Early Onset Research Articles

Familial Mediterranean fever in children from central-southern Italy: a multicentric retrospective cohort study.

Although familial Mediterranean fever (FMF) is a relevant disease in countries surrounding the Mediterranean Sea, there are still few reports from Italy. We retrospectively evaluated patients with FMF diagnosed according to the EuroFever/PRINTO classification criteria in three pediatric rheumatology referral centers in central-southern Italy. Logistic regression analysis assessed the associations between age at disease onset and symptoms. Overall, 48 patients were enrolled (28 females, 20 males), with a median age at onset of 3.3 [3.1] years, and a median follow-up period of 5.1 [10.8] years. The most common MEFV genotype was M694V/- (11 patients, 22.9%), followed by M694V/M694V (6 patients, 12.5%). At onset, recurrent fever was observed in 47 patients (97.9%), with a median time between attacks of 18 [11] days. Overall, recurrent fever was observed in all patients, abdominal pain in 44 (91.7%), and chest pain in 18 (37.5%). At the last follow-up visit, 24 patients were on colchicine (50%), 2 on biologic (4.2%), and 6 on both (12.5%). Canakinumab was the most used biologic drug, in 6 (12.5%) patients. MEFV genotype was associated with disease severity (p = 0.007) and the use of a biological drug (p = 0.01). FMF prevalence in the Abruzzo region was found highly than expected (at least 1:45,000). Differently, we found a relevant gap among FMF patients expected and observed in the Apulia and Sicily regions. FMF is a relevant issue in central-southern Italy. A large epidemiologic study should be performed to better define its prevalence in the country. Key Points • Italian children with familial Mediterranean fever tend to have an early age of onset, primarily manifesting with recurrent fever and characteristic associated symptoms. • Many MEFV gene variants are present in Italian children with familial Mediterranean fever, and these patients are most often heterozygous, exhibiting a mild to moderate phenotype. • The prevalence of familial Mediterranean fever in Italy is still unknown but recently estimated to be around 1:60,000, probably higher in central and southern Italy. • According to our cohort, the prevalence of FMF in the Abruzzo region is at least 1:45,000, higher than expected. Differently, we found lower prevalence rates of the disease in Apulia and Sicily.

Hormone Receptor Positive Breast Cancer in Young Women: A Review.

The global incidence of hormone-positive breast cancer (HR+ BC) in young women is rising, though the underlying reasons remain unclear. HR+ disease in younger women appears to represent a distinct clinical entity compared to that in older women, exhibiting distinct clinicopathological characteristics, outcomes and responses to treatment. Despite these differences, there is a paucity of large-volume data focusing on young women with HR+ in contemporary literature. Hormone receptor positive breast cancer in young women is associated with poorer prognoses compared to older women. Additionally, early age onset breast cancer presents unique challenges, including concerns related to fertility, the toxic effects of therapeutic agents, and specific surgical considerations. The purpose of this review is to report the existing literature on HR+ disease in young women.

Carrier frequency and incidence estimation of deficiency of adenosine deaminase 2 in the Chinese population based on massive exome sequencing data

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease characterised by early onset stroke, recurrent fever, and diverse vascular pathologies, caused by loss-of-function homozygous or compound heterozygous variants of ADA2. This research aimed to determine the carrier frequency and expected incidence of DADA2 in China, using massive exome sequencing (ES) data. A total of 50 likely pathogenic/pathogenic variants (LP/PVs) were identified among 69,413 Chinese individuals, including 20 novel and rare variants (<0.0022 % allele frequency), expanding the known spectrum of PVs in ADA2. The overall carrier frequency in the Chinese population was 1.05 % (732/69,413) and the estimated incidence of DADA2 was approximately one in 92,251 individuals. The present study provides an accurate estimation of the prevalence of DADA2 in China, supporting genetic counseling, early diagnosis treatment, and prognostic evaluation.

Are labor epidural catheters after a combined spinal epidural (CSE) technique more reliable than after a traditional epidural? A retrospective review of 9153 labor epidural catheters.

The combined spinal epidural (CSE) technique may associate with a lower failure rate of epidural catheters compared to traditional epidural catheters. This may be significant for the parturients as failure of neuraxial analgesia has been associated with a negative impact on birth experience. In this one-year retrospective study, the failure rate of epidural catheters was compared between 3201 and 5952 epidural catheters after initiation of neuraxial analgesia by the CSE or traditional epidural technique, respectively. Parturient background information, labor parameters, and neuraxial interventions were collected from 9153 parturients. Failure was defined as replacement of a used epidural catheter by new regional analgesia procedures or general anesthesia during intrapartum cesarean delivery. The primary outcome was the failure rate of epidural catheters. The secondary outcome was the time from the initial analgesia intervention to the epidural catheter replacement and progression of labor during this time. The CSE method was used at an earlier stage of labor, and the parturients were more often primiparous and undergoing induced labor. Earlier onset of analgesia, obesity, induced labor, anesthesiologist experience, and cesarean delivery were found to be significant cofactors for catheter failure. The unadjusted failure rate was 168/3201 (5.2%) and 223/5952 (3.7%) (OR 1.42 [1.16-1.75]) after initiation of analgesia by CSE or traditional epidural method. After controlling for the stage of labor, body mass index, induction of labor, and anesthesiologist's experience level, the adjusted OR for epidural catheter replacement was 1.04 (0.83-1.29) p = .736. The mean (SD) time until epidural catheter failure was 6.3 (4.4) and 4.0 (4.1) hours following initiation of analgesia by CSE or traditional epidural technique, respectively (p < .001). Cervical dilatation progressed from 4.3 (1.4) to 6.4 (2.1) cm and 5.1 (1.5) to 6.7 (1.7) cm between primary neuraxial analgesia and epidural catheter replacement. CSE technique was not associated with a better survival rate of epidural catheters for provision of analgesia or epidural top-up anesthesia for intrapartum CD. In addition, the time to replacement of the catheter was significantly longer when analgesia was initiated with the CSE technique. Maternal satisfaction scores were lower if catheters required replacement.

Moyamoya disease: insights into the clinical implications of the RNF213 gene

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive stenosis of the terminal internal carotid arteries and the formation of compensatory collateral vessels, which appear as a “puff of smoke” on cerebral angiography. It is a significant cause of stroke in East Asia, with an incidence of 0.5 to 1.5 cases per 100,000 people annually. The etiology of MMD remains unclear; however, the identification of the RNF213 gene, particularly the R4810K variant, as a major susceptibility factor among the East Asian population, has provided crucial insights into the disease's pathophysiology and clinical manifestations. MMD typically presents with transient ischemic attacks, ischemic and hemorrhagic strokes, seizures, headaches, and cognitive deficits. Diagnostic criteria have evolved to emphasize advanced imaging techniques. Pathological features include fibrocellular intimal thickening, irregular undulation of the elastic lamina, and the formation of moyamoya vessels. The mutation in the RNF213 gene impairs the degradation of proteins involved in vessel development, leading to abnormal angiogenesis. Genotype-phenotype studies indicate that the RNF213 variant is associated with an earlier onset, transient ischemic attacks, infarctions, and involvement of the posterior cerebral artery, although its effects vary between regions. Additionally, the homozygous RNF213 variant consistently correlates with an earlier age of onset and a higher risk of cerebral infarction. However, further research is necessary to fully understand its long-term impacts and its relationship with revascularization outcomes. Ongoing research is crucial to fully comprehend the pathophysiology and genetics of MMD, improve prognostic predictions, and develop novel therapies.

Efficacy of digital interventions for smoking prevention among children: a systematic review

Abstract Background Smoking remains a leading preventable cause of morbidity and mortality globally, with initiation often occurring in childhood. Early smoking onset is linked to increased difficulty in quitting and higher risk of long-term health complications. Traditional prevention strategies have not fully succeeded in curbing youth smoking rates, highlighting the need for innovative approaches. Digital interventions (DI), such as gamified education, social media campaigns, and virtual reality, offer a novel avenue for engagement and education. This systematic review aims to assess the efficacy of DI in preventing smoking, and improving knowledge and awareness about smoking damages, among children. This review is part of the PRIN project, whose goal is to evaluate the effectiveness of a DI aimed at school-aged children, intended to increase knowledge about the negative effects of smoking and prevent its use. Methods On the 18th of March 2024, PubMed, Scopus, and PsycINFO were surfed for trials and observational studies evaluating DI for smoking prevention among children aged 6-12 years. Study quality will be evaluated using the Cochrane Risk of Bias Tool and New Castle-Ottawa scale. The protocol has been registered in PROSPERO. Results From 3,081 initially identified articles, 328 papers were removed because duplicate. The screening process is ongoing. Conclusions DI are a promising tool for engaging young populations through platforms they are familiar with and receptive to. By leveraging the high penetration of digital technology in the daily lives of children, these interventions have the potential to deliver smoking prevention messages in a compelling and interactive manner. Understanding the effectiveness of DI in smoking prevention can significantly contribute to public health by providing viable alternatives to traditional methods and potentially reducing future smoking-related health burdens. Key messages • Evaluating digital strategies for smoking prevention among children could offer vital alternatives to traditional methods, potentially reducing long-term health risks. • Digital interventions (DI) offer promising new ways to engage young audiences on smoking prevention using familiar platforms, potentially reshaping public health approaches.

Serum DLK1 During Minipuberty and Pubertal Transition in Healthy Girls and in Girls with Precocious Puberty.

Delta-like non-canonical notch ligand 1 (DLK1) is negatively associated with bodyweight. DLK1 pathogenic variants cause central precocious puberty (CPP) and obesity, suggesting that DLK1 link the well-established association between higher BMI and earlier pubertal onset. However, little is known about the trajectories of circulating DKL1 in healthy girls as well as in girls with precocious puberty. To evaluate longitudinal changes in circulating DLK1 concentrations in 1) full-term, singleton healthy infant girls 2) healthy girls during pubertal transition 3) girls with CPP during treatment with gonadotropin-releasing hormone agonist (GnRHa). Three longitudinal studies of 1) healthy, infant girls (n=85), 2) healthy, peripubertal girls (n=15), 3) girls with CPP before and after GnRHa treatment (n=15).Body fat percentage (BF%) by Slaughter equation. Serum concentrations of DLK1 by ELISA. Serum concentration of DLK1 in healthy infant girls declined significantly through the first year of life (17.6 ng/mL to 9.9 nh/mL, p=0.020). DLK1 was inversely correlated with birth weight and BF%: r=-0.220, p=0.044 and r=-0.503, p<0.001, respectively. DLK1 declined from one year prior to pubertal onset to time of first examination after pubertal onset (10.4 ng/mL to 9.2 n/mL, p=0.004) as well as to time at the last pubertal evaluation (10.4 ng/mL to 9.8 ng/mL, p=0.006). DLK1 levels were not affected by GnRHa treatment. Circulating DLK1 levels declined steeply during infancy and less pronounced through pubertal development. Due to considerable inter-individual variation, DLK1 is not useful as a diagnostic marker of pubertal onset. Importantly, DLK1 was negatively associated with birth weight and body fat percentage.

Gene-echocardiography: unmasking the covert role of fatty acid metabolism gene mutations in adult cardiomyopathy

Abstract Background Although the role of fatty acid metabolic deficiencies in cardiomyopathy is established, the precise identity of causative genes and their respective phenotypes in adult cardiomyopathy remains unclear. Methods We implemented a combination of echocardiography and whole exome sequencing in clinically diagnosed cardiomyopathy patients to uncover this relationship. This involved recording cardiac phenotypes, identifying genes associated with disrupted fatty acid metabolism, and subsequently followed up with these patients. Results Out of 802 cardiomyopathy patients, 27 exhibited mutations in genes tied to fatty acid metabolism. Specifically, 16 patients demonstrated a hypertrophic cardiomyopathy (HCM) phenotype, and 11 showed a dilated cardiomyopathy (DCM) phenotype. The implicated genes were SLC22A5 (n=7), ACADVL (n=6), ACADS (n=4), ACADM (n=3), SLC25A20 (n=3), ACADL (n=2), HADH (n=1), and AGK (n=1), with a higher prevalence in males. Among these, the SLC22A5 mutation was predominant and correlated with HCM phenotype. Notably, compound mutations were frequently observed (16/27), leading to earlier disease onset and diminished aortic sinus dimension. Further investigation showed that smaller aortic sinus dimensions resulted from abnormal left ventricular myocardial work. HCM phenotype mutation carriers showed more consistent left ventricular hypertrophy and a higher probability of right ventricular hypertrophy, while DCM phenotype mutation carriers exhibited impaired contractile function across all left ventricle segments. After a 24-month follow-up, the DCM phenotype group demonstrated higher cardiovascular risk, including two fatalities. Conclusion Our investigation highlights the significant prevalence of mutations related to abnormal fatty acid metabolism in adult cardiomyopathy patients, underscoring the utility of a gene-echocardiography approach for diagnosis.

Compound heterozygous RYR1-RM mouse model reveals disease pathomechanisms and muscle adaptations to promote postnatal survival.

Pathogenic variants in the type I ryanodine receptor (RYR1) result in a wide range of muscle disorders referred to as RYR1-related myopathies (RYR1-RM). We developed the first RYR1-RM mouse model resulting from co-inheritance of two different RYR1 missense alleles (Ryr1TM/SC-ΔL mice). Ryr1TM/SC-ΔL mice exhibit a severe, early onset myopathy characterized by decreased body/muscle mass, muscle weakness, hypotrophy, reduced RYR1 expression, and unexpectedly, incomplete postnatal lethality with a plateau survival of ~50% at 12 weeks of age. Ryr1TM/SC-ΔL mice display reduced respiratory function, locomotor activity, and invivo muscle strength. Extensor digitorum longus muscles from Ryr1TM/SC-ΔL mice exhibit decreased cross-sectional area of type IIb and type IIx fibers, as well as a reduction in number of type IIb fibers. Exvivo functional analyses revealed reduced Ca2+ release and specific force production during electrically-evoked twitch stimulation. In spite of a ~threefold reduction in RYR1 expression in single muscle fibers from Ryr1TM/SC-ΔL mice at 4 weeks and 12 weeks of age, RYR1 Ca2+ leak was not different from that of fibers from control mice at either age. Proteomic analyses revealed alterations in protein synthesis, folding, and degradation pathways in the muscle of 4- and 12-week-old Ryr1TM/SC-ΔL mice, while proteins involved in the extracellular matrix, dystrophin-associated glycoprotein complex, and fatty acid metabolism were upregulated in Ryr1TM/SC-ΔL mice that survive to 12 weeks of age. These findings suggest that adaptations that optimize RYR1 expression/Ca2+ leak balance, sarcolemmal stability, and fatty acid biosynthesis provide Ryr1TM/SC-ΔL mice with an increased survival advantage during postnatal development.

Evaluating manganese removal in groundwater using pilot scale biofilters: The role of filter media characteristics during start-up

This study investigated the influence of filter media characteristics on manganese (Mn) removal in groundwater biofilters during the start-up phase. Six pilot scale biofilters containing three different granular activated carbons (GAC), two anthracite, and one sand media were run for 133 days to examine their Mn removal performance at a drinking water utility, while also monitoring ATP and bacterial growth as indicators of biological activity. Key findings demonstrate the critical role of media characteristics, especially for GAC media. Initial Mn adsorption on GAC, with its higher surface area, higher macropore volume, and surface charge, promoted physicochemical and biological oxidation, thus contributing to the early onset of Mn removal during the start-up of the GAC biofilters. In contrast, biological processes dominated Mn removal on anthracite and sand biofilters during start-up. As expected, the presence of Mn-oxidizing bacteria was detected in biofilters, and ATP levels were correlated to Mn removal until the biofilters were acclimated, showing the potential of ATP as an acclimation monitoring metric. Once acclimated, all biofilters consistently reduced Mn levels from 60.9 ± 4.5 µg/L to below 5 µg/L (>90 % removal), while concurrently removing iron, thereby highlighting the biofilter's effectiveness at low water temperatures (<15 °C). This study demonstrates the advantage of GAC media for Mn removal in biofilters during start-up in regions with lower water temperatures.

Association of epicardial adipose tissue with cardiac geometry alternation and diastolic dysfunction in the early stage of diabetic cardiomyopathy

Abstract Background Diastolic dysfunction and alterations in cardiac geometry are early indicators of diabetic cardiomyopathy. However, the association between cardiac changes across the glucose continuum and the contribution of epicardial adipose tissue (EAT) to these changes has not yet been investigated. Purpose In this study, we aim to investigated the EAT on cardiac diastolic function and structural alterations along the diabetic continuum using cardiac magnetic resonance imaging (CMR). Methods We enrolled individuals who were categorized into groups based on glucose tolerance status. Left ventricular structure and diastolic function were assessed using echocardiography and CMR to determine the EAT, intramyocardial fat, and associated parameters. Multivariate logistic regression models were also used. Results In a study of 370 patients (209 normal glucose tolerance, 82 prediabetes, 79 diabetes), those with prediabetes and diabetes showed increased heart dimensions and diastolic dysfunction, including E/E' (7.9±0.51 vs. 8.5±0.64 vs. 10.0±0.93, p=0.010), left atrial volume index (28.21±14.7 vs. 33.2±12.8 vs. 37.4±8.2 mL/m2, p&amp;lt;0.001), and left ventricular peak filling rate (4.46±1.75 vs. 3.61±1.55 vs. 3.20±1.30 mL/s, p&amp;lt;0.001). EAT significantly increased in prediabetes and diabetes (26.3±1.16 vs. 31.3±1.83 vs. 33.9±1.9 gm, p=0.001), while intramyocardial fat did not differ significantly. Prediabetes altered heart geometry, but not diastolic function (OR 1.22 [1.02–1.83], p=0.012; and 1.70 [0.79–3.68], p=0.135). Diabetes significantly affected both heart structure and diastolic function (OR 1.42 [1.11–1.97], p=0.032; and 2.56 [1.03–5.40], p=0.034) after adjusting for covariates. Conclusions Elevated EAT was observed in patients with prediabetes and is associated with adverse alterations in cardiac structure and diastolic function, potentially serving as an underlying mechanism for the early onset of diabetic cardiomyopathy.

Tuning collective behaviour in zebrafish with genetic modification.

Zebrafish collective behaviour is widely used to assess their physical and mental state, serving as a valuable tool to assess the impact of ageing, disease genetics, and the effect of drugs. The essence of these macroscopic phenomena can be represented by active matter models, where the individuals are abstracted as interactive self-propelling agents. The behaviour of these agents depends on a set of parameters in a manner reminiscent of those between the constituents of physical systems. In a few cases, the system may be controlled at the level of the individual constituents such as the interactions between colloidal particles, or the enzymatic behaviour of de novo proteins. Usually, however, while the collective behaviour may be influenced by environmental factors, it typically cannot be changed at will. Here, we challenge this scenario in a biological context by genetically modifying zebrafish. We thus demonstrate the potential of genetic modification in the context of controlling the collective behaviour of biological active matter systems at the level of the constituents, rather than externally. In particular, we probe the effect of the lack of col11a2 gene in zebrafish, which causes the early onset of osteoarthritis. The resulting col11a2 -/- zebrafish exhibited compromised vertebral column properties, bent their body less while swimming, and took longer to change their orientations. Surprisingly, a group of 25 mutant fish exhibited more orderly collective motion than the wildtype. We show that the collective behaviour of wildtype and col11a2 -/- zebrafish are captured with a simple active matter model, in which the mutant fish are modelled by self-propelling agents with a higher orientational noise on average. In this way, we demonstrate the possibility of tuning a biological system, changing the state space it occupies when interpreted with a simple active matter model.

The predisposing factors to heart failure diagnosis and early mortality among young adults in Africa: a narrative review

Abstract Introduction Heart failure (HF) is a major health concern mainly diagnosed among elderly individuals. Primarily, researchers have focused on this age group, nevertheless, compared to individuals from other regions of the world, Africans presents with HF two decades sooner (52 versus 79 years). Even though it manifests early, young persons (18–35 years old) are also diagnosed with HF with prognoses comparable to the older group. Less is known about how much study is concentrated on this age range, although globally, young adults of African origin make up the majority of those with an early onset of heart failure. Additionally, obtaining information about how HF impacts African youth remains challenging. Purpose To determine the cause of Africans' early HF diagnosis as well as the risk factors for HF diagnosis and early mortality among young adults. Methodology Three electronic databases— MEDLINE Ovid, Scopus, and CINAHL Plus—were searched using the Boolean operators. The first retrieved hits were checked for relevancy by titles and abstracts. Then, publications were fully screened for inclusion in the review based on the pre-established criteria. Also, reference lists of the articles were snowballed for pertinent studies. The scientific integrity of the studies was evaluated using a guided, in-depth peer-reviewed article on how to critically analyse clinical research and the Critical Appraisal Skill Programme (CASP) tool cohort checklist. Pertinent information regarding the study was analysed using a narrative review methodology. Eleven (11) articles out of the 135 pulled from the databases met the requirements for inclusion in the review after a thorough screening. One article was eliminated upon critical evaluation of the research's methodology, and an eligible article was discovered from snowballing reference lists. Therefore, only 11 articles qualified for this review study. Results Findings from the review show that HF is diagnosed earlier among Africans due to the early presentation of the major causes of HF before the age of 30 years. Rheumatic heart disease, cardiomyopathy, ischemic heart disease, HTN, and pulmonary illnesses (COPD, TB, and pulmonary arterial hypertension) are known aetiologies. More so, young adults who are diabetic, obese, have hyperlipidaemia or smoke cigarettes are more likely to develop HF. Furthermore, socioeconomic status, alcohol use, smoking, renal dysfunction, higher serum levels of brain natriuretic peptide (BNP) and creatine kinase (Isomer MB), cardiogenic shock, and decreased ejection fraction were the predictors of death with significant p-values (0.05). Conclusion Although HF affects young African adults disproportionately causing them to live lower quality of life and shorter lives, no research before this has been conducted. Therefore, further study is required to understand how HF affects this target age range (18 to 35 years) and to develop a long-term plan to fight this illness before it worsens.

SLC16A8 is a causal contributor to age-related macular degeneration risk

Age-related macular degeneration (AMD), a complex neurodegenerative disease, is a leading cause of visual impairment worldwide with a strong genetic component. Genetic studies have identified several loci, but few causal genes with functional characterization. Here we highlight multiple lines of evidence which show a causal role in AMD for SLC16A8, which encodes MCT3, a retinal pigment epithelium (RPE) specific lactate transporter. First, in an unbiased, genome-wide analysis of rare coding variants we show multiple SLC16A8 rare variants are associated with AMD risk, corroborating previous borderline significant reports from AMD rare variant studies. Second, we report a novel SLC16A8 mutation in a three-generation family with early onset macular degeneration. Finally, mis-expression in multiple model organisms shows functional and anatomic retinal consequences. This study highlights the important role for SLC16A8 and lactate regulation towards outer retina/RPE health and highlights a potential new therapeutic opportunity for the treatment of AMD.

Association between genetic predisposition of AF and the risk of ischemic stroke and thromboembolism

Abstract Background Ischemic stroke and thromboembolism are the major complications of atrial fibrillation (AF), however, its association with genetic background of AF remains unclear. To investigate the association between genetic predisposition of AF underlying common variants and the risk of ischemic stroke and thromboembolism. Methods We included unrelated individuals with non-valvular AF from UK biobank. The polygenic risk scores of AF (PRSAF) was calculated for each individual using the effect weight from a previous study which has been validated in both European and mixed-ancestry population[1, 2]. The SNPs from the original score were lifted over to GRCh38 and 6514708 of 6730541 were available in the UK biobank genotype data. The clinical data was defined by ICD-10 code. The primary endpoint is ischemic stroke or thromboembolism resulting in hospitalization after first AF diagnosis. Results A total of 28810 unrelated patients were included in the study. Among them, 4064 had PRSAF over 90th percentile of the general population, and were considered having high genetic risk. The rest 18746 with per SD increase in PRSAF lower than 90th percentile of the general population were considered having lower genetic risk. Generally, age and sex adjusted model demonstrated that per standard deviation change in PRSAF is associated with 9% increase in the risk of stroke or thromboembolism (HR=1.09, 95%CI: 1.03-1.14), and patients with high genetic risk was associated with 15% increase in the risk of stroke or thromboembolism (HR=1.15, 95%CI: 1.02-1.31).The result remained stable when further adjusted for clinical risk factors (1.09, 95%CI: 1.04-1.15 per SD increase in PRSAF) and competing risk of death (1.10, 95%CI: 1.05-1.16 per SD increase in PRSAF). There was no interaction between CHA2DS2-VASc score risk stratification and the per SD increase in PRSAF (P interaction = 0.751, Figure 1A). However, the association between per SD increase in PRSAF and the event tended to be affected by age at AF onset (HR = 1.02 95%CI: 0.94, 1.11 for early onset AF; HR = 1.12 95%CI: 1.05, 1.19 for non-early onset AF, P for interaction = 0.062, Figure 1B). Multi-variate COX regression including PRSAF, components of CHA2DS2-VASc score, and other AF risk factors revealed that history of stroke/thromboembolism, age over 65 years, hypertension, diabetes and high AF genetic risk were significantly associated with the outcome (Figure 1C). To evaluate the importance of these risk factors, average population attributable fraction for 10-year risk of stroke/thromboembolism in the study population was calculated, indicating that genetic risk of AF is responsible for 3.26% (0.89%-5.63%) of the events (Figure 1D). Conclusion Genetic predisposition of AF underlying common variants is associated with ischemic stroke and thromboembolism independent of clinical risk factors. But its role in different AF populations, like early onset AF, remains further investigation.Figure 1

High uric acid induces vascular endothelial cell injury via XBP1-PKM2 mediated glycolytic inhibition

Abstract Background/Introduction Although not fully understood, hyperuricemia induced endothelial dysfunction exhibits at the early onset of the pathology of atherosclerosis. Since aerobic glycolysis is the predominant energy source of endothelial cells, exploring the key glycolytic regulators that are responsible for maintaining the integrity of endothelial barrier may confer vascular homeostasis and prevent atherosclerosis. Purpose We aimed to investigate the role of high uric acid in the glycolysis of human umbilical vein endothelial cells (HUVECs), and reveal its potential molecular mechanism underlying endothelial cell injury early in their quiescence. Methods Glycolytic metabolism was determined by real-time extracellular flux analysis and seahorse test on the HUVECs exposed to high uric acid (600 and 800μmol/L). We examined the expression of pyruvate kinase muscle isoforms 2 (PKM2), a key enzyme of glycolysis, and transcription factor X-box binding protein 1 (XBP1), which was identified by RNA sequencing and chromatin immunoprecipitation combined with luciferase assay. Then, the effect of glycolytic regulation on the HUVECs functions under hypeuricemic condition was evaluated by molecular manipulating of XBP1-PKM2 signaling pathway. Results We observed that hyperuricemia inhibited glycolysis and led to reduced ATP production of HUVECs in vitro by inhibiting the expression of PKM2. In addition, both unsliced and sliced XBP1-(u/s) were also downregulated under the stimulation of high uric acid. Overexpression of XBP1-s increased the transcriptional level of PKM2 via binding the PKM2 promoter, and effectively recovered the glycolitic activity and ATP synthesis. Moreover, upregulating the XBP1-PKM2 pathway mitigated the HUVECs injury induced by hyperuricemia, including the abnormal release of endothelin-1, von Willebrand Factor, reactive oxygen species and nitric oxide, and poor cell proliferation, migration as well as tube formation. Conclusions Our data reveal that high uric acid induces HUVECs injury by downregulating glycolysis through the XBP1-PKM2 signaling axis.

Incidence of Retinopathy of Prematurity in Early Onset Neonatal Sepsis

Background: Retinopathy of prematurity (ROP) is a leading cause of visual impairment in premature neonates. Early-onset neonatal sepsis, has been identified as a potential contributing factor to the incidence of ROP. Aim of the study: The aim of this study was to assess the incidence of retinopathy of prematurity in early onset neonatal sepsis. Methods: This cross-sectional study was conducted in Department of Ophthamology and Neonatal Intensive Care Unit (NICU), Dr. Sirajul Islam Medical College &amp; Hospital Ltd., Dhaka, Bangladesh from June 2022 to July 2024. Total 300 preterm neonates with ROP were included in this study. Then, they were divided into two groups- group A: 150 patients with early onset neonatal sepsis and group B: 150 patients with late onset neonatal sepsis. Result: The mean gestational age in Group A was significantly lower (28.9 ± 2.3 weeks) than Group B (30.1 ± 2.2 weeks) (p &lt; 0.01). Maternal infections were higher in Group A (50%). Oxygen therapy duration was longer in Group A (14 ± 3 days) than in Group B (10 ± 2 days) (p &lt; 0.01). Group A had more cases of ROP (70% vs. 57%, p = 0.02). Risk factors for ROP included gestational age &lt;28 weeks (OR = 2.10), oxygen therapy (OR = 1.60), and mechanical ventilation (OR = 1.45). Conclusion: This study concludes that neonates with early-onset neonatal sepsis had higher incidence and severity of ROP, with key risk factors being low gestational age, prolonged oxygen therapy, mechanical ventilation, and maternal infections.

Socioeconomic inequalities in substance use among Norwegian adolescents between 2014 and 2022

Abstract Background Increasing use of substances is observed among adolescents in recent years. Early onset of substance use dramatically increases the risk of substance use disorder, dependence, and poorer psychological, social, and physical health, and is thus a public health concern. We explore trends in socioeconomic inequalities in past year use of cannabis and other illicit drugs between 2014 and 2022 among Norwegian adolescents. Methods This study is based on data retrieved from five waves of the nationwide Norwegian Ungdata survey (2014-2022) among adolescents attending upper secondary education (N = 282,259; 51 % girls). Trends in socioeconomic inequalities were assessed using the Slope Index of Inequality (SII) and the Relative Index of Inequality (RII). Results The use of cannabis and other illicit drugs increased among boys (from 13% to 19%, and from 2% to 5%, respectively) and girls (from 8% to 14%, and from 1% to 3%, respectively) between 2014 and 2022. Higher prevalence’s was observed among the least affluence girls between 2020 and 2022, both in absolute and relative terms (SII: 0.01 to 0.06, RII: 0.97 to 1.52, p &amp;lt; 0.001). No inequalities were observed among boys during this time. While relative and absolute inequalities in use of other illicit drugs decreased in boys, absolute inequalities increased in girls. Boys were more likely than girls to have used cannabis and other illicit drugs, although the gender gap in cannabis use narrowed slightly during the study period. Conclusions Our data suggest increasing use of cannabis and other illicit drugs among Norwegian adolescent boys and girls between 2014 and 2022. Future studies should examine the potential causes of increasing substance use as a basis for understanding, and distinguishing between, the many intertwining factors that influence adolescent drug use behaviors. Key messages • The use of cannabis and other illicit drugs increased between 2014 and 2022 among Norwegian boys and girls. • While inequalities in the use of cannabis and ither illicit drug use increased in girls, small or no inequalities was observed among boys.

Early-onset atrial fibrillation is a risk marker for cardiomyopathy: genetic insights from the UK Biobank

Abstract Introduction Atrial fibrillation (AF) is a common cardiac arrhythmia associated with an increased risk of stroke, heart failure and premature death. Genetic associations between AF and rare variants have been identified in several cardiomyopathy-associated genes, and previous studies have shown a high prevalence of deleterious variants among individuals with early onset of AF. Consequently, genetic testing has been suggested in patients with AF onset before 45 years of age. Purpose This study aimed to explore the prevalence and distribution of deleterious genetic variants in cardiomyopathy genes according to age at AF diagnosis. Methods The UK Biobank is a large population-based biobank, comprised of clinical and genetic information on more than 500,000 individuals, enrolled between 2006 and 2010. We analyzed whole-exome sequencing data among unrelated individuals of European ancestry. The cohort was stratified by age at AF onset (AF onset &amp;lt;45 years, AF onset between 45-54 years, AF onset between 55-64 years, AF onset &amp;gt;=65 years, and individuals with no AF diagnosis). We evaluated the presence of rare (minor allele frequency &amp;lt;0.1%) genetic variants in core cardiomyopathy genes, according to guidelines by the American College of Medical Genomics and focused on variants predicted to lead to loss of function. Individuals with a diagnosis of cardiomyopathy prior to AF were excluded. Results Among 374,365 unrelated individuals of European ancestry, 29,119 were diagnosed with AF. Of these, 685 had onset of AF&amp;lt;45 years (2.35%), 2465 had onset between 45-54 years (8.46%), 7778 had onset between 55-64 years (26.71%), and 18191 had onset at or above 65 years of age (62.48%). A total of 884 were carriers of rare loss-of-function variants in cardiomyopathy genes. Among carriers, the majority of variants were in key genes for dilated cardiomyopathy (TTN), hypertrophic cardiomyopathy (MYBPC3), and arrhythmogenic right ventricular cardiomyopathy (PKP2). We observed an inverse dose-response-like relationship between prevalence of the rare genetic variants and age at AF diagnosis. The highest prevalence of carriers was observed among individuals with onset before 45 years (4.96%). In comparison, the proportion of carriers was 3.45% in individuals with AF onset between 45-54 years, 2.96% in individuals with AF onset between 55-64 years, 2.75% in individuals with onset at or after 65 years, and 2.05% among individuals without AF diagnosis. Conclusions Using whole exome sequencing, we identified a high proportion of carriers of deleterious variants in actionable genes of cardiomyopathies among individuals with early onset of AF. We observed an inverse dose-response-like relationship between age of AF diagnosis and prevalence of deleterious genetic variants. Our findings support that very early onset of AF, before 45 years of age, is a potential risk marker for cardiomyopathy and support that genetic screening may be relevant in this patient group.

Genotype-phenotype relationship in hypertrophic cardiomyopathy

Abstract Background/Introduction Hypertrophic cardiomyopathy (HCM) is an inherited highly heterogeneous disease with variable penetrance and expression, but the exact relationship between the underlying genetic cause and the clinical course remains elusive. Purpose The aim of our study was to analyse the phenotypic and molecular characteristics of individuals with HCM examined and treated at our University Hospital. Methods Clinical data from adult HCM patients treated at our hospital between 2005 and 2023 were analysed. Informed consents to participate in the study were obtained from all participants. Clinical manifestation, instrumental examination and next generation sequencing (NGS) data of HCM related genes were collected. The Mann–Whitney U for two groups and Kruskal–Wallis tests for more than two groups were used to compare continuous variables. Univariate logistic regression was used to analyze categorical variables. Results The study involved 191 unrelated individuals, 58.6% males, the median age at HCM diagnosis was 50, interquartile range 37 – 60 years. A median follow-up was 3.9 [1.6-6.4] years. Pathogenic and likely pathogenic (P/LP) variants were identified in 45.5% (N=87) of affected individuals. Truncating variants were observed in 31 individuals. MYBPC3 P/LP variants were the most common (N=47), following by MYH7 (N=22) and other (N=18). Individuals with MYBPC3 P/LP truncating variants had higher HCM estimated 5-year risk of sudden cardiac death (SCD) during primary evaluation (3.1 [2.5-4.6]) compared to individuals with P/LP variants in other genes (2.4 [1.9-3.7]) and individuals with negative NGS results (1.8 [1.5-2.7], p&amp;lt;0,001). Patients with MYBPC3 P/LP variants experienced the earliest onset of symptoms (median age 37.0 [30.5-50.0] years) and HCM diagnosis (median age 38.0 [31.0-51.5] years) compared to individuals with other genes P/LP variants (median age 46.0 [31.0-56.2] years and 47.5 [31.5 – 59.5] years, respectively) and genotype negative individuals (median age 51.5 [44.0-61.0] years and 52.0 [45.0-63.2] years, respectively), p&amp;gt;0,001). The presence of P/LP variant was associated with significantly thicker left ventricular wall (maximal thickness) on cardiac imaging in comparison with negative NGS results (18.0 [15.0-21.0] mm vs. 16.0 [14.0-18.0] mm, p=0.002 on transthoracic echocardiography and 20.0 [17.0-22.5] mm vs. 18.0 [16.0-20.0] mm, p&amp;lt;0,001 on cardiac magnetic resonance). The presence of MYBPC3 truncating variants were associated with the greatest risk of ventricular tachycardia in comparison with negative NGS results (OR 3.05, 95% CI:1.3, 8.0, p=0.025). Conclusion More severe HCM phenotype is associated with detection of P/LP variants in HCM related genes. The presence of the MYBPC3 P/LP variant is associated with an earlier onset of the disease and truncating variants of this gene are related to a higher risk for ventricular tachycardia and an estimated 5-year risk of SCD.