👤 Medit‐Ageing Research Group

Intrinsic Capacity (IC) is defined as the composite of physical and mental abilities an individual possesses, encompassing five domains: cognition, psychological health, sensory function, vitality, and locomotion. This construct is central to the World Health Organization's framework for assessing functional ability in older adults. Growing evidence highlights the critical role of the musculoskeletal system in maintaining these domains, while conditions such as sarcopenia, osteoporosis, and their coexistence as osteosarcopenia (OS) are increasingly associated with IC decline. This narrative review compiles current evidence on the modulatory role of muscles and bones in IC and the impacts of sarcopenia, osteoporosis, and OS. Most findings suggest that musculoskeletal tissues influence IC not only through biomechanical functions but also as secretory organs, releasing myokines and osteokines with endocrine, paracrine, and autocrine effects. Among the most studied are brain-derived neurotrophic factor, irisin, osteocalcin, and interleukin-6. Dysregulation of these pathways, along with biomechanical dysfunction and systemic inflammation, links sarcopenia, osteoporosis, and OS to IC impairment. Further research is needed to clarify the specific mechanisms involved, particularly in the sensory and vitality domains, to inform targeted interventions that promote healthy aging. Show less

Alterations in lipids and apolipoproteins contribute to cardiovascular disease (CVD) and are common in people with HIV. The aim of our study was to compare lipid profiles and body composition between people with and without HIV and to explore whether any associations with HIV could be explained by socio-demographic, clinical characteristics and body composition. Cross-sectional analysis of a cohort study enrolling people with HIV and HIV-negative controls. Apolipoproteins [ApoB-100, ApoA1, Lp(a)] were analysed by immunoturbidimetry. Lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL]), clinical/demographic data and dual-energy X-ray absorptiometry (DXA)-measured body composition parameters were collected. Between-group differences were assessed with Student's T-test. Linear regression models assessed associations of lipids and apolipoproteins with HIV status and associations with socio-demographic, clinical characteristics and body composition. We included 108 people with HIV on treatment (93.5% with viral suppression) and 96 controls. People with HIV were younger, more likely to be male, with obesity, of African ethnicity, smokers and with a higher representation of CVD, hypertension, diabetes and statin use. ApoB-100, TC, HDL and LDL were significantly lower in people with HIV, with no between-group difference in ApoA, Lp(a) and body composition. HIV infection remained independently associated with lower TC and LDL after adjustment for possible confounders. People with HIV from a contemporary cohort had lower pro-atherogenic lipid parameters compared to controls, and no differences in body composition between people with HIV and controls were observed. Traditional risk factors for CVD and chronic inflammation might have a greater impact than dyslipidaemia itself on the increased CVD risk in people with HIV. Show less

BackgroundIdentifying genetic variants conferring resilience to Alzheimer's disease and related dementia (ADRD) may hold promise for developing therapeutics.ObjectiveTo determine genetic associations with being dementia-free at age 85 (DF85).MethodsWe examined genetic associations, using whole genome sequencing data, with DF85 in three Trans-Omics for Precision Medicine cohorts and the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium. We tested common variants individually and aggregation of rare (MAF ≤ 1%) coding and non-coding variants in DF85 participants (n = 3657) against individuals who were not DF85 (n = 20,010). We verified associations using a stricter control set who developed dementia before age 85 (n = 5552).ResultsWe observed an association at Show less

Allostatic load (AL), an index of cumulative physiological dysregulation from chronic stress, may contribute to Alzheimer's disease (AD) pathophysiology by accelerating brain aging. Higher AL has been associated with AD-related biomarkers, suggesting a mechanistic connection. Lifestyle factors influence both AL and AD vulnerability, but their moderating role in AL-AD biomarker associations remains unclear. We included 111 cognitively unimpaired older adults from the baseline visit of the Age-Well trial. AL was computed as a composite score of 18 biomarkers spanning neuroendocrine, immune, metabolic, cardiovascular-respiratory, and anthropometric systems. Plasma biomarkers included amyloid beta (Aβ)42, Aβ40, phosphorylated-tau (p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Physical activity, Mediterranean diet adherence, and cognitive activity were assessed using validated questionnaires. Multiple linear regressions tested associations between AL and (1) AD-related biomarkers and (2) lifestyle factors, as well as their interactions, controlling for age, sex, education, apolipoprotein E ε4 (APOE ε4) status, and glomerular filtration rate (GFR). Higher AL was associated with higher Aβ42/Aβ40 ratio ( Regular physical activity was associated with a weaker relationship between AL and early AD-related biomarkers in this cross-sectional sample. Longitudinal studies should confirm whether maintaining physical activity attenuates stress-related physiological dysregulation and reduces AD vulnerability. Show less

Healthy diet and lifestyle have been linked to improved gut microbiota diversity and neurocognitive outcomes. However, few human studies have simultaneously examined an antioxidant-rich diet (ARD) in combination with other lifestyle factors and their effects on gut microbiota diversity, brain morphometry, and cognitive function. Our aim was to investigate how the dietary antioxidant capacity and a healthy lifestyle profile influence gut microbiota diversity and composition, brain morphometry, and global cognitive function in older adults. In a cross-sectional analysis of the NutBrain study (2019-2023), a cohort of 246 dementia-free individuals aged ≥65 years, completed a 3-day food diary to estimate the total dietary antioxidant capacity (Oxygen Radical Absorbance Capacity - ORAC). Global cognitive function was assessed using the Mini-Mental State Examination (MMSE). Gut microbiota α- and β-diversities and taxa abundances were derived by 16S rRNA amplicon-based sequencing of stool samples. Brain morphometry - including total brain, white matter, grey matter, and ventricular cerebrospinal fluid volumes - was assessed using magnetic resonance imaging. Multiple linear regression models, accounting for many potential confounders (i.e.: socio-demographics, use of drugs, energy intake, inflammatory and anthropometric markers, and APOE genotyping) examined how ORAC, both alone and combined with smoking and physical activity (devising a healthy lifestyle score, Hscore), affected microbiota diversity, MMSE scores, and brain volumes. Higher ORAC adherence was associated with greater gut microbiota diversity (p ≤ 0.05). Several taxa, such as Barnesiella, Coprococcus, Ruminococcus, Parabacteroides, Lachnospiraceae NK4A136 group, and Clostridia UCG-014 group exhibited increased abundances within the highest ORAC and Hscore tertiles, as compared to the lowest ones. The highest tertile of total ORAC was also positively and significantly associated with greater total brain, white matter, and grey matter volumes (p ≤ 0.05). These associations were stronger in participants classified as having a favourable lifestyle profile (regular physical activity, non-smokers), with notable correlations observed for total brain volume, gut α-diversity, white matter volume and MMSE (p ≤ 0.05). ARD is associated with increased gut microbiota diversity and enrichment of specific taxa, better cognitive function and brain morphometry outcomes. These associations were stronger in individuals with a healthy lifestyle profile. NCT04461951, https://clinicaltrials.gov/. Show less

Decreasing body mass index (BMI) from midlife to late life has been linked to increased Alzheimer's disease (AD) risk and cognitive decline; however, the association with in vivo AD pathology remains unclear. This study aimed to clarify the relationship between midlife-to-late-life BMI changes and in vivo AD pathologies, specifically amyloid-β (Aβ), tau, and AD-signature region cerebral glucose metabolism (AD-CM). This observational cohort study included non-demented older adults recruited from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) between January 2014 and December 2020. Participants underwent clinical evaluations and positron emission tomography (PET) imaging to measure brain Aβ, tau, and AD-CM. Midlife BMI was retrospectively estimated from self-reported weight at ages 40–50 years, while late-life BMI was measured during the study. Participants were categorized based on BMI changes as decreasing (≤ − 4%), stable (− 4% to < 4%), or increasing (≥ 4%). Associations between BMI patterns and AD pathologies were analyzed using multiple linear regression models. A total of 268 participants (mean age 66.6 ± 7.9 years; 56.3% women; 22.5% APOE ε4 carriers) were analyzed. Higher midlife BMI correlated significantly with lower AD-CM (β = − 0.009; 95% CI, − 0.015 to − 0.003; A decreasing BMI trajectory from midlife to late life is associated with enhanced AD-related neurodegeneration, underscoring the clinical importance of monitoring long-term body weight changes in relation to Alzheimer's disease pathophysiology. The online version contains supplementary material available at 10.1186/s13195-026-01967-z. Show less

Lipoprotein(a) [Lp(a)] is a genetically determined and independent risk factor for atherosclerotic cardiovascular disease, including acute coronary syndrome, peripheral arterial disease, and stroke, as well as calcific aortic stenosis. Despite its high prevalence, affecting an estimated 20% of Canadians, Lp(a) remains under-recognized and undermeasured in clinical practice. This report provides guidance on the assessment and management of Lp(a) in primary and secondary prevention in the Canadian context. It outlines when and how to measure Lp(a), with a recommendation for universal, one-time testing in adulthood. The report summarizes the pathophysiologic role of Lp(a) in promoting atherosclerosis, thrombosis, and aortic stenosis, and highlights significant ethnic variability in Lp(a) levels and associated risk. It also addresses the limitations of existing cardiovascular risk calculators that omit Lp(a) and discusses the potential role of emerging imaging and treatment strategies, including novel Lp(a)-lowering therapies. Special attention is given to clinical interpretation of Lp(a) values, the role of cascade screening in families, and recommendations for preventive interventions, with an emphasis on current approaches for managing patients with elevated Lp(a) level while awaiting the availability of targeted therapies. The goal of this report is to support clinicians in identifying at-risk individuals earlier and guiding appropriate risk reduction strategies in primary and secondary prevention settings. Show less

Anxiety and depression are highly comorbid mental health disorders with heterogeneous symptom patterns and poorly understood transdiagnostic mechanisms. This study aims to characterize latent subgroups, risk factors, and symptom-level interactions underlying depression-anxiety comorbidity across adolescents and adults in multi-ethnic Southwest China. The study included a total of 41,394 adolescents (aged 9-19) and 17,345 adults (aged 18-80). Adolescents were recruited using multistage stratified cluster sampling, whereas adults were recruited by convenience sampling. All participants completed a self-designed sociodemographic questionnaire, the Patient Health Questionnaire-9 (PHQ-9), and the Generalized Anxiety Disorder-7 (GAD-7). Latent profile analysis identified subgroups, logistic regression analyzed risk/protective factors, and network analysis mapped symptom interactions and bridge nodes. This study found that three adolescent profiles emerged: high (11.66 %), moderate (31.95 %), and low/no depression-anxiety (56.39 %). Adults were classified into low/no comorbidity (90.63 %) and comorbid depression-anxiety (9.37 %). Risk factors for adolescents included female gender (OR = 2.77, 95 %CI: 2.55-3.00; OR = 1.59, 95 %CI: 1.52-1.67), higher grade levels (OR = 3.45, 95 %CI: 3.10-3.84; OR = 3.56, 95 %CI: 3.33-3.80), smoking (OR = 1.72, 95 %CI: 1.51-1.96; OR = 1.28, 95 %CI: 1.17-1.41),drinking (OR = 2.45, 95 %CI: 2.23-2.70; OR = 1.66, 95 %CI: 1.55-1.77), family instability (OR = 1.16, 95 %CI: 1.02-1.31; OR = 1.33, 95 %CI: 1.14-1.56) and "other" ethnic minority (OR = 1.15, 95 %CI: 1.04-1.26). For adults, female gender(OR = 1.68; 95 %CI: 1.44-1.97), living alone(OR = 1.37; 95 %CI: 1.14-1.65), poor self-rated health (OR = 0.13, 95 %CI: 0.11-0.15), and Dai ethnicity (OR = 0.70, 95 %CI: 0.49-0.96) predicted comorbidity. Network analysis revealed distinct bridge symptoms: adolescents in the high depression-anxiety group had five symptoms: depressed or sad mood (phq2), psychomotor agitation/retardation (phq8), nervousness or anxiety (gad1), restlessness (gad5), and irritable (gad6); however, adults with comorbidity had one symptom: afraid something will happen (gad7). This study identified three patterns of depression-anxiety comorbidity in adolescents and two in adults. Efforts should prioritize adolescents from "other" ethnic minorities, strengthening family and peer support, as well as smoking and drinking interventions for adolescents, and addressing social isolation, physical health, and catastrophizing cognition in adults may mitigate the comorbidity burden. Show less

Spinocerebellar ataxia type 3 (SCA3) is one of the most common dominantly inherited ataxias worldwide. Despite research advances, no approved disease-modifying treatment exists, and management focuses on symptom alleviation and functional capacity maximization. Symptomatic treatment guidelines are scarce, leaving decisions to physicians' discretion. The lack of studies on SCA3 symptom management hinders therapy standardization. The aim of this study was to investigate medication-usage patterns among SCA3 mutation carriers and controls included in the multicentric European Spinocerebellar Ataxia Type-3/Machado-Joseph Disease Initiative (ESMI) cohort. We conducted a retrospective cross-sectional analysis of the medication taken by ESMI participants enrolled in the study between 2016 and 2023. Medication being used at the most recent follow-up visit available was categorized according to the Anatomical Therapeutic Chemical system. Comparisons between groups were performed using nonparametric tests for continuous variables and Fisher's exact test for categorical variables. In addition, a retrospective longitudinal analysis was conducted to study the impact of medication subclasses on disease progression, using linear mixed-effects models adjusted for relevant covariates. A total of 474 participants were included, comprising 344 SCA3 mutation carriers and 130 controls. Compared with controls, SCA3 subjects took more vitamins, mineral supplements, muscle relaxants, and medications targeting the nervous system. Psychoanaleptics and vitamins were introduced early in the disease course, whereas most other subclasses were initiated in mid-to-late stages, coinciding with the onset of neurological symptoms. Substantial disparities in medication usage were observed across the study centers. None of the medication subclasses commonly used by patients with SCA3 showed a significant impact on disease progression. This is the first study to explore medication usage patterns in SCA3 mutation carriers. Our study provides a comprehensive overview of the medications administered in SCA3 and underscores the importance of collaborative efforts toward achieving standardized clinical practices in the management of this disease. Show less

We aimed to compare the molecular and clinical characteristics of patients identified in Italy as affected by either familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS) and to assess the overall benefit of novel triglyceride-lowering therapies prescribed to these patients within the routine clinical care. From the national LIPIGEN-sHTG (Lipid Transport Disorders Italian Genetic Network-Severe Hypertriglyceridemia) registry, 169 patients (57 FCS, 51 MCS, 61 variant-negative, variant-negative MCS) were retrospectively analyzed. Data on clinical and genetic characteristics, medical history, and medications were collected. Peak triglyceride levels were used to define untreated lipid phenotypes. In FCS, 72% exhibited biallelic As compared with MCS, patients with FCS showed a more severe phenotype and higher prevalence of Show less

Familial hypercholesterolemia (FH) is a genetic disorder driven in part by mutations in three genes that encode components of the cholesterol pathway: LDLR, APOB, and PCSK9. However, the majority of FH genetics has been performed in individuals of European descent. Here, we leveraged a cohort of 300 patients from the Mexican FH registry to understand how rare, high liability alleles and common variants might contribute to shaping individual risk. Using a combination of whole exome and of short- and long-read whole genome sequencing, we report three key findings. First, we observed that rare pathogenic point mutations and structural variants in all known FH genes, together with variants in APOE, CREB3L3, and PLIN1, contribute to a molecular FH diagnosis in 67% of families, including novel gene-disruptive copy number variants (CNVs) which arose in a native American background. Second, ancestry-adjusted polygenic risk score analysis identified a significant liability for coronary artery disease, hypertension, LDL, HDL, and Type 2 Diabetes. The polygenic signal for LDL was present in patients with rare, pathogenic FH mutations and was more prominent in individuals bereft of a molecular FH diagnosis. Finally, we report both a whole-gene duplication and common, non-coding variants in a novel locus, PDZK1, which contribute to the genetic burden of FH, a finding we replicated in the UK Biobank (UKB). Together, our analyses illustrate the value of genetic studies in non-European populations and reinforce the notion that individual risk to disease can arise from both rare, large effect alleles (alone or in combination across genes) and common variants that increase the mutational burden of a biological system. Show less

Amyloid deposition occurs decades before symptoms emerge in Alzheimer's disease (AD). We leveraged blood transcriptomics and positron emission tomography (PET) measures of amyloidosis to identify gene networks in the blood that relate to amyloid burden in the brain. Whole-blood RNA sequencing and amyloid PET were leveraged from 1739 cognitively unimpaired participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. Linear regression related gene module expression to amyloid covarying for age, sex, education, and apolipoprotein E (APOE) ε2 and ε4 genotypes. Of the 18 gene modules, one histone gene cluster module was associated with amyloid (β = -0.55, false discovery rate-adjusted p value = 0.029). We also observed nominal associations for the predicted proportion of activated natural killer (NK) cells (β = -0.454, p = 0.02) and CD4+ activated memory T cells (β = -0.169, p = 0.03) with amyloid deposition. Our results implicate the histone gene cluster on chromosome 6 and immune cell proportions as blood correlates of brain amyloid deposition in preclinical AD. Higher expression of network module with histone gene cluster on chromosome 6 associated with lower amyloid levels. Four histone genes, H1-5, H3C3, H2BC3, H2AC14, and RRM2, emerged as key genes driving this association, where H1-5 emerged as a hub gene for this module. Pathways, including nucleosome assembly and DNA damage, were enriched in the histone module. A higher fraction of activated NK and activated CD4+ T cells was related to lower amyloid burden. Show less

The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for Alzheimer's disease (AD) and is linked to poorer cerebrovascular health. Cerebrovascular reactivity (CVR), an indicator of vascular reserve, and cerebral pulsatility (CP), a marker of vascular stiffness, are sensitive biomarkers of early vascular dysfunction associated with aging and AD. However, the relationship between APOE4 status and these cerebrovascular metrics remains unclear. This study investigated whether the APOE genotype influences longitudinal changes in CVR and CP, and their association with cognitive performance in cognitively unimpaired individuals. We utilized the PREVENT-AD cohort, including 101 APOE4 carriers (30 males and 71 females) and 152 non-APOE4 carriers (48 males and 104 females) aged 55 and older. Relative CVR and CP were derived from resting state functional magnetic resonance imaging data, with regional values extracted from cerebral arterial territories. Results indicated significant interactions between APOE4 status and relative CVR in the left middle cerebral artery and left posterior cerebral artery (PCA) territories. APOE4 status disaggregated analyses revealed that APOE4 carriers uniquely presented a significant decline in relative CVR within the left PCA. Furthermore, sex-specific effects were identified, with female APOE4 carriers having lower relative CVR in the right anterior cerebral artery territory compared to female non-carriers. Importantly, higher relative CVR was positively associated with better cognitive performance in APOE4 carriers. No significant effects of APOE4 status on CP were found. Together, these findings suggest that relative CVR may be an important early measure of cerebrovascular health and cognition in cognitively intact APOE4 carriers. Show less

Lipoprotein (a) [Lp(a)] is an independent and causal risk factor for atherosclerotic cardiovascular disease. In this study we aimed at assessing the effect of currently available lipid-lowering therapies (LLTs) on Lp(a) plasma levels. A meta-analysis was performed according to the PRISMA guidelines. Databases were searched up to May 2025. Inclusion criteria were: (1) randomized controlled trials (RCTs) in adults (≥18 years), phase II, III or IV; (2) English language; (3) comparing the effect of lipid-lowering drugs vs placebo (addition of the same drug to both intervention and control group was acceptable); (4) reporting the effects on Lp(a) levels; (5) intervention duration of more than 3 weeks. The between-group (treatment-placebo) Lp(a) absolute mean differences and 95% confidence intervals were calculated for each drug class separately. A total of 145,314 subjects from 147 RCTs were included. Statins, bempedoic acid, ezetimibe, omega-3 fatty acids, and fibrates did not affect Lp(a) concentration. Lp(a) levels were significantly reduced by PCSK9 monoclonal antibodies (PCSK9mAbs, -6.37 mg/dL [-7.26 to -5.47], a 29% reduction from baseline), inclisiran (-4.76 mg/dL [-5.83 to -3.69], a 22% reduction from baseline), CETP inhibitors (CETPi, -6.77 mg/dL [-8.67 to -4.88], a 46% reduction from baseline), and niacin (-7.06 mg/dL [-9.27 to -4.85], a 37% reduction from baseline). In the subgroup analysis by baseline Lp(a) levels, a larger absolute reduction of Lp(a) levels was observed with increasing baseline levels of Lp(a) for PCSK9mAbs, inclisiran, and CETPi. Among available LLTs, PCSK9mAbs, inclisiran, CETPi, and niacin significantly decreased Lp(a) levels. Further research is necessary to understand whether this effect would translate into a clinically relevant cardiovascular benefit. Show less

To identify the susceptibility loci for myopic macular neovascularization (mMNV) in patients with high myopia. A genome-wide association study (GWAS) meta-analysis (meta-GWAS). We included 2783 highly myopic individuals, including 608 patients with mMNV and 2175 control participants without mMNV. We performed a meta-analysis of 3 independent GWASs conducted according to the genotyping platform (Illumina Asian Screening Array [ASA] data set, Illumina Human610 BeadChip [610K] data set, and whole genome sequencing [WGS] data set), adjusted for age, sex, axial length, and the first to third principal components. We used DeltaSVM to evaluate the binding affinity of transcription factors (TFs) to DNA sequences around the susceptibility of single nucleotide polymorphisms (SNPs). In addition, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci. The association between SNPs and mMNV in patients with high myopia. The meta-GWAS identified rs56257842 at TEX29- LINC02337 as a novel susceptibility SNP for mMNV (odds ratio [OR] Our study identified a novel locus associated with mMNV in high myopia. Subsequent analyses offered important insights into the molecular biology of mMNV, providing the potential therapeutic targets for mMNV. Furthermore, our findings imply shared genetic susceptibility between mMNV and AMD. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. Show less

FGFR inhibitors are a new therapeutic option for urothelial carcinoma (UC) with FGFR2/3 alterations. In this study, we analyzed genetic alterations, co-regulation, and differential expression for 45 genes encoding FGF, FGFR, or FGF-binding proteins (FGFBPs) in five published UC cohorts (n = 3939 MIBC) and 39 UC cell lines (DepMap portal). Network analyses identified FGFR1/3 genes as critical oncogenic hubs, co-regulated with their ligands and co-receptors, and abundantly expressed at protein level in the HPA immunohistochemistry data set. Machine learning with 38 FGFR-, FGF-, and FGFBP-coding transcripts reproduced consensus molecular subtypes with high accuracy of 0.72-0.84 (Cohen's κ 0.59-0.77). FGFR3 mutations in the transmembrane/hinge region, which were enriched in luminal papillary tumors, trigger ligand-independent signaling. Conversely, overexpression of FGFR1 and its ligands and accessory protein transcripts indicates ligand-dependent FGFR1 signaling in stroma-rich and basal/squamous subtypes. The sensitivity of most DepMap UC cell lines to pan-FGFR inhibitors in the GDSC and PRISM drug screens was independent of FGFR3 alterations. In vitro, erdafitinib reduced proliferation in FGFR wild-type UC cell lines in a similar manner to FGFR3-mutated cell lines. Our findings highlight FGFR1 and FGFR3 as pivotal signaling pathways with distinct, molecular subtype-specific activation mechanisms. The results suggest that FGFR inhibitors may have therapeutic applications beyond UC tumors with FGFR2/3 alterations. Show less

The 17q21.31 locus in humans harbors several complex structural haplotypes including a ~970kb inversion. Different inversion haplotypes have been associated with susceptibility to microdeletions causing Koolen-de Vries syndrome and variation in fecundity and recombination rates. Here, using 210 haplotype-resolved human genome assemblies and pangenome graph-based approaches we characterize 11 distinct structural haplotypes, several of which have not been previously described. Extending our analyses to a set of haplotype-resolved great-ape genomes, we characterize the structure of an independent inversion in chimpanzees which extends an additional 650kb, encompasses 5 additional genes, and is ~2 million years younger than the human inversion. We further determine that gorillas exhibit an independent duplication of the Show less

The 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP). To investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP. Utilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP. We found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub-haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up-regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down-regulating KANSL1. Single-nucleus RNA-seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up-regulates LRRC37A/LRRC37A2 in neuronal cells. The copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Show less

We report eight children with de novo pathogenic DNA variants in chromatin-related genes: MORC2, CHD7, KANSL1, KMT2D, ZMYND11, HIST1HIE, EP300, and KMT2B. All children experienced infection or vaccine-provoked neuroregression or abrupt-onset neuropsychiatric syndromes. Most had delayed development (n = 6) before the first regression, and four had immune deficiency or autoimmunity (n = 4). At a mean age of 4 years 2 months (range 1-8 years), symptoms included infection-provoked autistic/language regression (n = 6), cognitive decline (n = 3), gait deterioration (n = 3), or abrupt-onset anxiety, obsessive-compulsive disorder, and/or tics (n = 5). Three children had ongoing infection-provoked deteriorations. Six children benefited from intravenous immunoglobulin (n = 3) or antibiotics (n = 4). Ribonucleic acid expression of the eight chromatin genes was similar in neuronal, glial, and peripheral leukocytes, unlike non-chromatin neurodevelopmental genes, which have predominantly neuronal expression. These cases demonstrate the role of chromatin dysregulation in autistic regression and abrupt-onset neuropsychiatric syndromes, potentially related to brain and immune gene dysregulation. Show less

Progressive atherosclerotic cardiovascular disease (ASCVD) associated with high Lp(a) (>60 mg/dl) has been approved as indication for regular lipoprotein apheresis (LA) in Germany since 2008. This observational multicenter study enrolled 170 consecutive patients with high Lp(a) and progressive ASCVD despite effective treatment of other ASCVD risk factors as required for approval of reimbursement to analyse the long-term effect of LA on cardiovascular event rates. Additionally cardiovascular event rates were compared to an appropriate UK-Biobank cohort (UKBBC) with established ASCVD and verified impact of elevated Lp(a) on ASCVD risk. Investigations were conducted on patients retrospectively over a 5-year period before the initiation of regular LA, prospectively 5 years after the commencement of LA, and again retrospectively until the completion of 12 years of LA. 154 patients (90.6 %) completed 5 years follow-up, 129 patients (75.9 %) were available in year 12. A decline in the mean annual rate of cardiovascular events per patient was observed from y-5 to y-1 (0.27 ± 0.25) versus y+1 until y+12 (0.06 ± 0.08) (p < 0.001). One year before commencing LA mean event rates per 100 patient years of the primary composite endpoint parameter of major adverse cardiac events (MACE) including nonfatal ischemic stroke (IS) were significantly higher in Pro(a)LiFe patients compared to the UKBBC. Most importantly they were significantly lower one year after commencing LA. Regular LA was associated with a decreased rate of cardiovascular events in patients with high Lp(a) (>60 mg/dl) and progressive ASCVD up to 12 years. Comparison with corresponding incidence rates in the UKBBC supports the clinical efficacy of LA to bring progressive ASCVD associated with high Lp(a) to a halt. However, this comparative analysis cannot replace a true control group or determine the exact effect size. Show less

Speech impairment is a recognized but unpredictable adverse effect of sub-thalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD). To evaluate the prevalence of speech impairment 1 year after STN-DBS in PD patients and to determine the predictive factors for speech outcome following STN-DBS. Data for 417 patients from the French national PREDISTIM study were collected preoperatively. The combined effect of medical treatment and surgery on speech was compared using specific items from dedicated clinical scales (MDS-UPDRS III.1: primary endpoint) and patient self-assessment questionnaires (items 34 and 35 of the PDQ39: secondary endpoints). For each variable, three patient groups were generated according to speech outcome at 1 year: worsening, stability, and improvement. In the second step analysis, the three groups were compared for demographic and clinical variables at baseline and STN-DBS parameters. There was a significant deterioration in speech of all considered items 1 year after combined STN-DBS and dopaminergic treatment. Four predictive factors for speech deterioration were detected: (i) the absence of preoperative speech impairment (p < 0.001); (ii) severity of motor activity of daily living (MDS-UPDRS II off total score) (p = 0.037); (iii) high-intensity stimulation of the left electrode (i.e., above 3.6 V) (p = 0.046); and (iv) the absence of any change in non-motor experiences of daily life (MDS-UPDRS I total score) (p = 0.048). Speech outcome should be carefully monitored after STN-DBS, especially in PD patients without preoperative speech impairment, with motor difficulties in daily-living activities, and with increased left electrode intensity. ClinicalTrials.gov identifier: NCT02360683. Show less

There are many options for the surgical management of complicated diverticulitis, and standards vary widely despite international practice recommendations. We conducted a survey to capture the variation in practice across Europe. An online questionnaire was distributed to fellow and surgeon members of the European Association of Endoscopic Surgery (EAES) via email using the Opinio survey platform. Participants shared their demographic details. We asked members to rank the most likely intervention for patients with both stable and unstable Hinchey Class III, as well as Hinchey Class IV diverticulitis based on practice standards in their country. We used descriptive statistics, including counts and percentages, to characterize survey results. We created a heatmap to visualize the percentage of votes received for each intervention. We received 233 responses from surgeons and fellows across Europe from various countries, including Italy (35.6%), Greece (11.2%), and the United Kingdom (9.9%). Most members (79.4%) self-reported having expertise in colorectal surgery. For patients with stable Hinchey III diverticulitis, surgeons offered Hartmann's resection (HR) (41.6%), primary resection and anastomosis (PRA) (18.5%), laparoscopic peritonea lavage (LPL) prior to HR (16.9%), or LPL prior to PRA (15.5%), or LPL only (8.6%). In total, 31.4% of respondents offered LPL prior to sigmoid resection (HR + PRA). For patients with unstable Hinchey III diverticulitis, respondents offered HR (73.9%), PRA (3.85%), LPL only (6.84%), or LPL followed by sigmoid resection (15.4%). For patients with stable Hinchey IV diverticulitis, surgeons offered HR (71.7%), PRA (4.7%), LPL only (1.3%), or LPL then sigmoid resection (22.3%). Finally, for patients with unstable Hinchey IV diverticulitis, surgeons offered HR (83.1%), PRA (1.3%), LPL only (3.5%), or LPL followed by sigmoid resection (12.1%). Significant variation exists in the surgical management of complicated diverticulitis across Europe. Efforts must be made to increase the awareness and uptake of surgical guideline recommendations in clinical practice. Show less

The purpose of this study was to identify conjunctival transcriptome differences in patients with Acanthamoeba keratitis compared with keratitis with no known associated pathogen. The host conjunctival transcriptome of 9 patients with Acanthamoeba keratitis (AK) is compared with the host conjunctival transcriptome of 13 patients with pathogen-free keratitis. Culture and/or confocal confirmed Acanthamoeba in 8 of 9 participants with AK who underwent metagenomic RNA sequencing as the likely pathogen. Cultures were negative in all 13 cases where metagenomic RNA sequencing did not identify a pathogen. Transcriptome analysis identified 36 genes differently expressed between patients with AK and patients with presumed sterile, or pathogen-free, keratitis. Gene enrichment analysis revealed that some of these genes participate in several biologic pathways important for cellular signaling, ion transport and homeostasis, glucose transport, and mitochondrial metabolism. Notable relatively differentially expressed genes with potential relevance to Acanthamoeba infection included CPS1 , SLC35B4 , STEAP2 , ATP2B2 , NMNAT3 , and AKAP12 . This research suggests that the local transcriptome in Acanthamoeba keratitis may be sufficiently robust to be detected in the conjunctiva and that corneas infected with Acanthamoeba may be distinguished from the inflamed cornea where no pathogen was identified. Given the low sensitivity for corneal cultures, identification of differentially expressed genes may serve as a suggestive transcriptional signature allowing for a complementary diagnostic technique to identify this blinding parasite. Knowledge of differentially expressed genes may also direct investigation of disease pathophysiology and suggest novel pathways for therapeutic targets. Show less

Neuroendocrine neoplasms are a group of heterogeneous tumors originating from the neuroendocrine system, which can occur in any part of the body. Pulmonary and gastroenteropancreatic neuroendocrine tumors are the most common. In recent years, the global incidence of neuroendocrine tumors has increased more significantly than other types of tumors, especially in the past 40 years. The drug treatment of neuroendocrine tumors includes somatostatin analogues, anti-angiogenesis targeting drugs, nuclide therapy and chemotherapy. Surufatinib is an oral tyrosine kinase receptor inhibitors that targets for vascular endothelial growth factor receptor (VEGFR1-3), fibroblast growth factor receptor 1 (FGFR1), and colony-stimulating factor-1 receptor (CSF-1R), has received approval in 2020 and 2021 for the treatment of locally advanced or metastatic, progressive nonfunctional, well-differentiated (G1, G2) neuroendocrine tumors (NETs) of both pancreatic and extrapancreatic origin that are unresectable. Ongoing exploratory studies are investigating its potential application in other tumor types. Common adverse reactions observed during surufatinib treatment include hypertension, proteinuria, bleeding events, and hepatic lab test abnormal and diarrhea. Chinese multidisciplinary expert consensus on the rational use of surufatinib in clinical practice (2024 edition) aims to provide standardized guidance for its rational use and enhance patient compliance to maximize therapeutic benefits. Show less

Integrated analyses of plasma proteomics and genetic data in prospective studies can help assess the causal relevance of proteins, improve risk prediction, and discover novel protein drug targets for type 2 diabetes (T2D). We measured plasma levels of 2,923 proteins using Olink Explore among ∼2,000 randomly selected participants from China Kadoorie Biobank (CKB) without prior diabetes at baseline. Cox regression assessed associations of individual protein with incident T2D (n = 92 cases). Proteomic-based risk models were developed with discrimination, calibration, reclassification assessed using area under the curve (AUC), calibration plots, and net reclassification index (NRI), respectively. Two-sample Mendelian randomization (MR) analyses using cis-protein quantitative trait loci identified in a genome-wide association study of CKB and UK Biobank for specific proteins were conducted to assess their causal relevance for T2D, along with colocalization analyses to examine shared causal variants between proteins and T2D. Overall, 33 proteins were significantly associated (false discovery rate <0.05) with risk of incident T2D, including IGFBP1, GHR, and amylase. The addition of these 33 proteins to a conventional risk prediction model improved AUC from 0.77 (0.73-0.82) to 0.88 (0.85-0.91) and NRI by 38%, with predicted risks well calibrated with observed risks. MR analyses provided support for the causal relevance for T2D of ENTR1, LPL, and PON3, with replication of ENTR1 and LPL in Europeans using different genetic instruments. Moreover, colocalization analyses showed strong evidence (pH4 > 0.6) of shared genetic variants of LPL and PON3 with T2D. Proteomic analyses in Chinese adults identified novel associations of multiple proteins with T2D with strong genetic evidence supporting their causal relevance and potential as novel drug targets for prevention and treatment of T2D. Show less

Inflammageing is a condition of perpetual low-grade inflammation induced by ageing. Inflammageing may be predicted by the C-reactive protein (CRP) or by a recently described biomarker which measures N-glycosylated side chains of the carbohydrate component of several acute-phase proteins known as GlycA. The objective of this study was to examine in depth the genetic relationships between CRP and GlycA as well as between each of them and other selected cytokines, which may shed light on the mechanisms of inflammageing. Using the Olink 96 Inflammation panel, data on inflammatory mediators for 1518 twins from the TwinsUK dataset were acquired. Summary statistics for genome-wide association studies for several cytokines as well as CRP and GlycA were collected from public sources. Extensive genetic correlation analyses, colocalization and genetic enrichment analyses were carried out to detect the shared genetic architecture between GlycA and CRP. Mendelian randomization was carried out to assess potential causal relationships. GlycA predicted examined cytokines with a magnitude twice as great as that of CRP. GlycA and CRP were significantly genetically correlated (Rg = 0.4397 ± 0.0854, Show less

Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored. We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes. During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort. Show less

Community-acquired pneumonia remains a major contributor to global communicable disease-mediated mortality. Neutrophils play a leading role in trying to contain bacterial lung infection, but they also drive detrimental pulmonary inflammation, when dysregulated. Here we aimed at understanding the role of microRNA-223 in orchestrating pulmonary inflammation during pneumococcal pneumonia. Serum microRNA-223 was measured in patients with pneumococcal pneumonia and in healthy subjects. Pulmonary inflammation in wild-type and microRNA-223-knockout mice was assessed in terms of disease course, histopathology, cellular recruitment and evaluation of inflammatory protein and gene signatures following pneumococcal infection. Low levels of serum microRNA-223 correlated with increased disease severity in pneumococcal pneumonia patients. Prolonged neutrophilic influx into the lungs and alveolar spaces was detected in pneumococci-infected microRNA-223-knockout mice, possibly accounting for aggravated histopathology and acute lung injury. Expression of microRNA-223 in wild-type mice was induced by pneumococcal infection in a time-dependent manner in whole lungs and lung neutrophils. Single-cell transcriptome analyses of murine lungs revealed a unique profile of antimicrobial and cellular maturation genes that are dysregulated in neutrophils lacking microRNA-223. Taken together, low levels of microRNA-223 in human pneumonia patient serum were associated with increased disease severity, whilst its absence provoked dysregulation of the neutrophil transcriptome in murine pneumococcal pneumonia. Show less

REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18. Show less