Adult Disease Research Articles

From bench to clinic: the development of VLA1553/IXCHIQ, a live-attenuated chikungunya vaccine.

Over the past 20years, over 5 million cases of chikungunya, a mosquito-transmitted viral disease, have been reported in over 110 countries. Until recently, preventative strategies for chikungunya were largely ineffective, relying on vector control and individual avoidance of mosquito bites. This review outlines the preclinical and clinical efficacy and safety data that led to the approval of VLA1553 (IXCHIQ®), a live-attenuated vaccine against chikungunya disease. It also describes the innovative development pathway of VLA1553, based on an immunological surrogate of protection, and discusses ongoing and future post-licensure studies. In mice and non-human primate models, VLA1553 elicited high titres of neutralizing antibodies, conferred protection against wild-type chikungunya virus challenge and raised no safety concerns. A Phase 1 clinical trial of VLA1553 demonstrated 100% seroconversion among 120 healthy participants, with sustained neutralizing antibody titres after 12months. These results and determination of a surrogate marker of protection led to advancement of VLA1553 directly into Phase 3 clinical development, as agreed with the US Food and Drug Administration (FDA) and the European Medicines Agency. The pivotal Phase 3 trial met its primary immunogenicity endpoint, achieving seroprotective levels based on immuno-bridging in baseline seronegative participants 28days post-vaccination. These findings enabled submission of a Biologics Licence Application to the FDA for accelerated approval of VLA1553 in the US for adults aged ≥18years. Ongoing and planned studies will confirm the clinical efficacy/effectiveness and safety of VLA1553 in adults and younger individuals, and will generate data in chikungunya endemic countries that have the highest unmet need. VLA1553 is the first vaccine approved for the prevention of chikungunya disease in adults, following accelerated development based on a serological surrogate marker of protection. VLA1553 adds to strategies to reduce the spread and burden of chikungunya in endemic populations and travellers.

Describing the kidney health of ARDAC study participants using data linkage

ObjectivesThe Antecedents of Renal Disease in Aboriginal Children and Young Adults (“ARDAC”) study is the largest data linkage study on the kidney health of First Nations Peoples internationally. Using this data linkage this study aimed to describe the kidney health of ARDAC study participants (both Indigenous and non-Indigenous) aged under 25 years old. MethodsAdministrative data from hospital and community healthcare utilisation, pharmaceutical claims, and biomedical measurements were used to create a hybrid case definition for CKD. Using this definition, descriptive statistics and bivariate analysis were used to describe sociodemographic characteristics of ARDAC participants with CKD. A ‘strengths-based’ regression analysis was also undertaken to challenge past ways of reporting kidney health outcomes and improve equity among young Aboriginal peoples. ResultsFrom the 3758 participants enrolled at baseline, approximately 1.5% of young people developed CKD between 2002 to 2019 (follow-up: 2-4 years). The current median age of the cohort is 26.7 years. The majority of those with CKD were identified through biomedical and pharmaceutical data combined, followed by community healthcare claims, and hospitalizations. Findings from the regression analysis will provide insight into the socioeconomic factors that lead to CKD in young people and will be the focus of this presentation. Conclusions/ImplicationsOur findings report for the first time the socioeconomic drivers of kidney health equity for young Aboriginal peoples. Understanding these drivers provides opportunities to work in partnership with communities to develop culturally safe health promotion.

Phylogenetic Lineages and Diseases Associated with Moraxella catarrhalis Isolates Recovered from Bulgarian Patients.

Moraxella catarrhalis has been recognized as an important cause of upper respiratory tract and middle ear infections in children, as well as chronic obstructive pulmonary disease and chronic bronchitis in adults. We aim to study the clonal structure, antimicrobial resistance, and serotypes of M. catarrhalis strains recovered from patients of different ages. Nasopharyngeal swabs, middle ear fluid, and sputum samples were collected. In vitro susceptibility testing was performed according to EUCAST criteria. The monoclonal Ab hybridoma technique was used for serotyping. All strains were subjected to MLST. The studied population demonstrated susceptibility to all tested antimicrobials M. catarrhalis strains, with the majority being serotype A (90.4%), followed by B (6.8%), and C (2.7%). We observed a predominant clonal complex CC224 (21.9%) along with other clusters including CC141 (8.2%), CC184 (8.2%), CC449 (6.8%), CC390 (5.5%), and CC67 (2.7%). Two primary founders, namely, ST224 and ST141, were identified. The analyzed genetic lineages displayed diversity but revealed the predominance of two main clusters, CC224 and CC141, encompassing multidrug-resistant sequence types distributed in other regions. These data underscore the need for ongoing epidemiological monitoring of successfully circulating clones and the implementation of adequate antibiotic policies to limit or delay the spread of multidrug-resistant strains in our region.

Hypertension in children and adolescents: perspectives in Japan.

Hypertension in children and adolescents is associated with increased risk of hypertension and cardiovascular disease (CVD) in adulthood. Therefore, preventing hypertension among children and adolescents is an important public health objective worldwide. Although the importance of hypertension in children and adolescents has increasingly been recognized, the field of research is relatively new and evidence for etiologies, prevention and treatment is sparse. This review mainly summarizes the content regarding hypertension in children and adolescents published in Hypertension Research in 2023/24. Highlights include the following: The prevalence of hypertension was higher in female than male Japanese junior high school students (13.7% vs. 4.7%), but there was no significant gender difference among Japanese senior high school students (7.4% vs. 5.4%). Hematological parameters, including red blood cell counts, hemoglobin counts, hematocrit and iron levels, were positively associated with blood pressure (BP) levels in healthy children and adolescents. Higher-risk longitudinal BP trajectories in early life were associated with increased risk of target organ damage (TOD) and higher combined TOD load in midlife. BP phenotypes (e.g., masked hypertension, white-coat hypertension) assessed using office and 24-h ambulatory BP monitoring were not highly reproducible in children. The salt check sheet was a useful tool for evaluating the approximate dietary salt intake in Japanese children and adolescents. It is recommended that healthcare providers screen for hypertension in children and adolescents and recognize the importance of early intervention for those with elevated BP levels. Beginning in childhood, continuous education on hypertension and proper dietary salt intake are key to reducing the risk of hypertension and decreasing the burden of CVD in adulthood.

Methodological Guidelines of the Scientific Community for Human Microbiome Research (CHMR) and the Russian Gastroenterology Association (RGA) on the Use of Probiotics, Prebiotics, Synbiotics, Metabiotics and Functional Foods Enriched with Them for the Treatment and Prevention of Gastrointestinal Diseases in Adults and Children

Aim: to optimize outcomes of the treatment and prevention of gastrointestinal diseases in adults and children. Key points. The Methodological Guidelines contain sections on the terminology, classification, mechanisms of action, requirements for sale in the Russian Federation, requirements for proving the efficacy and safety of probiotics, prebiotics, synbiotics and metabiotics, as well as functional foods enriched with them. An overview of relevant data allowing to include these drugs and products in the treatment an d prevention of gastrointestinal diseases in adults and children is presented. Conclusion. The clinical efficacy of probiotics, prebiotics, synbiotics and metabiotics depends on the specificity and quantity of their components, the dosage form, the regimen and duration of treatment. Products and functional foods with proven efficacy and safety are recommended for the treatment and prevention of gastrointestinal diseases in adults and children.

Different types and numbers metabolic abnormalities and risk of gallbladder stone disease in adults.

Metabolic abnormalities in the body increase the risk of gallbladder stones and their complications, which brings a great economic and social burden. The relationship between different types and amounts of metabolic abnormalities and gallstone risk in different sexes is poorly documented and controversial. Based on the baseline survey data of the Chinese Multi-Ethnic Cohort (CMEC) study, 4,075 Chinese adults aged 30-79 years with complete abdominal ultrasound results and metabolic index data. Logistic regression model was used to evaluate the correlation between five metabolic abnormalities and gallstones, and to explore the gender difference. The detection rate of gallbladder stones was found to be 7.0%, with a higher rate in women (8.6%) than in men (4.1%). Logistic results showed adjustment odds ratio (ORs) and 95% confidence interval (95% CI) of dysglycemia + hypertension + central obesity in 3 metabolic combinations was 4.459 (1.653, 12.029). The four metabolic combinations, dysglycemia + dyslipidemia + hypertension + central obesity, dysglycemia + dyslipidemia + hypertension + abnormal blood uric acid and dysglycemia + dyslipidemia + central obesity + abnormal blood uric acid adjusted OR and 95%CI were 3.342 (1.459, 7.659), 5.439 (1.555, 19.018) and 2.971 (1.187, 7.435), respectively. Gender-stratified analysis found that "any three or more metabolic abnormalities and their components were associated with gallstone risk, more significantly in women. Different types and amounts of five metabolic abnormalities were associated with the risk of gallstone development, and the differences were more significant in women than men.

Integrative analysis of multi-omics data reveals importance of collagen and the PI3K AKT signalling pathway in CAKUT

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is the leading cause of childhood chronic kidney failure and a significant cause of chronic kidney disease in adults. Genetic and environmental factors are known to influence CAKUT development, but the currently known disease mechanism remains incomplete. Our goal is to identify affected pathways and networks in CAKUT, and thereby aid in getting a better understanding of its pathophysiology. With this goal, the miRNome, peptidome, and proteome of over 30 amniotic fluid samples of patients with non-severe CAKUT was compared to patients with severe CAKUT. These omics data sets were made findable, accessible, interoperable, and reusable (FAIR) to facilitate their integration with external data resources. Furthermore, we analysed and integrated the omics data sets using three different bioinformatics strategies: integrative analysis with mixOmics, joint dimensionality reduction and pathway analysis. The three bioinformatics analyses provided complementary features, but all pointed towards an important role for collagen in CAKUT development and the PI3K-AKT signalling pathway. Additionally, several key genes (CSF1, IGF2, ITGB1, and RAC1) and microRNAs were identified. We published the three analysis strategies as containerized workflows. These workflows can be applied to other FAIR data sets and help gaining knowledge on other rare diseases.

Heavy metal contamination in soil and food crops and associated human health risks in the vicinity of Iringa Municipal dumpsite, Tanzania

Heavy metal contamination and potential risks to human health related to consuming major food crops near Iringa Municipal dumpsite are presented. Soil samples, maize (Zea mays L.) and common beans (Phaseolus vulgaris L.) were collected downslope around the dumpsite during wet season. Soil samples were analyzed using Energy-Dispersive X-Ray Fluorescence (EDXRF) while crop (maize and beans) samples were analyzed using Flame Atomic Absorption Spectrophotometer (FAAS). The potential health risks associated with human exposure to heavy metals in maize and common beans was evaluated according to the method prescribed by the United States Environmental Protection Agency. The concentrations Cd (3.25–10.78 mg/kg), As (1.84–10.98 mg/kg) and Ni (71.74–55.10 mg/kg) in soil samples exceed the maximum allowable limits set by Tanzania Bureau of Standards (TBS). The average heavy metal concentration in food crops followed the trend Cd, As < Cr, Pb < Ni < Cu < Mn < Zn with Pb in maize (0.96 mg/kg) and common beans (0.81 mg/kg) above FAO/WHO regulatory standards of 0.3 mg/kg. This implied health concerns to consuming food crops grown in the vicinity of the dumpsite. Further, lifetime–incremental cancer risk (ILCR) assessment suggest that consuming maize and common beans from the study area could increase the risk of both cancer and non-cancerous diseases in both adults and children. However, the degree of ILCR in children was noticeably higher (1.0 × 10–2) than in adults (5.10. × 10–6) for Pb in common beans. Therefore sustainable waste management should be stressed and continuous monitoring of environments around dumpsites is crucial to mitigate the negative impacts on public and environments.

Association between plant-based diets and risk of metabolic dysfunction–associated steatotic liver disease in Korean adults: A prospective cohort study

ObjectivesFew studies have investigated the correlation between plant-based diet indices (PDIs) and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in the Korean population. Therefore, this study aimed to investigate the association between PDIs and the risk of MASLD in Korean adults. MethodsThis cohort study utilized data from the Health Examinees Study conducted in the South Korean population. Dietary and nutrient intake were assessed at baseline and follow-up using a food frequency questionnaire and the Korean Food Consumption Table. Food items were categorized into overall PDI, healthy PDI (hPDI), and unhealthy PDI (uPDI), with MASLD defined using the fatty liver index. Baseline characteristics and food intake groups were evaluated based on PDI quintiles and stratified by sex. Further analyses involved stratification by age, body mass index, alcohol intake, and physical activity in men and women. ResultsOver a median follow-up period of 4.2 y, MASLD occurred in 1532 participants. Both men and women in the highest hPDI quintile had a reduced risk of MASLD (men: HR: 0.71, 95% CI: 0.55–0.91, p = 0.0031; women: HR: 0.61, 95% CI: 0.48–0.78, p < 0.0001). Conversely, the highest uPDI quintile was associated with a higher risk of MASLD. ConclusionsThis cohort study revealed an association of the overall PDI and hPDI with a lower risk of MASLD, highlighting the importance of adhering to these types of plant-based diets to prevent MASLD among Korean adults.

E-Selectin and Asymmetric Dimethylarginine Levels in Adult Cyanotic Congenital Heart Disease: Their Relation to Biochemical Parameters, Vascular Function, and Clinical Status.

Background and Aim: Patients with cyanosis secondary to congenital heart disease (CHD) are characterized by erythrocytosis and increased blood viscosity, which contribute to endothelial dysfunction, increased arterial stiffness, and impaired vascular function, which may affect the final clinical presentation. Asymmetric dimethylarginine (ADMA) and e-selectin (e-sel) are valuable biomarkers for endothelial and vascular dysfunction. Their concentration levels in blood serum have the potential to be an accessible tool that reflects the severity of the disease. We aimed to assess e-sel and ADMA levels and their relationship with the clinical status and endothelial and vascular function. Methods: A cross-sectional study, including 36 adult CHD cyanotic patients [(17 males) (42.3 ± 16.3 years)] with an arterial blood oxygen saturation less than 92% and 20 healthy controls [(10 males) (38.2 ± 8.5 years)], was performed. All the patients underwent a clinical examination, blood testing, and cardiopulmonary tests. Their endothelial function was assessed using the intima media thickness and flow-mediated dilatation. Vascular function, using applanation tonometry methods, was determined using the aortic systolic pressure, aortic pulse pressure, augmentation pressure, augmentation index, pulse pressure amplification, and pulse wave velocity. Results: The concentrations of e-sel and ADMA were significantly higher in the patients with CHD. The E-sel levels correlated positively with red blood cells, hemoglobin concentration, hematocrit, and augmentation pressure; they correlated negatively with blood oxygen saturation, the forced expiratory one-second volume, forced vital capacity, and oxygen uptake. The ADMA levels were found to correlate only with age. Conclusions: The E-sel level, unlike ADMA concentration, reflects the severity of erythrocytosis and hypoxia and, thus, the physical status of patients with cyanotic CHD.

The Relationship of Certain Diseases and Dietary Inflammatory Index in Older Adults: A Narrative Review.

One of the important markers affecting aging processes is the increase in inflammatory markers. Many chronic diseases are associated with inflammation and chronic inflammation increases with aging. Inflammation can change with dietary components. Foods, compounds and nutrients that have anti-inflammatory or proinflammatory properties attract attention. According to the Dietary Inflammatory Index, positive scores are obtained if the nutrient has a proinflammatory effect on cytokines, and negative scores are obtained if it has an anti-inflammatory effect. A higher proinflammatory diet is associated with cardiometabolic diseases, neurodegenerative disease, cancers and musculoskeletal health and related mortality. In this study, its relationship with type 2 diabetes mellitus, obesity, metabolic syndrome, musculoskeletal diseases, dementia, depression and cancer, which are more common in older adults and known to be associated with inflammation, was examined. Although studies involving under 65years old are more prevalent, research involving older adults and Dietary Inflammatory Index (DII) is more limited. It is known that chronic inflammation increases with aging. Diet is one of the factors affecting inflammation. In the light of these investigations, the topics of anti-inflammatory nutrition and DII for the treatment of inflammation-related diseases in older adults are strong and open to development topics of discussion. Despite the significant interest in the potential positive effects of anti-inflammatory nutrition on diseases, contributing to clearer evidence of its protective effects on health necessitates further randomized controlled trials, in vivo, in vitro, cell, animal, human and case-control studies for better risk assessment.

Genetic determinants of age at menarche: does the LIN28B gene play a role? A narrative review.

Menarche, the first menstrual period marking the onset of female reproduction, is a milestone of female puberty. The timing of menarche determines the timing of later phases of pubertal maturation in girls and has major implications for health later in life, including behavioral and psychosocial disorders during adolescence and fertility problems and increased risk for certain diseases in adulthood. Over the last few decades, a continuous decline in age at menarche has been noted, with environmental factors contributing to this change in the timing of menarche. However, a genetic component of age at menarche and pubertal onset has been strongly suggested by studies in families and twins wherein up to approximately 80% of the variance in puberty onset can be explained by heritability. Gene association studies have revealed several genetic loci involved in age at menarche, among which LIN28B has emerged as a key regulator of female growth and puberty. LIN28B, a human homolog of Lin28 of C. elegans, is a known RNA-binding protein that regulates let-7 microRNA biogenesis. Genome-wide association studies have identified the association of polymorphisms in the LIN28B gene with age at menarche in several population cohorts worldwide. In this paper, we review the genetic factors contributing to age of menarche, with particular focus on the identified polymorphisms in LIN28B gene.

Blood pressure variability in elderly and senior hypertensive patients

Background. In recent years the deterioration of the demographic situation has been noted in most countries of the world that is due to the steady increase in population of arterial hypertension and the aging of the population. According to the statistical forecast of the UN by 2025, the number of people over 60 will exceed 1 billion which is 15% of the entire global population. In Ukraine, according to epidemiological studies, the prevalence of hypertension among circulatory system diseases in adults (18 years and older) is 46.8% and almost half of patients with circulatory system diseases have elevated blood pressure. In patients aged 65 years and older, the prevalence of hypertension varies in the range of 53-72%. It has long been proven that the risk of cardiovascular and cerebrovascular complications in hypertensive patients depends not only on the absolute blood pressure level but also on fluctuations in blood pressure over different periods that is blood pressure variability. Blood pressure is not a static parameter but rather undergoes continuous fluctuations over time due to the interaction between environmental factors and behaviour on the one hand and the internal regulatory mechanisms of the cardiovascular system on the other hand. Elevated blood pressure may indicate cardiovascular dysregulation and itself may be a cardiovascular risk factor associated with increased all-cause mortality and cardiovascular mortality, stroke, coronary artery disease, heart failure, end-stage renal disease and incidence of dementia. Aim. The study aimed to improve the system of prevention and diagnosis of elderly and senior hypertensive patients at the ambulatory-polyclinic stage due to the study of the contribution of blood pressure variability. Materials and methods. The group of examinees was formed taking into account 27 elderly and senile hypertensive patients including those combined with coronary artery disease. For this purpose, ambulatory blood pressure monitoring was used. Results. Systolic blood pressure variability (SD) in hypertensive patients was higher than in the control group (p&lt;0.001). So, during the study, SD was 17.9±7.1 mm Hg. while in the control group 12.1±2.6 mm Hg. The frequency of high blood pressure variability detection in elderly and senile hypertensive patients was 51.9% (n=14). High blood pressure variability compared to low blood pressure variability and control was associated with a more pronounced systolic blood pressure variability (during the active monitoring period), and it was equalled 23.7±5.2 mm Hg compared to 14.8±6.5 mm Hg (p&lt;0.001) and 12.1±2.6 mm Hg. (p&lt;0.001). In elderly and senile hypertensive patients with high and low blood pressure variability, the non-dipper group prevailed over the dipper group in the structure of daily blood pressure rhythm (71.4% vs. 28.6% and 84.6% vs. 15.4% respectively). According to the ambulatory blood pressure monitoring data high blood pressure variability group compared to low blood pressure variability and controls was characterised by higher average values of the number of blood pressure indicators. In the group of high blood pressure variability patients, the average daily systolic blood pressure exceeded the control value by 10% (р&lt;0.05). The daily index of systolic blood pressure in the group of high blood pressure variability patients was 111% higher than in patients with low blood pressure variability (p&lt;0.05). The daily index of diastolic blood pressure in the group of high blood pressure variability patients was 140% higher than in patients with low blood pressure variability (p&lt;0.05). The daily index of average blood pressure in the group of high blood pressure variability patients was 191% higher than in patients with low blood pressure variability (p&lt;0.01). Conclusions. 1. High blood pressure variability has occurred in 16 out of 27 (51.9%) hypertensive elderly and senile patients. 2. The non-dipper group has predominated in the structure of blood pressure diurnal rhythm in elderly and senile hypertensive patients with high and low blood pressure variability patients. _________________________________________________________________________________________ Keywords: arterial hypertension; essential hypertension; blood pressure variability; high blood pressure variability; low blood pressure variability; elderly and senile hypertensive patients

The relationship between sarcopenia and related bioindicators and changes after intensive lifestyle intervention in elderly East-China populations

BackgroundAs populations live longer, there is a progressive increase in chronic degenerative diseases, particularly those related to the musculoskeletal system. Sarcopenia is characterized by loss of skeletal muscle mass, muscle strength, and loss of physical function. It is a common disease in older adults associated with various adverse health outcomes. There is a lack of bioindicators to screen for sarcopenia. Albumin and lymphocyte counts are commonly used to assess the degree of malnutrition, and blood routine, lipids, and thyroid function are relatively easy to obtain as part of a routine physical examination. Therefore, finding blood markers that can screen for sarcopenia is essential. Our primary aim was to explore whether the bioindicators of body composition, lymphocytes, albumin, lipids, and thyroid hormones are associated with sarcopenia, and a secondary aim was to investigate changes in these indicators after an intensive lifestyle intervention preliminarily.Methods60 subjects were selected from Runda and Bailian community health centers in Suzhou, China. They underwent body composition analysis and tested lymphocyte, albumin, lipid, and thyroid hormone levels. The 30 sarcopenia subjects underwent a 3-month intensive lifestyle intervention program. At the end of the intervention, we rechecked the bioindicators. Statistical analyses were performed in IBM SPSS v26.0.ResultsThe blood indices of sarcopenia subjects were generally lower in albumin, non-high-density lipoprotein cholesterol (non-HDL-C), and free triiodothyronine (FT3). Body mass index (BMI)(r = 0.6266, p < 0.0001), fat-free mass (r = 0.8110, p < 0.0001), basal metabolism (r = 0.7782, p < 0.0001), and fat mass (r = 0.3916, p = 0.0020) were positively correlated with appendicular skeletal muscle index (ASMI). Higher BMI and FT3 were associated with lower odds of sarcopenia, while higher fat mass was associated with higher odds of sarcopenia. After a 3-month intensive intervention, sarcopenia subjects had a significant increase in BMI, ASMI, lymphocyte, and albumin levels, and an increase in FT3, but with a non-significant difference (p = 0.342).ConclusionsLow BMI, FT3, and high fat mass were associated with sarcopenia. Intensive lifestyle intervention can significantly improve ASMI, BMI, lymphocytes, albumin, and FT3 in sarcopenia subjects, which is favorable for delaying the progression of sarcopenia.Trial registrationThis study was retrospectively registered on ClinicalTrials.gov, registration number NCT06128577, date of registration: 07/11/2023.

Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Idiopathic Inflammatory Myopathies-associated Interstitial Lung Disease in Adults.

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of autoimmune diseases characterized by muscle involvement and various extramuscular manifestations. Interstitial lung disease (ILD) is one of the most common extramuscular manifestations of IIM and is associated with significant mortality and morbidity. The clinical phenotypes, treatment responses, and prognosis of IIM-ILD are significantly related to myositis-specific antibody (MSA) profiles, with some racial differences. The features associated with MSA in IIM-ILD could also be relevant to cases of ILD where MSA is present but does not meet the criteria for IIM. The anti-melanoma differentiation-associated gene 5 antibody is highly associated with rapidly progressive ILD (RP-ILD), especially in Asian populations, and with characteristic cutaneous manifestations, such as skin ulcers. Radiologically, ground-glass opacities, consolidations, and nonsegmental linear opacities were more predominant than reticular opacities and honeycombing. While the mortality rate is still around 30%, the prognosis can be improved with early intensive therapy with corticosteroids and multiple immunosuppressants. In contrast, anti-aminoacyl-tRNA synthetase (ARS) antibodies are associated with chronic ILD, although RP-ILD is also common. Patients with anti-ARS antibodies often show lung-predominant presentations, with subtle muscle and skin involvement. Radiologically, reticular opacities, with or without consolidation, are predominant and may progress to honeycombing over time. Combination therapy with corticosteroids and a single immunosuppressant is recommended to prevent relapses, which often lead to a decline in lung function and fatal long-term outcomes. Significant advances in immunology and genetics holds promise for fostering more personalized approaches to managing IIM-ILD.

Unraveling the Mfn2-Warburg effect nexus: a therapeutic strategy to combat pulmonary arterial hypertension arising from catch-up growth after IUGR

BackgroundThe interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive.Methods and resultsTo elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats.ConclusionsImbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH.

Improved Risk Prediction Using a Refined European Guidelines Instrument in Pulmonary Arterial Hypertension Related to Congenital Heart Disease

European guidelines advocate a goal-oriented treatment approach in pulmonary arterial hypertension (PAH), based on a comprehensive risk assessment instrument, which has been validated in several PAH subgroups. We investigated its discriminatory ability, and explored tricuspid annular plane systolic excursion (TAPSE) and revised thresholds to improve its predictability within the adult congenital heart disease (CHD) population.In total, 223 adults (42±16 years, 66% female, 68% Eisenmenger) were enrolled from five European PAH-CHD expert centers. Patients were classified as ‘Low’, ‘Intermediate’, or ‘High’ risk at baseline visit and at follow-up within 4-18 months. By the general PAH guidelines instrument, survival did not differ between the risk groups (P=n.s.), mostly due to skewed group distribution. Reclassifying patients using revised thresholds for N-terminal pro-brain natriuretic peptide (NT-proBNP) and 6-minute walk distance (6MWD) (i.e., ‘Low’, ‘Intermediate’, ‘High’ as <500, 500-1400, >1400 ng/l and >400, 165-400 and <165 m, respectively) and use of TAPSE (‘Low’, ‘Intermediate’, ‘High’ as >20, 16-20 and <16mm) significantly improved discrimination between the risk groups both at baseline and follow-up (P=0.001, ROC increase from 0.648 to 0.701), reclassifying 64 (29%) patients. Irrespective of follow-up risk group, survival was better for patients with higher proportions of low-risk variables. Improvement to a ‘Low-risk’ profile at a median of 9 months follow-up provided improved survival comparable to survival of patients who remained in the ‘Low risk’ group.In conclusion, the external validity of general risk instrument for PAH appeared to be of limited discriminatory value in PAH-CHD patients. We propose a refined risk instrument with improved discrimination for PAH-CHD.

Longitudinal assessment of health-related quality of life in patients with adult congenital heart disease undergoing cardiac surgery

ObjectiveThe study objective was to assess longitudinal postoperative health-related quality of life among patients with adult congenital heart disease facilitated by a novel electronic medical record–based patient-reported outcomes follow-up platform. MethodsFrom January 2022 to October 2023, 559 patients with adult congenital heart disease underwent cardiac surgery; 491 (88%) completed a 23-element health-related quality of life questionnaire covering 3 domains (physical, mental, and social) yielding 911 assessments. Automated questionnaires via electronic medical record were sent at 7 days preoperatively and postoperatively at 1, 3, 6, and 12 months. Nonlinear multiphase mixed effects models and boosting approach using multivariate trees were used to assess longitudinal trends and the relationship among patient characteristics, clinical variables, and health-related quality of life outcomes. ResultsMean age of patients was 53 years (range, 19-86), 238 (43%) were female, 109 (20%) were STAT category 3 or 4, postoperative mortality was 0, and stroke was 4 (0.7%). Diagnosis included hypertrophic obstructive cardiomyopathy (276, 50%), anomalous coronary artery (42, 7.5%), congenital aortic valve disease (42, 7.5%), bicuspid aortic valve (64, 12%), and aortic aneurysm (25, 4.5%). Although baseline health-related quality of life scores were below population norms, rapid postoperative increases were seen in physical, mental, and social scores, surpassing population norms between 2 and 6 months. Patients with higher baseline health-related quality of life had higher longitudinal scores. Female patients and those of Black race had higher Area Deprivation Index and lower postoperative physical health-related quality of life scores. ConclusionsPatients with adult congenital heart disease require lifelong medical surveillance and repeated interventions. Our innovative electronic medical record–embedded time-series tool assessing health-related quality of life after cardiac surgery shows improved patient-reported outcomes across mental, physical, and social domains that endure through at least the first postoperative year.

53907 Amlitelimab improves extent and severity of disease in adults with moderate-to-severe atopic dermatitis (AD): 24-week results from a Phase 2b trial (STREAM-AD)

53907 Amlitelimab improves extent and severity of disease in adults with moderate-to-severe atopic dermatitis (AD): 24-week results from a Phase 2b trial (STREAM-AD)