Four road injury types and 47 nature-of-injury categories were examined. Morbidity and mortality data from clinical records, vital registration, and police reports were harmonised using meta-analytic techniques to ensure consistency and correct for systematic bias. Incidence was modelled with the meta-regression tool Disease Modelling-Meta-Regression version 2.1 and cause-specific mortality with the Cause of Death Ensemble model, both incorporating location-specific covariates to support interpolation. Years of life lived with disability (YLDs) were estimated from the prevalence and severity of the nature of road injury, and years of life lost (YLLs) from the number of cause-specific deaths multiplied by the standard life expectancy at the age of death. Disability-adjusted life-years (DALYs) were the sum of YLLs and YLDs. All metrics were calculated with 95% uncertainty intervals (UIs). FINDINGS/RESULTS:In 2023, there were 50·9 million (95% UI 46·1-56·1) road injury incident cases, 1·34 million (1·04-1·58) deaths, and 75·3 million (59·8-89·2) DALYs globally. Road injuries were the leading global cause of death among males aged 10-39 years. Between 1990 and 2023, age-standardised incidence decreased by 38·3% (95% UI 36·9-39·7) and mortality decreased by 32·3% (6·1-49·0), but progress varied widely by World Bank income group. Mortality in low-income countries (43·8 [95% UI 31·7-56·0] deaths per 100 000 population) was approximately six times higher than in high-income countries (7·5 [7·1-7·9] deaths per 100 000), despite the high-income countries showing the highest age-standardised incidence rates (858·1 [95% UI 781·9-947·1] cases per 100 000). In the past decade, many countries achieved notable reductions in road injuries, but others, including Ghana and the USA, saw increases. More severe injuries tended to occur in low-income and middle-income countries. INTERPRETATION/CONCLUSIONS:Although global incidence, mortality, and DALY rates from road injuries have declined, progress remains uneven, with pronounced disparities across income groups reflecting systemic inadequacies in infrastructure, vehicle standards, enforcement, and post-crash care. Strengthening emergency response, improving road design, enforcing safety measures, and adapting policies to the evolving demographics remain essential. FUNDING/BACKGROUND:Gates Foundation.

INTRODUCTION AND AIMS/OBJECTIVE:The bidirectional relationship between periodontitis and chronic kidney disease (CKD) underscores the importance of oral health in CKD management. However, interdisciplinary collaboration between dental and nephrology professionals remains limited. This study assessed dental professionals' knowledge, clinical experiences, referral patterns, perceived barriers, and attitudes towards integrated oral-renal care. METHODS:A cross-sectional web-based survey was conducted internationally in Asia, North America, Africa, Europe, South America, and Australia from November 2025 to February 2026. The instrument explored demographics, clinical exposure to CKD/end-stage kidney disease patients, self-assessed knowledge and confidence, referral/communication patterns, barriers to coordination, and interest in interdisciplinary protocols. Data from 89 valid responses were analysed using descriptive and inferential statistical methods. RESULTS:Respondents were predominantly experienced practitioners (74.2% with >10 years of practice; 67.4% had treated CKD patients; 53.9% dialysis patients). The self-assessed composite knowledge-and-confidence score for oral-renal interactions was moderate (mean 7.67/12). Referrals from nephrologists and direct interdisciplinary communication were infrequent. Primary barriers included a lack of a clear point of contact (51.7%) and a lack of shared patient records (50.6%). Oral health was rated as very or moderately important in CKD management by 94.4% of respondents, and 100% expressed definite or possible interest in formal interdisciplinary care protocols. CONCLUSIONS:Despite moderate self-assessed knowledge and substantial clinical exposure, structural and systems-level barriers appear to impede the integration of oral-renal care. Dental professionals nevertheless demonstrate near-universal motivation for interdisciplinary collaboration and strong interest in formal care protocols. CLINICAL RELEVANCE/CONCLUSIONS:Findings highlight the need for educational initiatives, standardized referral pathways, interoperable records, and policy support to advance multidisciplinary care for CKD patients.

KEY POINTS/CONCLUSIONS:We developed assays to measure genetic variant effects on polycystin-1, the protein mutated in most autosomal dominant polycystic kidney disease. All tested pathogenic variants disrupted either polycystin-1 ciliary trafficking or channel function. Trafficking and channel function of some pathogenic variants was restored by low temperature culture to promote polycystin folding. BACKGROUND:Autosomal dominant polycystic kidney disease (ADPKD) is the leading monogenic cause of kidney failure and affects millions of people worldwide. Despite the prevalence of ADPKD, limited mechanistic understanding has hindered therapeutic development. Most ADPKD is caused by loss-of-function variants in polycystin-1 (PC1). METHODS:We developed assays that quantify the effect of nontruncating variants on PC1 ciliary localization, membrane trafficking, and polycystin channel function. RESULTS:We evaluated 29 nontruncating variants in PC1 and found that pathogenic variants disrupt two molecular phenotypes: ( 1 ) localization of PC1 at the primary cilium or ( 2 ) polycystin ion channel activity. Ciliary localization of a subset of polycystin variants was restored when cells were cultured at low temperature. A subset of variants with localization restored by low temperature formed functional channels. CONCLUSIONS:This study demonstrated that disruptions in polycystin ciliary trafficking and channel function are common causes of ADPKD. Defects in ciliary trafficking and channel function can be rescued for a subset of pathogenic variants, establishing a foundation for polycystin-targeted therapies in ADPKD.

β-Arrestins are multifunctional regulators of G-protein-coupled receptor (GPCR) signalling and orchestrate diverse downstream signalling events and physiological responses across the GPCR superfamily^1-3. Although GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GPCR kinases, direct chemical tools to modulate β-arrestin activities have remained conspicuously absent. Here we report the identification of small-molecule inhibitors that selectively target β-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical and structural analyses. These inhibitors disrupt β-arrestin engagement with agonist-activated GPCRs, impairing desensitization, internalization and β-arrestin-dependent physiological functions while sparing G protein-receptor coupling. Cryo-electron microscopy, molecular dynamics simulations and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a pocket within the central crest of β-arrestin1 formed by the middle, C and lariat loops, a critical receptor-binding interface, stabilizing a distinct conformation that is incompatible with full β-arrestin-receptor engagement. Together, these findings establish a mechanistic framework for β-arrestin modulation, reveal a novel allosteric site for structure-based drug design, and open new avenues for transducer-targeted, pathway-specific GPCR therapeutic agents.

INTRODUCTION/BACKGROUND:Traumatic dental injuries (TDIs) require prompt and accurate guidance, yet little is known about how the prompting influences the quality of artificial intelligence (AI) chatbot responses in these situations. METHODS:Four dental trauma scenarios were developed by expert endodontists. For each scenario, a series of questions was posed to 4 AI chatbots (Claude Sonnet 3.5, Microsoft Copilot, GPT-4, Gemini Pro 2.5) using 2 approaches: unprompted layperson phrasing (n = 10) and endodontist's prompts referencing International Association of Dental Traumatology guidelines (n = 10). Responses were independently evaluated by 2 raters for validity, completeness, and relevance using a 5-point ordinal scale. RESULTS:Scores (n = 1920) of responses to endodontist questions were associated with significantly higher odds of receiving superior ratings across all 3 domains: validity (odds ratio [OR] = 1.82; 95% confidence interval [CI]: 1.35-2.38; P < .001); completeness (OR = 2.50; 95% CI: 1.85-3.33; P < .001) and relevance (OR = 2.94; 95% CI: 2.04-4.17; P < .001). When a threshold-based acceptability (score ≥4) was applied, responses to endodontist queries were more often acceptable in criterion-based as well as overall analyses (P < .05). CONCLUSIONS:The quality of AI chatbot guidance in TDIs is significantly associated with how questions are asked. While clinically structured prompts yield more reliable responses, most patients facing dental trauma are unlikely to formulate questions in this way. This gap highlights an important limitation of current AI chatbot applications in TDIs and underscores the need for caution when relying on these tools without professional input.

BACKGROUND:Understanding the size, gender composition, and cadre mix of the health workforce and how it has evolved across time and locations can inform policies for planning, recruitment, training, and retention of human resources for health (HRH), and improvement of access to the health-care workforce among populations. Using comparable and standardised data sources, we aim to describe the composition and density of health workers by sex among 20 cadres for 204 countries and territories over 1990-2023 and quantify workforce shortfalls relative to universal health coverage (UHC) attainment. METHODS:We used 1816 country-years of data from population-based surveys, 82 from censuses, 3888 from administrative sources, and 96 from scientific literature. We harmonised reported occupation in all sources with the International Standard Classification of Occupations 2008. We produced estimates for 20 cadres and the total health workforce disaggregated by sex using spatiotemporal Gaussian process regression, a standardised method in the Global Burden of Diseases, Injuries, and Risk Factors study. Finally, stochastic frontier meta-regression was used to estimate the minimum density of doctors, nurses and midwives, dentists, and pharmacists required to reach a score of 80 out of 100 on the UHC effective coverage index. FINDINGS/RESULTS:In 2023, there were 122·1 million (95% uncertainty interval 115·4-130·5) health workers across 20 cadres, an increase of 81·2 million (72·0-90·5) or 198·5% (161·9-245·6) relative to 1990. Of that total, there were 15·1 million (13·1-18·2) doctors, 33·2 million (30·8-36·3) nurses, 2·4 million (2·0-2·9) midwives, and 7·6 million (6·7-8·6) community health workers (CHWs). 68·9% (66·9-70·6) of all health workers in 2023 were female, and female health workers accounted for 71·4% (64·5-77·4) of net HRH workforce growth. Less than half of doctors were female (43·9%, 34·5-53·2) and most nurses (80·7%, 76·2-83·1), midwives (96·0%, 83·9-98·5), and CHWs (89·5%, 83·6-93·7) were female. Substantial differences in HRH density remained into 2023: sub-Saharan Africa had the lowest HRH densities across cadres, with the exception of CHWs, while high-income countries had the highest HRH densities. To reach 80 out of 100 on the UHC index, an additional 7·1 million (6·6-7·5) doctors, 23·9 million (21·8-26·1) nurses and midwives, 1·8 million (1·6-1·9) dentists, and 1·6 million (1·4-1·9) pharmacists are required globally. INTERPRETATION/CONCLUSIONS:The global health workforce has expanded substantially since 1990, largely due to women entering the formal health workforce. However, this expansion has been uneven across regions and persistent shortfalls remain in doctors, nurses and midwives, dentists, and pharmacists relative to moderate UHC attainment. Addressing these gaps will require expansion of training capacity, retention and remuneration policies for early-career workers, and gender-responsive workforce arrangements. FUNDING/BACKGROUND:Gates Foundation.