Climate change will alter the distribution and burden of infectious diseases. Anticipating future impacts requires characterizing how climate drivers alter transmission of vector-borne, waterborne and respiratory pathoge...Climate change will alter the distribution and burden of infectious diseases. Anticipating future impacts requires characterizing how climate drivers alter transmission of vector-borne, waterborne and respiratory pathogens, accounting for nonlinear relationships between climate variables and disease outcomes. Here we show how inference from laboratory and observational studies in the present can be used to develop projections for the future impact of climate change on infectious disease, and to understand how climate change to date may have impacted existing disease trajectories. We synthesize data from multiple pathogens to show the broad implications of climate change for spatial and temporal outbreak patterns and predictability. One of the most immediate consequences of climate change may be to exacerbate the impact of weather extremes and climate variability, requiring novel data streams and modeling tools to tune interventions. At the same time, climate change is set to occur against the backdrop of demographic change; therefore, determining global shifts in vulnerability, both in the present and the future, is an important task for public health.
Human mobility, climate change and demographic trends increase the risk of pathogen spillover and expansion. Data that can inform our responses to outbreaks have increased in availability and volume, but access to highly...Human mobility, climate change and demographic trends increase the risk of pathogen spillover and expansion. Data that can inform our responses to outbreaks have increased in availability and volume, but access to highly confidential outbreak data and commercially sensitive contextual information remains difficult. Despite ongoing efforts to adopt global health data infrastructures and sharing protocols, there remain regulatory, logistical, human and computational barriers to data sharing. Federated approaches-in which data remain stored locally but analyses are performed across datasets from different sources-offer a potential way to address these challenges. While federated approaches have been used in some clinical and biomedical contexts, their adoption in infectious disease surveillance and modeling has been limited. Here, we discuss global approaches to infectious disease modeling and analysis, with a focus on federated methods. We outline how these can be used to address key epidemiological questions during outbreaks by enabling the secure use of multimodal data and integration with existing surveillance and modeling efforts. We summarize current methods for combining distributed and locally stored data and identify limitations, opportunities and organizational structures needed to achieve equitable global public health impacts.
Martinez-Valbuena I, Emamikhah M, Olszewska DA
… +17 more, Weber SK, Schnell S, Fereshtehnejad SM, Reyes NGD, Sousa M, Di Luca DG, Ta J, Anastassiadis C, Li J, Sasitharan J, Bhakta P, Visanji NP, Fox SH, Mollenhauer B, Tartaglia MC, Kovacs GG, Lang AE
Differential diagnosis of neurodegenerative parkinsonian syndromes is complicated by overlapping clinical features and frequent co-pathology that challenges the interpretation of single-protein biomarkers. We evaluated a...Differential diagnosis of neurodegenerative parkinsonian syndromes is complicated by overlapping clinical features and frequent co-pathology that challenges the interpretation of single-protein biomarkers. We evaluated a multimodal, minimally invasive biomarker strategy integrating dermal α-synuclein and 4-repeat tau seed amplification assays (SAAs) with serum neurofilament light chain. In a prospective cohort of 166 participants (Parkinson's disease, n = 40; multiple system atrophy, n = 29; progressive supranuclear palsy (PSP), n = 77; healthy controls, n = 20) with independent external validation (63 participants), α-synuclein SAA identified synucleinopathies with high sensitivity but was positive in a subset of PSP, which is consistent with α-synuclein co-pathology. Dermal 4-repeat tau SAA identified PSP with high sensitivity and specificity. Serum neurofilament light chain distinguished multiple system atrophy from Parkinson's disease and correlated with disease severity in PSP. Integrating these complementary biomarkers improved diagnostic discrimination compared with individual markers and enabled further stratification within PSP. These findings support a multimodal biomarker approach for biologically informed diagnosis of parkinsonian syndromes.
Erameh C, Okwaraeke K, Kleist C
… +25 more, Edeawe O, Adedosu N, Ekata E, Abejegah C, Owhin S, Babatunde F, Omansen T, Meneguim A, Duvignaud A, Mischlinger J, Ithete N, Oestereich L, Hinzmann J, Ahmed L, Duraffour S, Eifedyi R, Okogbenin S, Akhideno P, Ayodeji OO, Günther S, Wicha SG, Jaspard M, Pahlmann M, Ramharter M, Groger M
Lassa fever (LF) is a viral hemorrhagic fever endemic to West Africa, with high case fatality in hospitalized patients and limited treatment options, including ribavirin. Preclinical evidence suggests high-dose fav... Lassa fever (LF) is a viral hemorrhagic fever endemic to West Africa, with high case fatality in hospitalized patients and limited treatment options, including ribavirin. Preclinical evidence suggests high-dose favipiravir is a promising antiviral treatment alternative. We conducted a randomized controlled open-label phase 2 clinical trial at two reference hospitals in Nigeria to evaluate favipiravir in the treatment of LF. Primary endpoints were the description of classic pharmacokinetic parameters (maximum plasma concentration, time to reach maximum plasma concentration, area under the curve (AUC), half-life and volume of distribution) as well as the safety and tolerability of favipiravir compared with ribavirin in the treatment of acute LF. Hospitalized adult patients with mild-to-moderate RT-PCR-confirmed LF were eligible to participate. In total, 41 patients were randomized (ribavirin n = 21; favipiravir n = 20), and 36 completed the 10-day follow-up period. A total of 19 (46.3%) participants were female, and the median age was 37 years. The primary endpoints were met. Pharmacokinetic analysis of favipiravir in a one-compartment model indicated reliable exposure with maximum plasma concentration of 50.9 (IQR 42.1 to 75.1) mg l in steady state, half-life of 10.9 (IQR 8.2 to 17.1) h and AUC (0-240 h) of 9,275 (IQR 7,139.4 to 15,794.8) mg l h. The 30 drug-related treatment-emergent adverse events were evenly distributed between the treatment arms; 16 (53.5%) events occurred in the favipiravir group, and none of these were classified as severe or serious. Anemia was the most frequently observed adverse event in the ribavirin arm and vomiting in the favipiravir arm. All study participants survived and were successfully discharged from the isolation ward. This trial indicates favipiravir's potential as a safe and well-tolerated alternative treatment regimen for LF and pharmacokinetic data suggest an optimized favipiravir regimen for future clinical evaluation. Clinicaltrials.gov: NCT04907682 .
Ying D, Cheung CL, O CK
… +37 more, Lam WKJ, Au Yeung SL, Lau CS, Luk HM, Leung CKS, Tse DMS, Liu JSC, Hue SPY, Kwok JSL, Yeung DLH, Preusch CB, Ma W, Tang W, Tong AHY, Au LWC, Chan JC, Chan YH, Cheng SSW, Chong SC, Fung CW, Ho S, Krishnamoorthy S, Leung GM, Li PH, Li Q, Loong HH, Lui RNS, Luo S, Ma BM, Ma RCW, Na R, Tan KCB, Wong SS, Lo SV, Hong Kong Genome Project, Chu ATW, Chung BHY
The Hong Kong Genome Project (HKGP) aims to build a foundational resource for precision medicine in the Chinese population through large-scale genome sequencing and integrated analyses. Here we report findings from over...The Hong Kong Genome Project (HKGP) aims to build a foundational resource for precision medicine in the Chinese population through large-scale genome sequencing and integrated analyses. Here we report findings from over 20,000 HKGP participants across two cohorts: a rare disease cohort including 2,227 patients with suspected genetic diseases and a population cohort including 18,261 participants undergoing genomic screening for medically actionable findings. The rare disease cohort achieved a diagnostic rate of 25%. When benchmarked against panels designed for European ancestries, the analysis revealed that 3.7% of the individuals in the population cohort had pathogenic or likely pathogenic variants associated with dominant disorders. While 48% of individuals were found to carry recessive disorder genes in the gene list based upon European ancestries, our analysis revealed that 38 additional clinically important genes would have been overlooked in the Chinese population. Pharmacogenomic analysis demonstrated that nearly all participants harbored at least one actionable phenotype, potentially informing nearly one million annual prescriptions in Hong Kong. The ongoing HKGP establishes a curated Hong Kong Chinese reference for clinically relevant genetic variation and serves as a blueprint for the implementation of precision medicine in underrepresented populations.
Sanmarti R, Pérez-García C, de-Toro FJ
… +36 more, Salvador G, Escudero-Contreras A, Cuervo A, Graell E, Reina D, Kanterewicz E, Corominas H, Urionaguena-Onaindia I, López-Lasanta M, Olivé A, Sala-Gómez M, Frade-Sosa B, Morlà-Novell RM, Polino L, Meraz-Ostiz JA, Oreiro N, Blanco FJ, Pérez-Nadales I, Ortega-Castro R, Busquets-Pérez N, Gómez-Centeno AD, Camacho O, Rodríguez-Cros JR, Millan-Arciniegas AM, García-Llorente JF, Borrell H, Prior-Español Á, Castell-Quiñones S, Cruceta A, Bonfill E, Domenech-Gómez G, Roca-Fàbregas A, Ríos J, Tobalina-Maestre L, Gómara MJ, Haro I
A substantial proportion of individuals with palindromic rheumatism develop rheumatoid arthritis (RA). This randomized, open-label, multicenter trial aimed to assess whether 2 years of treatment with abatacept (n = 34; 1...A substantial proportion of individuals with palindromic rheumatism develop rheumatoid arthritis (RA). This randomized, open-label, multicenter trial aimed to assess whether 2 years of treatment with abatacept (n = 34; 125 mg subcutaneous injections weekly during the first year and every 2 weeks during the second year) compared with oral hydroxychloroquine (n = 36; 5 mg kg per day) could reduce the frequency of RA development in individuals with palindromic rheumatism positive for rheumatoid factor and/or anticitrullinated protein antibody. The primary outcome was the development of persistent arthritis that fulfilled the 2010 RA classification criteria of the American College of Rheumatology and the European Alliance of Associations for Rheumatology, as evaluated by the participant clinicians during the 24 months of follow-up. Secondary outcomes included the frequency, intensity and duration of joint attacks, the proportion of patients in remission and the frequency of adverse events. In the primary analysis, in the modified full analysis set with failure imputation, 7 (20.6%) of the 34 participants treated with abatacept and 18 (50.0%) of the 36 participants treated with hydroxychloroquine developed RA during the 24 months of follow-up (P = 0.010; risk difference 29.4%, 95% confidence interval 8.2 to 50.7), meeting the primary endpoint. Using the available-data-only approach, the corresponding figures were 3 (10.0%) of 30 individuals and 10 (35.7%) of 28 individuals, respectively (P = 0.019). Compared with participants treated with hydroxychloroquine, participants treated with abatacept had a significantly longer time to progression to RA (hazard ratio 0.27, 95% confidence interval 0.07 to 0.96; log-rank test P = 0.0299). Abatacept was also associated with a reduced intensity of joint attacks and a higher frequency of symptom remission; however, there were no differences in the frequency of attacks between the two study drugs. No relevant differences in the evolution of antimodified peptide and/or protein antibody titers were observed between the two treatment arms. Both drugs were well tolerated. In patients with seropositive palindromic rheumatism, compared with hydroxychloroquine, abatacept given for 2 years reduced the risk of progression to RA and improved symptoms. ClinicalTrials.gov identifier NCT03669367 and EudraCT no. 2017-004543-20.
Saab K, Park C, Strother T
… +33 more, Freyberg J, Barrett DGT, Cheng Y, Weng WH, Stutz D, Tomasev N, Palepu A, Liévin V, Sharma Y, Ruparel R, Ahmed A, Vedadi E, Kanada K, Hughes C, Liu Y, Brown G, Gao Y, Li S, Mahdavi SS, Manyika J, Chou K, Matias Y, Hassidim A, Webster DR, Barral J, Eslami SMA, Kohli P, Rodman A, Natarajan V, Schaekermann M, Tu T, Karthikesalingam A, Tanno R
Real-world clinical practice is inherently multimodal, relying on the synthesis of patient history with visual information such as medical imagery and clinical documents. Although large language models (LLMs) have shown...Real-world clinical practice is inherently multimodal, relying on the synthesis of patient history with visual information such as medical imagery and clinical documents. Although large language models (LLMs) have shown promise in diagnostic dialogue, their evaluation has been largely restricted to text-only interactions, failing to capture the complexity of modern remote care delivery. Here we introduce a multimodal extension of the Articulate Medical Intelligence Explorer (multimodal AMIE), capable of gathering, interpreting and reasoning about multimodal data within a diagnostic conversation. To achieve this, we developed a state-aware dialogue framework that dynamically guides history-taking based on diagnostic uncertainty and evolving patient states, emulating the structured reasoning of experienced clinicians. We evaluated this updated, state-aware version of multimodal AMIE against primary care physicians (PCPs) in a randomized, blinded exploratory study comprising 105 simulated telehealth consultations, which included dermatology photographs, electrocardiograms and clinical documents. As assessed by 18 specialist physicians, multimodal AMIE outperformed PCPs not only in diagnostic accuracy but also in conversation quality, including history-taking and empathy. Specifically, multimodal AMIE demonstrated superior performance on 29 of 32 evaluation axes, including seven of nine metrics that assess multimodal reasoning. These results validate the efficacy of state-aware reasoning in bridging the gap between text and visual information and demonstrate the potential for artificial intelligence (AI) systems to augment clinicians in complex, multimodal diagnostic settings.
The discovery of chronic traumatic encephalopathy neuropathologic change (CTE-NC) in the brains of former athletes has generated an explosion in public and scientific interest. As CTE-NC can only be diagnosed postmortem,...The discovery of chronic traumatic encephalopathy neuropathologic change (CTE-NC) in the brains of former athletes has generated an explosion in public and scientific interest. As CTE-NC can only be diagnosed postmortem, consensus diagnostic criteria have been developed for the proposed clinical correlate, that is, traumatic encephalopathy syndrome (TES). However, the diagnostic accuracy of TES criteria in predicting CTE-NC remains unproven and considerable concerns exist regarding the specificity of proposed clinical features. Here we reviewed antemortem clinical records for 1,038 cases in a neurodegenerative brain bank. Neuropathological evaluation for CTE-NC was then conducted in all cases. In total, 25 (2.4%) cases fulfilled the criteria for a diagnosis of TES, of which six demonstrated CTE-NC (positive predictive value = 24.0%, 95% confidence interval 9.4-45.1%). Of the remaining 1,013 cases, CTE-NC was present in seven (0.69%). The diagnostic accuracy of TES for CTE-NC was driven by exposure to repetitive head impacts rather than proposed clinical features. There was no difference in the prevalence of core or supportive clinical features of TES among cases with CTE-NC compared to a matched sample. The poor performance of TES criteria raises substantial concern for its potential negative psychological impact on current and former contact sport athletes, who may be incorrectly diagnosed with a progressive neurodegenerative pathology.
Mpox is a re-emerging zoonotic disease caused by MPXV, which has led to outbreaks across multiple countries in recent years. Sierra Leone reported its first mpox case in 8 years in January 2025, rapidly becoming the epic...Mpox is a re-emerging zoonotic disease caused by MPXV, which has led to outbreaks across multiple countries in recent years. Sierra Leone reported its first mpox case in 8 years in January 2025, rapidly becoming the epicenter of a continental outbreak with more than 5,000 confirmed cases by August, a surge with unknown origins, timings and drivers. Phylodynamic analyses using 338 genomes generated from 14 districts suggests that the outbreak was caused by lineage G.1 (A.2.2.1) which descended from lineages circulating in Nigeria. Here we observed a strong APOBEC3 mutational enrichment, consistent with sustained human transmission that circulated undetected for ~3 months before the first confirmed case in January 2025. The Western Area Urban district served as the primary hub for nationwide spread and persistence, as well as multiple international export events. We further estimated that the true epidemic size was nearly double official case counts, highlighting substantial surveillance gaps. These findings underscore the urgent need for strengthened genomic and diagnostic surveillance systems across West Africa to pre-empt epidemics.
DiPersio JF, Koehne G, Shah NN
… +25 more, Bernard L, Suh HC, Koura D, Tamari R, Mushtaq MU, Maakaron J, Rimando J, Kennedy VE, Patel SS, Hudson C, Loken MR, Slapak CA, Lloyd DM, Stanizzi DA, Lee-Sundlov MM, Thosar S, Mundelboim G, Guo G, Ge HG, Li BE, Xavier-Ferrucio J, Hyzy SL, Lin MI, Raffel GD, Cooper BW
Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are likely to relapse despite allogenic hematopoietic cell transplantation (HCT). Post-HCT preventative maintenance can be limited b...Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are likely to relapse despite allogenic hematopoietic cell transplantation (HCT). Post-HCT preventative maintenance can be limited by toxicity toward the normal donor cells. Tremtelectogene empogeditemcel (trem-cel) is a CRISPR-Cas9 gene-edited allogeneic HCT product lacking CD33, designed to shield the donor graft from cytotoxicity of subsequent CD33-targeted therapies such as gemtuzumab ozogamicin (GO). In this multicenter, phase 1/2a, open-label study, adult patients with AML/MDS with high relapse risk received trem-cel after myeloablative conditioning followed by GO maintenance (0.5-2.0 mg m day 1 per 28-day cycles). Patients receiving trem-cel were assessed for the primary safety endpoint of neutrophil engraftment by day 28 and secondary endpoints including time to neutrophil engraftment, incidence of graft-versus-host disease and graft failure, transplant-related mortality, percentage of CD33-negative myeloid cells and survival. Patients receiving trem-cel and GO were assessed for the additional secondary endpoints of safety of maintenance GO with trem-cel and pharmacokinetics of GO after trem-cel transplant. All 30 patients receiving trem-cel achieved the primary safety endpoint of neutrophil engraftment by day 28 with a median engraftment time of 10 days (95% confidence interval: 9-10). Nineteen patients received GO maintenance in phase 1 dose escalation (n = 15) and in phase 2 dose expansion (n = 4). The trial was stopped early, and this is the final report on the trial including the completed phase 1 portion. GO treatment was safely tolerated up to the recommended phase 2 dose of 2 mg m, and no prolonged high-grade cytopenias were observed. The most common adverse events were cytopenias and infections. Three cases of transplant-related mortality were observed due to renal failure, sepsis and sinusoidal obstruction syndrome, respectively. In summary, trem-cel demonstrated safe, rapid, robust engraftment, and GO maintenance was administered without prolonged hematologic toxicity. ClinicalTrials.gov identifier: NCT04849910 .
Mount S, Canfora EE, Jocken JW
… +11 more, Umanets A, Hul G, Coenjaerds M, Aldaz Laquidain P, Adriaens ME, Holst JJ, Jardon KM, Segers A, Suenaert P, de Vos WM, Blaak EE
Preclinical research suggests that the mucosal symbiont Akkermansia muciniphila prevents diet-induced obesity. In this randomized controlled trial, adults with overweight/obesity (n = 90) underwent an 8-week low-energy d...Preclinical research suggests that the mucosal symbiont Akkermansia muciniphila prevents diet-induced obesity. In this randomized controlled trial, adults with overweight/obesity (n = 90) underwent an 8-week low-energy diet for ≥8% weight loss, followed by a 24-week healthy ad libitum diet with daily supplementation of pasteurized A. muciniphila Muc or placebo. The primary outcome was change in body weight during the maintenance period. Here we show that Muc led to lower body weight regain versus placebo at the end of the weight maintenance period (Muc: 1.2 ± 0.7 kg, placebo: 3.2 ± 0.4 kg, P = 0.012). Additionally, the Muc group had a greater net weight loss from baseline to end of maintenance than the placebo group (3.1 ± 0.7 kg, P = 0.009). Initial Akkermansia spp. abundance was associated with cardiometabolic response to Muc. No serious adverse events related to the treatment were observed. The relative short-term intervention and absence of groups receiving modified strains of Muc lacking active components are limitations that should be addressed in the future. Our findings suggest pasteurized A. muciniphila Muc as a strategy for weight loss maintenance. ClinicalTrials.gov: NCT05417360 .
Incretins have improved the management of obesity and its related complications, but maintaining these health benefits requires ongoing administration, which can be challenging. Orforglipron, a once-daily oral nonpeptide...Incretins have improved the management of obesity and its related complications, but maintaining these health benefits requires ongoing administration, which can be challenging. Orforglipron, a once-daily oral nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated weight loss efficacy, improvements in cardiometabolic risk factors, and safety generally similar to injectable GLP-1 receptor agonists. Here this double-blind, placebo-controlled trial randomized participants previously treated with tirzepatide (cohort 1: N = 205) or semaglutide (cohort 2: N = 171) during the SURMOUNT-5 study to orforglipron once daily or placebo. Cohort 1 participants who achieved body weight plateau maintained a model-based estimate (MBE) of 74.7% (s.e.m. 4.05) of body weight reduction with orforglipron compared with an MBE of 49.2% (s.e.m. 3.92) with placebo, resulting in an estimated treatment difference of MBE 25.5% (95% confidence interval 14.5 to 36.5); P < 0.001; treatment-regimen estimand) at week 52. Cohort 2 participants who achieved body weight plateau maintained an MBE of 79.3% (s.e.m. 4.42) of body weight reduction with orforglipron compared with an MBE of 37.6% (s.e.m. 7.46) with placebo, resulting in an estimated treatment difference of MBE 41.7 (95% confidence interval 24.4 to 59.0); P < 0.001; treatment-regimen estimand) at week 52. All key secondary endpoints were met. The most common adverse events were gastrointestinal effects, which were mostly mild to moderate in severity. These data demonstrate orforglipron's potential as a globally scalable option for minimizing weight changes after injectable therapy. Trial limitations include the absence of a comparator arm involving continued use of injectable obesity-management medications and the trial's 1-year duration. ClinicalTrials.gov registration: NCT06584916 .