Honey MIJ, Hok-A-Hin YS, Thijssen EH
… +26 more, Cousins KAQ, van der Weijden B, In 't Veld L, Stoops E, de Boer SCM, Duits FH, de Houwer JFH, Morrema THJ, Alcolea D, Illán-Gala I, Fortea J, Lleó A, Boxer AL, Irwin DJ, Lee EB, Shaw L, McMillan CT, Wolk DA, Hoozemans JJM, van der Flier WM, van der Ende E, Seelaar H, Verberk IMW, Gan L, Pijnenburg Y, Teunissen CE
Biomarkers to determine underlying frontotemporal lobar degeneration (FTLD) tau or TAR DNA-binding protein (TDP) pathology during life are needed to advance clinical trials targeting specific FTD pathologies. For this pu...Biomarkers to determine underlying frontotemporal lobar degeneration (FTLD) tau or TAR DNA-binding protein (TDP) pathology during life are needed to advance clinical trials targeting specific FTD pathologies. For this purpose, we developed a new ultrasensitive immunoassay to quantify acetylated tau at lysine 174 (AcTau174) in cerebrospinal fluid (CSF). In a sporadic cohort (n = 513), AcTau174 concentrations were higher in all dementia groups (FTLD-TDP, FTLD-Tau, Alzheimer's disease (AD), mild cognitive impairment (MCI)-AD and dementia with Lewy bodies (DLB)) compared to controls. The largest increase was observed in the FTLD-TDP group, particularly patients with semantic variant primary progressive aphasia (svPPA) and GRN mutation carriers. Notably, AcTau174 discriminated FTLD-TDP from FTLD-Tau (area under the curve (AUC) = 0.83, 95% confidence interval (CI) = 0.75-0.91) and FTLD-TDP from controls (AUC = 0.95, 95% CI = 0.92-0.99) with high accuracy. This was replicated in independent, sporadic and genetic validation cohorts (164 patients and 24 controls), albeit with somewhat lower accuracy (FTLD-TDP versus FTLD-Tau; AUC range = 0.75-0.79) and wider CIs. Within the FTLD-TDP, AD and MCI-AD groups, higher AcTau174 concentrations were associated with a faster cognitive decline over time. In summary, CSF AcTau174 has great potential to discriminate FTLD-TDP from FTLD-Tau as a biomarker reflecting FTLD-TDP disease severity and progression.
Verweij PE, Alastruey-Izquierdo A, Amilon K
… +64 more, Cavling Arendrup M, Armstrong-James D, Bignell E, Boulware DR, Brandão J, Bromley M, Brown GD, Buil JB, Chakrabarti A, Chayakulkeeree M, Chiller T, Chindamporn A, Colombo AL, Cornely OA, Dannaoui E, Dufresne PJ, Forastiero A, Gangneux JP, Giske C, Govender NP, Gow NAR, Guillot J, Harrison T, Hoenigl M, Kontoyiannis DP, Lass-Flörl C, Le T, Li R, Medina N, Meis JF, Meletiadis J, Oladele RO, Ostrosky-Zeichner L, Patel AK, Perfect JR, Queiroz-Telles F, Rodriguez-Tudela JL, Rudramurthy SM, Salmanton García J, Dos Santos AR, Segal E, Seyedmousavi A, Song Y, Thompson GR, Vena A, Warris A, Wiederhold NP, Lackner M, International Society for Human and Animal Mycology (ISHAM), Asia Fungal Working Group (AFWG), Pan-Africa Mycology Working Group (PAMWG), INFOCUS LATAM ISHAM associated Working Group, ISHAM/ECMM One Health Working Group (Focus AMR), ISHAM Environmental Fungal Exposure and Human Health Working Group, ISHAM Veterinary Mycology and One Health Working Group, ISHAM Sporotrichosis One Health Working Group, European Confederation for Medical Mycology (ECMM), ESCMID Fungal Infection Study Group (EFISG), Antifungal Susceptibility Testing Subcommittee of the European Committee on Antimicrobial Susceptibility Testing (EUCAST‑AFST), Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antifungal Susceptibility Tests, Mycoses Study Group Education and Research Consortium (MSGERC), Global Action for Fungal Infection (GAFFI), Medical Research Council Centre for Medical Mycology at the University of Exeter, Fungal One Health and Antimicrobial Resistance Network (F1AMR)
Metastatic pancreatic ductal adenocarcinoma (mPDAC) is one of the leading causes of cancer-related mortality, but advances in therapeutic treatments remain limited. Elraglusib (9-ING-41), an inhibitor of GSK-3β, exhibits...Metastatic pancreatic ductal adenocarcinoma (mPDAC) is one of the leading causes of cancer-related mortality, but advances in therapeutic treatments remain limited. Elraglusib (9-ING-41), an inhibitor of GSK-3β, exhibits a multimodal mechanism of action based on antitumor activity in preclinical models of cancer, including pancreatic. The efficacy and safety of elraglusib with gemcitabine plus nab-paclitaxel (GnP) were assessed in patients with previously untreated mPDAC. In an open-label, international, multicenter, phase 2 study, patients were randomized 2:1 to weekly elraglusib/GnP or GnP alone. Primary endpoints were median overall survival (OS) and 1-year survival rate. The prespecified modified intention-to-treat population included 155 patients on elraglusib/GnP and 78 on GnP. As of the data cutoff of 27 April 2025, elraglusib/GnP improved median OS by 2.9 months and decreased the risk of death by 38% versus GnP (median OS 10.1 months versus 7.2 months, respectively (hazard ratio 0.62; 95% confidence interval 0.46 to 0.84; P = 0.01)). The 1-year survival rates were 44.1% versus 22.3%, respectively. The safety profile of elraglusib/GnP was manageable. The most common grade 3 or higher treatment-emergent adverse events (TEAEs) with elraglusib/GnP versus GnP alone were neutropenia (52.3% versus 30.8%), anemia (25.2% versus 29.5%) and fatigue (16.8% versus 5.1%). Explorative correlative analyses demonstrated that baseline circulating immune-related factors (that is, CXCL2 and TRAIL ligands) were associated with improved survival in the elraglusib/GnP arm. Treatment was accompanied by increases in intratumoral cytotoxic immune cell populations. Together, these findings support the clinical activity of elraglusib/GnP as first-line treatment in mPDAC and provide a biological context for the observed survival benefit. Based on the results of this phase 2 trial, a phase 3 trial is being planned. ClinicalTrials.gov registration: NCT03678883.
A small azobenzene photoswitch molecule (KIO-301), designed to confer light responsiveness to retinal ganglion cells, was evaluated for safety and feasibility in a first-in-human, phase 1, gene-agnostic, open-label, dose...A small azobenzene photoswitch molecule (KIO-301), designed to confer light responsiveness to retinal ganglion cells, was evaluated for safety and feasibility in a first-in-human, phase 1, gene-agnostic, open-label, dose-escalation clinical trial in individuals with advanced retinitis pigmentosa (RP). KIO-301 was administered by intravitreal injection to 12 eyes of 6 participants. The primary outcome was ocular and systemic safety over 30 days. Secondary and exploratory assessments included functional vision testing, visual acuity, kinetic visual field, functional magnetic resonance imaging and participant-reported outcomes. The primary safety outcome was met, with no serious adverse events or dose-limiting toxicities observed at any point. No drug-related intraocular inflammation occurred, and all ocular adverse events were mild and procedure-related. Exploratory assessments identified variation in light perception and functional vision measures in some participants. Light-evoked blood-oxygen-level-dependent signal changes in visual cortical regions were observed following dosing and showed a temporal pattern compatible with pharmacodynamic activity. Participant-reported quality-of-life scores varied over time. In this small, nonrandomized phase 1 study in individuals with late-stage RP, intravitreal KIO-301 demonstrated an acceptable safety and tolerability profile, supporting the feasibility of photoswitch therapy in advanced RP, and motivating further evaluation in larger trials. ClinicalTrials.gov identifier: NCT05282953.
Nakayama T, El Achkar CM, Burbano LE
… +32 more, Quraishi IH, Wu J, Li M, Asami Y, Golinski SR, Sherrill E, Goodlett BD, de Gusmao CM, Friedman DA, Lentucci C, Suslovitch V, Riccardi O, Faour KNW, Kuniholm A, Soucy Verran A, Coffman S, Ahtam B, Zhao B, Chin DH, DiDonato RL, Hu CA, Lopez E, Hills S, Maljevic S, Tran H, Bush LW, Grant PE, Madsen JR, Smith RS, Kaczmarek LK, Berde CB, Yu TW
KCNT1-related epileptic encephalopathy, including epilepsy of infancy with migrating focal seizures, is a severe neurodevelopmental disorder associated with refractory seizures, profound neurologic impairment and prematu...KCNT1-related epileptic encephalopathy, including epilepsy of infancy with migrating focal seizures, is a severe neurodevelopmental disorder associated with refractory seizures, profound neurologic impairment and premature death. It is caused by de novo genetic variants in KCNT1 that alter the function of Slack, an evolutionarily conserved sodium-gated potassium channel that modulates neuronal firing patterns and excitability. Pathogenic KCNT1 variants lead to overactive Slack channels, boosting total neuronal potassium currents by up to 40%, driving cortical hyperexcitability and causing seizures. Here we investigate antisense oligonucleotide-mediated KCNT1 knockdown as a therapeutic strategy for patients with epilepsy of infancy with migrating focal seizures. Intrathecal delivery of an experimental, non-allele-specific, KCNT1-targeting antisense oligonucleotide by lumbar puncture in two 2-year-old females with KCNT1 p.R474H, a severe, recurrent pathogenic variant, led to a significant reduction in seizure frequency and intensity. However, investigational treatment was also associated with the development of ventricular enlargement or hydrocephalus in both patients, prompting in one case the redirection of goals of care, pointing to a potential monitorable toxicity of some intrathecal antisense oligonucleotides.
The menstrual cycle is one of the most fundamental biological rhythms in human physiology, yet its systemic molecular changes remain poorly understood. Here we show that the menstrual cycle is accompanied by widespread c...The menstrual cycle is one of the most fundamental biological rhythms in human physiology, yet its systemic molecular changes remain poorly understood. Here we show that the menstrual cycle is accompanied by widespread changes in the circulating proteome. By profiling nearly 3,000 plasma proteins in 2,760 women from the UK Biobank, we identified 198 proteins that vary across the cycle, forming distinct temporal patterns aligned with menstrual phases. These proteins include reproductive hormones, cytokines and growth factors, many of which are enriched in endometrial tissue and expressed in epithelial and stromal cell types, highlighting their biological specificity. Several proteins were linked to common reproductive disorders, including endometriosis, leiomyoma and abnormal bleeding. Finally, we developed a proteomic score on the basis of 75 proteins that accurately predicts menstrual cycle phase. Together, these findings provide a systems-level atlas of menstrual cycle biology and inform biomarker discovery in women's health.
Loss-of-function variants in the gene encoding angiopoietin-like protein 3 (ANGPTL3) are associated with decreased triglyceride and low-density lipoprotein cholesterol levels, as well as with lower cardiovascular risk. H...Loss-of-function variants in the gene encoding angiopoietin-like protein 3 (ANGPTL3) are associated with decreased triglyceride and low-density lipoprotein cholesterol levels, as well as with lower cardiovascular risk. Here we describe a 16-week phase 1 trial of zodasiran, an ANGPTL3‑targeting small interfering RNA, in patients on lipid-lowering therapy with either hyperlipidemia (with a placebo control arm) (n = 9; 7 male and 2 female), familial hypercholesterolemia (n = 17; 9 male and 8 female) or moderate-to-severe hypertriglyceridemia (n = 6; 4 male and 2 female). Patients received zodasiran subcutaneously on days 1 and 29, followed by a 48-week open-label extension in the familial hypercholesterolemia cohort (n = 13; 7 male and 6 female) in which zodasiran was dosed every 12 weeks. No serious treatment-related adverse events, the primary endpoint of the trial, were observed. Moreover, no elevations in hepatic aminotransferases, bilirubin or glycated hemoglobin were observed, and there were no drug discontinuations. All cohorts showed reductions at week 16 (12 weeks postdosing) in serum ANGPTL3 (≤-85.4%) and triglycerides (≤-67.1%), which were secondary endpoints. Reduction in ANGPTL3 was sustained to end-of-open-label extension in the familial hypercholesterolemia cohort. These results indicate a favorable safety profile for zodasiran, with promise for correcting isolated hypercholesterolemia and moderate-to-severe hypertriglyceridemia, and support further studies of zodasiran in treating a wide spectrum of dyslipidemias. ClinicalTrials.gov registration: NCT03747224 .
Gay F, Roeloffzen W, Dimopoulos MA
… +25 more, Rosiñol L, van der Klift M, Mina R, Oriol A, Katodritou E, Wu KL, Rodríguez Otero P, Hájek R, Antonioli E, van Duin M, D'Agostino M, Martínez-López J, van Leeuwen-Segarceanu EM, Zamagni E, van de Donk NWCJ, Weisel KC, Pour L, Radocha J, Belotti A, Schjesvold F, Bladé J, Einsele H, Sonneveld P, Boccadoro M, Broijl A
Induction and consolidation with a quadruplet therapy of a CD38-targeting monoclonal antibody, a proteasome inhibitor, an immunomodulatory drug and dexamethasone are a standard-of-care treatment in transplant-eligible (T...Induction and consolidation with a quadruplet therapy of a CD38-targeting monoclonal antibody, a proteasome inhibitor, an immunomodulatory drug and dexamethasone are a standard-of-care treatment in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM) with the optimal drugs to be used still under debate. The ongoing, phase 3 EMN24 IsKia trial randomized 302 TE patients with NDMM aged ≤70 years 1:1 to isatuximab-carfilzomib-lenalidomide-dexamethasone (Isa-KRd) versus KRd pretransplant induction and post-transplant consolidation. The primary endpoint was the rate of measurable residual disease (MRD) negativity (sensitivity of 10 or better) by next-generation sequencing (NGS) after consolidation. Key secondary endpoints were the rates of NGS-MRD negativity after induction and progression-free survival (PFS). MRD negativity rates at higher sensitivity (10 or better) were exploratory. Post-consolidation MRD negativity was significantly higher with Isa-KRd versus KRd at the 10 (77% versus 67%; odds ratio (OR) 1.67, P = 0.049) and 10 (68% versus 48%; OR 2.36, P = 0.0004) sensitivities. Deep MRD responses were rapid (post-induction Isa-KRd versus KRd: 10 46% versus 27%, OR 2.32, P = 0.0007; 10 28% versus 14%, OR 2.44, P = 0.0029) and durable (1-year sustained 10 MRD negativity 52% versus 38%, OR 1.82, P = 0.012). At current follow-up, PFS data were immature. Grade 3-4 non-hematologic adverse events (AEs), treatment discontinuations and deaths due to AEs were similar in the two arms. Isa-KRd significantly improved NGS-MRD negativity in TE patients with NDMM, with a manageable safety profile. ClinicalTrials.gov registration: NCT04483739 .
Psychedelic drugs are re-emerging as promising scientific and clinical tools. However, despite a rapidly expanding literature on their therapeutic value, the neural mechanisms underlying psychedelic effects remain unclea...Psychedelic drugs are re-emerging as promising scientific and clinical tools. However, despite a rapidly expanding literature on their therapeutic value, the neural mechanisms underlying psychedelic effects remain unclear. Resting-state functional magnetic resonance imaging studies of acute psychedelic effects, conducted independently by several research groups, have so far yielded fragmented and sometimes inconsistent findings. Here, to help facilitate greater convergence, we conducted a 'mega-analysis' integrating 11 independent resting-state functional magnetic resonance imaging datasets across five psychedelic drugs (psilocybin, lysergic acid diethylamide, mescaline, N,N-dimethyltryptamine and ayahuasca) from research groups spanning three continents and five countries. By applying a uniform preprocessing pipeline and a Bayesian hierarchical modeling framework, we discovered several common features in the induced alterations to brain function across drugs and sites. Most prominently, we identified a core signature of increased functional connectivity between transmodal (default, frontoparietal and limbic) and unimodal networks (visual and somatomotor), with subnetwork specificity. Furthermore, key subcortical regions (thalamus, caudate and putamen) and the cerebellum exhibited altered coupling with sensorimotor networks. In contrast to several single-site reports, Bayesian modeling revealed weak-to-moderate and selective reductions in within-network functional connectivity, with substantial variability across drugs and networks. Together, these findings extend past work by demonstrating that psychedelics reconfigure large-scale cortical organization while selectively engaging subcortical circuitry. This study provides the most comprehensive synthesis of psychedelic brain action to date, helping resolve inconsistencies and offering a probabilistic map of how psychedelics alter large-scale brain organization. We hereby provide a cornerstone to benchmark and shepherd future psychedelic neuroimaging research.
Despite advances in understanding the mechanisms, risk factors and treatment strategies for Alzheimer's disease (AD), no approved therapies exist to prevent or delay onset in at-risk individuals or those with elevated bi...Despite advances in understanding the mechanisms, risk factors and treatment strategies for Alzheimer's disease (AD), no approved therapies exist to prevent or delay onset in at-risk individuals or those with elevated biomarkers who do not yet show symptoms. Multiple candidate interventions are now being evaluated in clinical trials in these settings, raising key questions around which populations are most appropriate and what criteria should guide regulatory and clinical decision-making. Data are expected within 1-2 years, underscoring the need for stakeholder alignment on clinically meaningful and acceptable characteristics of preventative therapies or other products. To address this need, the Global CEO Initiative on Alzheimer's Disease convened an international group of experts to develop target product profiles for therapies designed to delay or prevent the onset of clinical symptoms in AD. These target product profiles outline minimum and preferred characteristics, including intended use, target populations, safety expectations and efficacy benchmarks. This effort provides a foundational framework to accelerate therapeutic development and guide researchers, regulators and patients in the evaluation of emerging therapies for preventing symptomatic AD.
In 2022, monkeypox virus (MPXV) clade IIb emerged resulting in a global epidemic driven by human-to-human transmission, mostly through sexual contact mainly among the population of men who have sex with men. To date, pub...In 2022, monkeypox virus (MPXV) clade IIb emerged resulting in a global epidemic driven by human-to-human transmission, mostly through sexual contact mainly among the population of men who have sex with men. To date, published data on the circulation of MPXV clade IIb in the central African region are absent. Here we describe a case of laboratory-confirmed mpox clade IIb lineage A2.2 in Pointe-Noire, the second largest city of the Republic of the Congo. Whole-genome phylogenetic analysis placed the MPXV in clade IIb, lineage A.2.2 currently emerging in West Africa, in particular Sierra Leone. An additional 16 cases of clade Ia, 32 cases of clade Ib and one additional introduction of clade IIb were identified by passive surveillance in the Republic of the Congo in 2025. The detection of clade IIb mpox marks the third distinct MPXV clade and lineage co-circulating in the human population, together with clade Ia and Ib. This underscores the need for improved surveillance and diagnostic strategies to identify the respective clade and lineage circulating in the human population. Strengthening of regional capacity for case detection, contact-tracing, public health measures and affordable vaccines are urgently needed to reduce the global risk for both clade I and clade II MPXV.
The physical and social exposome affects human aging, and brain clocks may track its effects. However, most studies neglect multidomain exposures (physical, social and political) across diverse settings globally and thei...The physical and social exposome affects human aging, and brain clocks may track its effects. However, most studies neglect multidomain exposures (physical, social and political) across diverse settings globally and their associations with brain aging. In this study, we characterized the associations between 73 country-level physical and social exposomal factors and multimodal brain age in 18,701 participants from 34 countries (healthy individuals and those with Alzheimer's disease, frontotemporal lobar degeneration or mild cognitive impairment). Exposome effects were assessed using generalized additive models and meta-analytic frameworks. Aggregated exposome models explained up to 15.5-fold more variance than individual exposures (delta Akaike information criterion (ΔAIC): 2,034-3,127). Physical exposome was primarily associated with accelerated structural brain aging (limbic, subcortical and cerebellar regions), whereas social exposome was more strongly associated with functional brain aging (frontotemporal and limbic networks). Exposome burden accounted for 3.3-9.1-fold higher risk of accelerated aging, exceeding effects of clinical diagnoses. Findings were out-of-sample validated in cross-sectional and longitudinal designs, remained consistent across clinical subgroups and persisted after adjustment for demographics, age correction bias, cognition, scanner type and data quality. The exposome accelerates brain aging in health and disease, underscoring the need to address physical, social and political inequities.
van Putten J, Snaebjornsson P, Bosch LJW
… +13 more, Koster R, Roepman P, Usset J, Boelens MC, van Wezel T, Rosenberg EH, Marchetti S, Vollebergh M, Lambregts DMJ, van der Kolk LE, Cuppen E, Nienhuis HH, Monkhorst K
In the SELECT trial, once-weekly subcutaneous semaglutide reduced major adverse cardiovascular events (MACE) by 20% versus placebo in patients with atherosclerotic cardiovascular disease and obesity but without diabetes....In the SELECT trial, once-weekly subcutaneous semaglutide reduced major adverse cardiovascular events (MACE) by 20% versus placebo in patients with atherosclerotic cardiovascular disease and obesity but without diabetes. We examined semaglutide in SELECT patients at high risk for substantial liver fibrosis in a prespecified secondary analysis. Liver biochemical tests and steatosis risk according to fatty liver index were assessed over 104 weeks. Subgroup analyses of the primary MACE (a composite endpoint including cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) outcome used baseline Fibrosis-4 scores ≥ 1.3, age-specific (≥1.3 (<65 years) or ≥2.0 (≥65 years)) and any age with Fibrosis-4 > 2.67. MACE was reduced by 26% (hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.63-0.88; P = 0.0004), 21% (HR 0.79; 95% CI 0.63-0.98; P = 0.035) and 34% (HR 0.66; 95% CI 0.39-1.10; P = 0.11), respectively. Semaglutide led to a 28% greater decrease in fatty liver index versus placebo (HR 0.72; 95% CI 0.71-0.73; P < 0.0001). In conclusion, semaglutide reduced MACE versus placebo in patients at risk for substantial liver fibrosis, as seen in the overall SELECT population. ClinicalTrials.gov registration no. NCT03574597.