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Telomeres form protective caps at the ends of chromosomes, and their attrition is a marker of biological aging. Short telomeres are associated with an increased risk of neurological and psychiatric disorders including dementia. The mechanism underlying this risk is unclear, and may involve brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized. Here we show that leucocyte telomere length (LTL) is associated with multi-modal MRI phenotypes in 31,661 UK Biobank participants. Longer LTL is associated with: i) larger global and subcortical grey matter volumes including the hippocampus, ii) lower T1-weighted grey-white tissue contrast in sensory cortices, iii) white-matter microstructure measures in corpus callosum and association fibres, iv) lower volume of white matter hyperintensities, and v) lower basal ganglia iron. Longer LTL was protective against certain related clinical manifestations, namely all-cause dementia (HR 0.93, 95% CI: 0.91–0.96), but not stroke or Parkinson’s disease. LTL is associated with multiple MRI endophenotypes of neurodegenerative disease, suggesting a pathway by which longer LTL may confer protective against dementia.

The third trimester of human gestation is characterised by rapid increases in brain volume and cortical surface area. Recent studies have revealed a remarkable molecular diversity across the prenatal cortex but little is known about how this diversity translates into the differential rates of cortical expansion observed during gestation. We present a digital resource, μBrain, to facilitate knowledge translation between molecular and anatomical descriptions of the prenatal brain. Using μBrain, we evaluate the molecular signatures of preferentially-expanded cortical regions, quantified in utero using magnetic resonance imaging. Our findings demonstrate a spatial coupling between areal differences in the timing of neurogenesis and rates of neocortical expansion during gestation. We identify genes, upregulated from mid-gestation, that are highly expressed in rapidly expanding neocortex and implicated in genetic disorders with cognitive sequelae. The μBrain atlas provides a tool to comprehensively map early brain development across domains, model systems and resolution scales. The third trimester of human gestation is characterised by rapid increases in cortical surface area. Here, authors show that increased rates of cortical expansion are associated with differences in the timing of neurogenesis.

This study provides a holistic view of the coupled ocean-atmosphere-sea ice processes responsible for generating interannual variability in sea ice coverage in the Sea of Okhotsk as well as the atmospheric response to this variability. Simulations from the Community Earth System Model Large Ensemble project are analyzed, providing the ability to elucidate the time evolution of these relationships through weekly lead-lag composite analysis, while maintaining a large number of samples to provide robust conclusions. We find that thermodynamic processes involving anomalous ocean-atmosphere heat fluxes affect the timing of initial sea ice growth in the Sea of Okhotsk as early as November. Low-level wind anomalies in the winter affect the extent to which sea ice fully develops, both through advection of the sea ice itself and through changes in the transport of air masses over the Sea of Okhotsk. In this study, the results synthesize and support a diverse set of mechanisms identified in previous observational studies to be responsible for anomalous sea ice conditions, but in a coupled global climate model framework with a large sample size. We also find evidence that anomalous ocean-atmosphere heat fluxes in the winter can trigger an atmospheric response comprised of a local negative sea-level pressure anomaly and Rossby wave that extends over North America. The sign of the turbulent heat fluxes relative to the sea ice anomalies confirm that this is indeed a lagged response of the atmosphere forced by sea ice anomalies. This validates the Rossby wave train response identified in more idealized model simulations with prescribed sea ice and sea surface temperature by demonstrating that this process also occurs in a more realistic coupled model framework.

BackgroundWith improvements in the risks of relapse and mortality in ANCA-associated vasculitis (AAV), a better understanding of disease- and treatment-related complications in people with AAV is necessary to optimize outcomes and personalize care. Multimorbidity (MM) is a patient-centered approach to measuring complications and is defined as the presence of multiple chronic conditions[1]. MM is associated with risk of death and quality of life in other conditions. MM remains poorly understood in AAV[2].ObjectivesTo determine the burden of multimorbidity in AAV.MethodsWe used the 2002-2019 Mass General Brigham (MGB) AAV cohort: an inception cohort of consecutive MPO- or PR3-ANCA+ incident AAV cases at a multi-center healthcare system in New England, USA. Comparators without systemic rheumatic disease were identified from MGB and matched to cases (10:1 ratio) by encounter date, age, sex, and race. We adapted a definition of MM as the presence of ≥ 2 of 37 chronic conditions, identified by use of ICD-9/10 codes ≥ twice over ≥ 30 days[1]. Manifestations of AAV (e.g., kidney disease) were excluded from the MM definition. Conditions present ≥ 6 months prior to the index date (date of treatment initiation) were excluded. First, we determined the proportion of cases and comparators with MM using the Aalen-Johansen method, accounting for the competing risks of death and loss to follow up. Second, we used Cox proportional hazard models to estimate the hazard ratio (HR) of MM in cases vs comparators and restricted mean survival time to estimate days free of MM in cases vs comparators. Third, we used latent class analysis to characterize clusters of morbidity among people with MM.ResultsThere were 547 cases matched to 5,259 comparators (Table 1); mean age was 59 years and the majority were female (61%) and white (88%). Median follow-up in cases and comparators was 102 months and 66 months, respectively. MM was substantially more common in cases vs comparators and AAV cases had nearly an 8-fold higher risk of MM vs comparators (Figure 1, HR 7.6, 95% CI 6.6-8.7). Over 5 years, each case had an average of 707 fewer days with MM than comparators (963.4 vs 1670.5 days, p<0.001). At 1 year, two clusters of MM in AAV were identified with 76% and 24% captured in Clusters 1A and 1B, respectively. Hypertension and hyperlipidemia were common in Cluster 1A whereas Cluster 1B was characterized by painful conditions (e.g., headache, back pain, GERD). At 2 years, two clusters were identified with 82% and 18% captured in Clusters 2A and 2B. Cluster 2B was distinguished from 2A by a high burden of cardiovascular (CV) and pulmonary disease along with typical CV risk factors. At 5 years, three clusters were identified with 81%, 11%, and 8% captured in Cluster 5A, 5B, and 5C. Morbidities most common in Cluster 5A were hypertension and hyperlipidemia. Cluster 5B was distinguished by a higher burden of CV and pulmonary disease whereas Cluster 5C had the highest burden of certain glucocorticoid toxicities (e.g., osteoporosis, obesity, hypertension).ConclusionAAV is associated with a high burden of MM and carries a greater risk of MM than the general population. MM in AAV is characterized by clusters defined by morbidity burdens that vary over disease course and reflect a high impact of disease and its treatment. The development of interventions to prevent MM and minimize its impacts are needed. These findings identify an important direction for future investigations to improve the care and outcomes of patients with AAV.References[1]England BR, et al. Ann Rheum Dis 2021;80:286–92.[2]Sarica SH, et al. Arthritis Rheumatol 2021;73:651-9.Table 1.The Burden of Multimorbidity in AAVAAV CasesComparatorsN5475259Age (mean, SD)59 (17)59 (17)Female (%)39%39%RaceWhite88%92%Black/African American2%2%Asian1%1%Other2%2%Unknown3%1%BMI (mean, SD)28.3 (6.9)28.5 (7.3)Proportion with MultimorbidityYear 137.8%5.7%Year 250.7%8.7%Year 354.4%11.8%Year 461.4%14.9%Year 566.2%19.1%Days Free from Multimorbidity*Year 1282353Year 2489696Year 36661028Year 48231353Year 59631671*Adjusted for age, sex, raceAcknowledgements:NIL.Disclosure of InterestsNone Declared.

Insight regarding the impact of COVID-19 on return to sporting participation is a key issue for many athletes. We report time-loss following respiratory tract infection (RTI), over the pandemic, in UK athletes preparing for international competition. During the study, 566 athletes developed COVID-19 and 217 developed other causes of RTI. Time-loss from COVID-19 reduced from a median (interquartile range) of 27 days (13- 40) in April-June 2020 to 10 days (8-13) from October-December 2022 (P<0.001). There was no change in time-loss following RTi (P=0.13). The time-loss period following COVID-19 has shortened over the pandemic. Further work is needed to explore why some athletes still have prolonged sporting time-loss.

The early life environment programmes cortical architecture and cognition across the life course. A measure of cortical organisation that integrates information from multimodal MRI and is unbound by arbitrary parcellations has proven elusive, which hampers efforts to uncover the perinatal origins of cortical health. Here, we use the Vogt‐Bailey index to provide a fine‐grained description of regional homogeneities and sharp variations in cortical microstructure based on feature gradients, and we investigate the impact of being born preterm on cortical development at term‐equivalent age. Compared with term‐born controls, preterm infants have a homogeneous microstructure in temporal and occipital lobes, and the medial parietal, cingulate, and frontal cortices, compared with term infants. These observations replicated across two independent datasets and were robust to differences that remain in the data after matching samples and alignment of processing and quality control strategies. We conclude that cortical microstructural architecture is altered in preterm infants in a spatially distributed rather than localised fashion. The Vogt‐Bailey index is a measure of local homogeneity computed at each vertex of a cortical surface by integrating information from multiple MRI features. We use it to study the impact of being born preterm on cortical development. We found widespread alterations that replicate across two neonatal datasets.

Background:People with rheumatoid arthritis (RA), psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), and axial spondyloarthritis (axSpA) are at risk for poor acute COVID-19 outcomes because of their disease, comorbidities, and/or treatments. Less is known about the impact of COVID-19 infection and ‘long COVID’ on post-acute COVID-19 outcomes in this vulnerable population, particularly with regard to rheumatic disease activity, disability, and quality of life.Objectives:To examine the association of COVID-19 infection and ‘long COVID’ with disease activity, disability, and quality of life in people with inflammatory arthritis.Methods:RheumCARD is a prospective cohort study recruiting people with systemic rheumatic disease with (cases) and without (comparators) a history of COVID-19 from a large US healthcare system. Participants are recruited ≥ 28 days after acute COVID-19 onset. Surveys include the Routine Assessment of Patient Index Data 3 (RAPID-3), modified health assessment questionnaire (MHAQ), short form 12 (SF-12), fatigue symptom inventory (FSI), and short form McGill Pain Questionnaire (SF-MPQ). Participants report rheumatic disease control (scale 0-10, 10 being well-controlled) before and after COVID-19 (cases) or test for COVID-19 (comparators). Here, we analyzed only participants with inflammatory arthritis (RA, PsA, JIA, or axSpA) who completed surveys 3/2021-10/2023. ‘Long COVID’ was defined as symptoms of acute COVID-19 for ≥ 28 days (US CDC Definition). We assessed the association of having had vs not had COVID-19 with measures as well as the association of ‘long COVID’ with these measures in unadjusted and adjusted models. We performed a subgroup analysis restricted to patients with RA.Results:We analyzed 276 post-COVID-19 cases and 59 comparators without COVID-19; 39.5% cases had ‘long COVID’ (Table 1). Most cases and comparators, respectively, had RA (67% and 85%), were female (80% and 80%), and White (88% and 93%). The most used medications were methotrexate and/or TNF inhibitors. RAPID-3, MHAQ, SF-12 physical and mental health, FSI, and SF-MPQ scores were similar among those with and without a history of COVID-19; rheumatic disease control was worse after COVID-19 infection among those with prior COVID-19 (Table 2). After stratifying by ‘long COVID’ status, worse RAPID-3 (3.7 vs 2.3, p<0.01), MHAQ (0.4 vs 0.1, p<0.01), SF-12 physical (38.1 vs 47.2, p<0.01) and mental health (48.6 vs 53.0, p=0.03), FSI (5 vs 4 (p<0.01), SF-MPQ scores for sensory (4.5 vs 3, p<0.01), affective (1 vs 1, p=0.01), and present pain (2 vs 1, p<0.01), and rheumatic disease control scores (6 vs 7, p=0.05) were observed among those with vs without ‘long COVID’. Of note, perceived rheumatic disease control prior to COVID-19 or testing was similar among those with ‘long COVID’, without ‘long COVID’, and no prior history of COVID-19. Those without ‘long COVID’ had similar outcomes compared to those with no history of COVID-19 except for rheumatic disease control which was worse among those without ‘long COVID’ (Table 2). Findings were similar when the analyses were limited to those with RA and adjusted for age, sex, and race.Conclusion:In the post-acute period, COVID-19 has a substantial impact on people with inflammatory arthritis. Those with ‘long COVID’ have significantly worse rheumatic disease activity, disability, fatigue, pain, and quality of life. Even those who do not have ‘long COVID’ report worse disease control than those without prior COVID-19. These differences may reflect features of ‘long COVID’ and/or exacerbations of the underlying inflammatory arthritis. Additional studies are needed to elucidate the immunologic or other factors driving these differences.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Zachary S. Wallace Viela Bio, Zenas BioPharma, Horizon Therapeutics, Sanofi, MedPace, BioCryst, Amgen, PPD, Shionogi, Otsuka/Visterra, BMS, Sanofi, Amgen, Miao Lin: None declared, Xiaosong Wang: None declared, Naomi Patel: None declared, Yumeko Kawano: None declared, Abigail Schiff: None declared, Andrew King: None declared, Jennifer Hanberg: None declared, Shruthi Srivatsan: None declared, Emily Kowalski: None declared, Colebrook Johnson: None declared, Kathleen Vanni: None declared, Zachary Williams: None declared, Grace Qian: None declared, Caleb Bolden: None declared, Kevin Mueller: None declared, Katarina Bade: None declared, Alene Saavedra: None declared, Rathnam Venkat: None declared, Jeffrey A. Sparks AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi, and UCB, BMS, Boehringer Ingelheim.

Background:While the incidence of severe acute COVID-19 has decreased, post-acute sequelae of COVID-19, or ‘long COVID,’ is common and associated with lower quality of life and morbidity. Long COVID is likely multifactorial, but may be in part driven by systemic inflammation and immune dysregulation. Patients with systemic autoimmune rheumatic diseases (SARDs) may be at risk for long COVID due to underlying altered immunity, immunosuppressive drug use, and propensity for systemic inflammation. Thus, identifying inflammatory biomarkers for long COVID may be helpful to identify biologic pathways and develop treatments and diagnostic tests.Objectives:We aimed to examine whether circulating inflammatory cytokines after COVID-19 were associated with presence of long COVID among patients with SARDs.Methods:We investigated biomarkers of inflammation and long COVID using RheumCARD, a prospective study of people with prevalent SARDs with (cases) and without (comparators) a history of COVID-19 from a large healthcare system in the US. Cases are recruited ≥28 days following onset of acute COVID-19 to answer surveys and provide blood samples (March 2021 to July 2023). We measured circulating cytokines in serum using the proximity extension assay (Olink Target 48 cytokine panel). If patients were on a DMARD targeted to a cytokine (e.g., TNF), their data was excluded. The primary outcome was long COVID defined according to US CDC criteria as persisting for ≥28 days. The primary analysis compared those with vs without long COVID among SARDs after COVID-19. We compared median cytokine levels between groups using Wilcoxon rank sum tests. We compared those with vs. without long COVID for cytokine levels using linear regression, adjusting for age, sex, vaccine status, and SARS-CoV-2 variant. We performed subgroup analyses among those with inflammatory arthritis, pre-Omicron variants, Omicron variants, remission/low disease activity, moderate/high disease activity as well as a more stringent definition of long COVID (≥90 days of persistent symptoms). We also analyzed comparators, SARDs who never had COVID-19 before sample collection.Results:We analyzed a total of 201 cases (prevalent SARDs after COVID-19; mean age 56 years, 81% female) and 47 comparators (SARDs without COVID-19; mean age 62 years, 75% female). The most common SARD type among cases was inflammatory arthritis (60%), followed by connective tissue disease (22%, Table 1). Considering SARD treatment, 63 (31%) were only on conventional synthetic DMARDs, and 53 (26%) were on TNF inhibitors. A total of 54 (27%) cases were unvaccinated at COVID-19 onset, and 76 (38%) had pre-Omicron SARS-CoV-2 variants. Among cases, 78 (39%) reported COVID-19 symptoms persisting for ≥28 days and were classified as long COVID for the primary outcome; 44 (22%) had symptoms for ≥90 days. IL18 levels were lower among those with long COVID (199 pg/mL) vs without long COVID (221 pg/mL; p=0.001). In the multivariable analysis, long COVID cases had lower IL-18 levels than those without long COVID (β -55 pg/mL, SE 17, p=0.0011, Table 2). There were also associations of lower levels of CSF2 and CCL7 as well as higher levels of IL-2 with long COVID. IL-18 levels were consistently lower in those with vs without long COVID in all additional analyses: inflammatory arthritis (p=0.021), remission/low disease activity (p=0.02), moderate/high disease activity (p=0.015), pre-Omicron variants (p=0.004), Omicron variants (p=0.06), long COVID defined as ≥90 days of persistent symptoms (p=0.004), and vs comparators (p=0.011).Conclusion:In this prospective study performed among SARDs after COVID-19, lower IL-18 levels were associated with long COVID. This finding was robust across all analyses examined and not explained by vaccination or viral variants. IL-18 is produced by inflammasome activation and induces cell-mediated immunity following infection, implicating a blunted immune response, rather than exuberant hyperinflammation, as a potential mechanism for long COVID among patients with SARDs.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Jeffrey A. Sparks AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi, and UCB, Bristol Myers Squibb and Boehringer Ingelheim, Xiaosong Wang: None declared, Pui.Y Lee: None declared, Kailey Brodeur: None declared, Miao Lin: None declared, Naomi Patel FVC, Yumeko Kawano: None declared, Abigail Schiff: None declared, Andrew King: None declared, Jennifer Hanberg: None declared, Shruthi Srivatsan: None declared, Emily Kowalski: None declared, Colebrook Johnson: None declared, Kathleen Vanni: None declared, Zachary Williams: None declared, Grace Qian: None declared, Caleb Bolden: None declared, Kevin Mueller: None declared, Katarina Bade: None declared, Alene Saavedra: None declared, Rathnam Venkat: None declared, Zachary S. Wallace Viela Bio, Zenas BioPharma, Horizon Therapeutics, Sanofi, MedPace, BioCryst, Amgen, PPD, Shionogi, Otsuka/Visterra, BMS, Sanofi, Amgen, Bristol-Myers Squibb and Principia/Sanofi.

While mutations in the fragile X mental retardation-1 (FMR1) gene are associated with varying reproductive outcomes in females, the effects of a complete lack of FMR1 expression are not known. Here, we studied the ovarian and reproductive phenotypes in an Fmr1 knockout (KO) mouse model and the role of mammalian target of rapamycin (mTOR) signaling. Breeding, histologic and mTOR signaling data were obtained at multiple time points in KO and wild type (WT) mice fed a control or rapamycin (mTOR inhibitor) diet. KO mice showed an earlier decline in ovarian reserve than WT mice with an increased proportion of activated follicles. mTOR and phosphorylated S6 kinase (p-S6K) levels, a measure of downstream mTOR signaling, were elevated in the KO ovaries. Rapamycin blocked these effects in KO mice, and increased the primordial follicle pool and age of last litter in WT mice. Our data demonstrates an early decline in reproductive capacity in Fmr1 KO mice and proposes that premature recruitment of the primordial pool via altered mTOR signaling may be the mechanism. Reversal of phenotypes and protein levels in rapamycin-treated KO mice, as well as increased reproductive lifespan of rapamycin-fed WT mice, suggest the mTOR pathway as a potential therapeutic target.

Age-period-cohort (APC) study. Using data from the 1978-2014 General Social Survey-National Death Index (GSS-NDI), we conducted APC analyses using generalized linear models to quantify the temporal trends of racial differences in our selected measures of well-being, beliefs, and emotional states. We then conducted APC survival analysis using mixed-effects Cox proportional hazard models to quantify the temporal trends of racial differences in survival after removing the effects of racial differences in our selected measures. For whites, the decline in happiness was steeper than for blacks despite an increase in high school graduation rates among whites relative to blacks over the entire period, 1978-2010. Self-rated health increased in whites relative to blacks from 1978 through 1989 but underwent a relative decline thereafter. After adjusting for age, sex, period effects, and birth cohort effects, whites, overall, had higher rates of self-rated health (odds ratio [OR] = 1.88; 95% confidence interval [CI] = 1.63, 2.16), happiness (OR = 2.05; 1.77, 2.36), and high school graduation (OR = 2.88; 2.34, 3.53) compared with blacks. Self-rated health, happiness, and high school graduation also mediated racial differences in survival over time. We showed that some racial differences in survival could be partly mitigated by eliminating racial differences in health, happiness, and educational attainment. Future research is needed to analyze longitudinal clusters and identify causal mechanisms by which social, behavioral, and economic interventions can reduce survival differences.