Predominant Cause Research Articles

Utility of polygenic risk score for prediction of dilated cardiomyopathy and modulation of severity of LV dysfunction among cases

Abstract Background Dilated cardiomyopathy (DCM) is a predominant cause of heart failure and a leading indication for cardiac transplantation. While rare genetic variants are established as causative factors in familial forms of the disease, recent genome-wide association studies (GWAS) have also underscored the significant contribution of common genetic variation to DCM. Polygenic scores (PGS) constructed from GWAS have demonstrated promise in risk stratification for a range of common diseases and may similarly have value for risk prediction in DCM. However, data regarding the clinical utility of PGS in DCM remains sparse. Purpose We aimed to evaluate the utility of PGS for prediction of DCM and its association with left ventricular ejection fraction (LVEF) and family history. We further aimed to assess the contribution of PGS in DCM patients with established causative rare variants (genotype-positive) and those without (genotype-negative). Methods We used a previously-constructed PGS, which was developed from a GWAS meta-analysis (8387 DCM cases and 939161 controls) and multi-trait analysis (MTAG) with cardiac MRI traits. In the present analysis, we calculated PGS for a newly assembled cohort of 978 DCM cases from a major university medical centre and 7207 controls from a national register. To evaluate the clinical utility of PGS, we built logistic regression models and assessed the association between PGS and DCM status. Subsequently, we performed subgroup analyses, including: i) individuals of European ancestry, ii) non-European ancestry, iii) males, iv) females, v) genotype-positive participants(n=193), and vi) genotype-negative participants (n=294). We then used linear and logistic regression models, respectively, to assess the associations of PGS with LVEF and documented family history of DCM. Results PGS demonstrated a significant enrichment among DCM cases compared to controls (OR per SD 1.93, P = 9.47E-68). This association persisted with consistent effect estimates - ranging from OR 1.5 to 2.2 - across all examined subgroups and demonstrated sufficient statistical significance (all P<1.58E-06) (Figure 1). Genotype-negative cases had a significantly higher PGS compared to genotype-positive individuals (P = 0.0015), although PGS was significantly enriched in both groups as compared to controls. Furthermore, among DCM cases, higher PGS was significantly associated with lower LVEF at first presentation (P=0.03, beta=-0.5% per SD) (Figure 2). There was no significant association found between PGS and family history. Conclusions PGS is strongly associated with risk of DCM, and may modulate the severity of LV dysfunction among DCM cases. Polygenic burden contributes to DCM risk in both genotype-positive and negative cases, although the contribution is stronger in patients without known causative rare variants. Overall, our results suggest a potential clinical applicability for PGS in DCM risk stratification.Figure 1.Association of PGS with DCMFigure 2.Association of PGS with LVEF

Causes and predictors of long-term mortality in patients referred to a cardiac rehabilitation program

Abstract Introduction Cardiac rehabilitation (CR) programs have proven to reduce short-term mortality in patients with ischemic heart disease (IHD) and hospitalization rates in patients with heart failure (HF) (1-3). However, there is insufficient evidence about long-term mortality (>24-36 months) for patients receiving treatments based on recent clinical practice recommendations. Purpose To assess the long-term prognosis and predictors of mortality in a heterogenous group of patients referred to cardiac rehabilitation, and to obtain a detailed overview of death causes. Methods An inferential analysis of consecutive patients referred for exercise-based CR at a single site between January 2016 and January 2021 was performed. Included subjects were classified attending to four indications for referral: IHD, HF, valvular heart disease (VHD) and cancer therapy-related cardiovascular toxicity (CTR-CVT). Patients who did not initiate the CR program or were referred for other indications were excluded. The primary endpoint was all cause death. The secondary endpoint was cardiovascular (CV) death. A survival analysis was performed using Kaplan Meier estimates for each referral indication and a Cox proportional hazards model was fitted to investigate mortality predictors. The initiation of the exercise program was considered the inclusion date, and patients were followed until they met the primary endpoint or censored by January 2024. Results A total of 1180 patients were included in the analysis (81% male, mean age 61 ± 11 years), with a median follow-up of 5.3 years. Most of the patients had been referred due to IHD (87%), while the proportion for HF, VHD, and CTR-CVT was 9.9%, 1.8% and 1.4%, respectively. Seventy-eight patients (6.6%) died during follow-up, with a Kaplan-Meier estimated survival of 94.5% at 5 years (95% CI 93.2%-95.9%). Nineteen patients (24.4%) died due to a cardiovascular event, mostly sudden cardiac death (47%). The predominant non-CV causes of death were infectious disease (36%) and cancer (34%). A multivariate Cox model analysis (Table 1) showed an increased risk of all cause death for patients referred due to HF (HR 2.95, 95% CI 1.33 - 6.55), VHD (HR 5.55, 95% CI 1.19 - 25.9) and CTR-CVT (22.47, 95% IC 7.32 - 68.95) when compared to IHD (Figure 1). Other significant predictors of mortality were LVEF <40%, male sex, age, diabetes, peripheral vascular disease, and multivessel coronary disease. Only LVEF <40%, VHD, CTR-CVT and peripheral vascular disease were independent predictors of CV death. Conclusion Patients who initiated an exercise-based CR program had a low risk of all cause death at 5 years. Indications for CR other than IHD were associated with higher mortality rates after adjusting for confounder variables, likely due to a selection bias of patients in advanced stages of the disease.Table 1.Cox models for all-cause deathFigure 1.KM plot for all-cause death

Comparative Analysis of Burn Injuries in Toddler and Preschool Children: Implications for Triage and Outcome Assessment.

This study aims to compare the demographic, clinical characteristics, and outcomes of burn injuries in toddler and preschool children, and to validate the American Burn Association (ABA) Burn Triage Decision Matrix in the Turkish pediatric population. A retrospective analysis was conducted on 684 pediatric burn patients (494 toddlers, 190 preschoolers) admitted to our burn center over a 5-year period. Variables including gender, burn etiology, burn area, depth, treatment modalities, complications, length of hospital stay, and mortality were analyzed. The performance of the ABA Burn Triage Decision Matrix was evaluated in both groups. Scalding was the predominant cause of burns in both groups, with a significant difference in the involvement of anterior trunk (p = 0.027). The mean Total Body Surface Area (TBSA) was comparable between the groups (p = 0.286). There was no significant difference in mortality rates (p = 0.385), treatment modalities, and complications. The ABA Burn Triage Decision Matrix demonstrated consistency in triaging the severity of burn injuries, with a notable discrepancy observed in the moderate risk category of toddler group. This study highlights the distinct characteristics and outcomes of burn injuries in different pediatric age groups. The ABA Burn Triage Decision Matrix's validation suggests its utility in enhancing triage accuracy and resource allocation in pediatric populations, especially in disaster-prone regions.

Genetic analysis using next-generation sequencing and multiplex ligation probe amplification in Chinese aniridia patients

BackgroundCongenital aniridia is a rare pan-ocular disease characterized by complete irideremia, partial iridocoloboma. The progressive nature of aniridia is frequently accompanied by secondary ocular complications such as glaucoma and aniridia-associated keratopathy, which can lead to severely impaired vision or blindness. The genetic basis of aniridia has been the subject of numerous studies, leading to the development of innovative therapeutic options based on PAX6 nonsense mutations. Specific knowledge of the genetics of aniridia has become increasingly important. To report the clinical features, elucidate the genetic etiology, and reveal the mutational spectrum of congenital aniridia in the Chinese population, sixty patients with congenital aniridia from 51 families were recruited. Candidate genes associated with developmental eye diseases were identified and analyzed using panel-based next-generation sequencing (NGS), and mutations were confirmed through polymerase chain reaction and Sanger sequencing. Multiplex ligation probe amplification (MLPA) of PAX6 and FOXC1 was performed to detect copy number variations in the patients without intragenic mutations.ResultsClinical examination revealed complete iris hypoplasia in 58 patients and partial iris hypoplasia in two patients. Additionally, two patients were diagnosed with Wilms’ tumor-aniridia-genital anomalies-retardation syndrome and nephroblastoma. By combining panel-based NGS and MLPA, 43 intragenic mutations or deletions of PAX6, FOXC1, and BCOR were identified in 59 patients, including 33 point mutations (76.7%) in 43 patients and 10 deletions (23.3%) in 16 patients. The total detection rate was 98.3%. Phenotypic variation was observed between and within families.ConclusionsVariations in PAX6 and its adjacent regions were the predominant causes of aniridia in China. In addition to intragenic point mutations in PAX6, deletion of PAX6 or its adjacent genes is a common cause of congenital aniridia. Furthermore, FOXC1 is an important gene associated with congenital aniridia. The combination of panel-based NGS and MLPA significantly enhanced the detection rate of gene mutations in patients with congenital aniridia.

Acquired immunostimulatory phenotype of migratory CD103+ DCs promotes alloimmunity following corneal transplantation.

After transplantation, Th1-mediated immune rejection is the predominant cause of graft failure. Th1 cell sensitization occurs through complex and context-dependent interaction among antigen-presenting cell subsets, particularly CD11b+ DCs (DC2) and CD103+ DCs (DC1). This interaction necessitates further investigation in the context of transplant immunity. We used well-established preclinical models of corneal transplantation and identified distinct roles of migratory CD103+ DC1 in influencing the outcomes of the grafted tissue. In recipients with uninflamed corneal beds, migratory CD103+ DC1 demonstrate a tolerogenic phenotype that modulates the immunogenic capacity of CD11b+ DC2 primarily mediated by IL-10, suppressing alloreactive CD4+ Th1 cells via the PD-L1/PD-1 pathway and enhancing Treg-mediated tolerance via αvβ8 integrin-activated TGF-β1, thus facilitating graft survival. Conversely, in recipients with inflamed and vascularized corneal beds, IFN-γ produced by CD4+ Th1 cells induced migratory CD103+ DC1 to adopt an immunostimulatory phenotype, characterized by the downregulation of regulatory markers, including αvβ8 integrin and IL-10, and the upregulation of IL-12 and costimulatory molecules CD80/86, resulting in graft failure. The adoptive transfer of ex vivo induced tolerogenic CD103+ DC1 (iDC1) effectively inhibited Th1 polarization and preserved the tolerogenic phenotype of their physiological counterparts. Collectively, our findings underscore the essential role played by CD103+ DC1 in modulating host alloimmune responses.

Seasonal and monthly stroke incidence in relation to weather variables: a preliminary single-centre epidemiologic study

This single-centre epidemiologic study investigated seasonal/monthly stroke incidence and stroke-related mortality in relation to weather variables, gender, age, as well as stroke subtype and stroke aetiology. The study involved 638 patients hospitalised due to stroke at the Neurology Ward with a stroke unit at the Regional Hospital in Poland, during one complete calendar year. The data collected included the date of admission to the ward, year of birth, sex, type and subtype of stroke relative to the aetiology and location within different arteries as well as mortality. The data related to wind speed, atmospheric pressure, and temperature were acquired from the archive at the weather station in Tarnów, Poland. Majority of the patients in the study group were aged 66–85 years (57.2%), and there were more women than men. Ischaemic stroke was significantly more common than haemorrhagic stroke (87 vs 13%). Large artery atherosclerosis was the predominant cause of stroke, particularly in June and October, and total anterior circulation stroke (TACS) was the most common type, particularly in January and December. The analysis showed that stroke type and aetiology, as well as weather variables such as temperature and pressure, were associated with stroke incidence and mortality rates. The findings suggest that both high and low temperatures may contribute to an increased stroke incidence, as significant differences in the number of stroke cases are observed during periods of extreme temperatures. Therefore, increased vigilance is necessary during periods of both hot and cold weather. Further research is needed to better understand these relationships and develop effective prevention strategies.

Risk and clinical characteristics of spinal cord compression across different mucopolysaccharidosis types: A retrospective cohort study.

In patients with mucopolysaccharidosis (MPS), the accumulation of glycosaminoglycans leads to various complications, including spinal cord compression (SCC). Although SCC is a well-known complication in MPS, data comparing its clinical features across different MPS types remain limited. This study aimed to investigate the timing, location, and underlying causes of SCC in MPS, as well as to compare the risk and clinical characteristics by MPS type. We conducted a retrospective cohort study, reviewing the medical records of 183 patients with all types of MPS who were followed at Samsung Medical Center from January 1995 to March 2024. The distribution of patients diagnosed with SCC by MPS type was 33.3% for type I, 10.5% for type II, 55.0% for type IV, and 100% for type VI. The median age at SCC diagnosis was 16.3 years. Compared to type II, the risk of SCC was higher for type I (2.4 times, 95% confidence interval [CI]: 0.9-6.2), type IV (3.5 times; 95% CI: 1.5-8.1), and type VI (4.5 times, 95% CI: 1.2-16.4). Enzyme replacement therapy did not reduce the risk of SCC (P = .70). Moreover, SCC most frequently occurred at the C0 to C4 and T11 to L2 spinal levels. In the cervical spine, ligament thickening, and skeletal deformities were the predominant causes, whereas in the thoracolumbar spine, kyphoscoliosis and intervertebral disc issues were the main contributors. Although there was no significant difference in the location of SCC (P = .99), the underlying causes varied significantly by MPS type (P < .001). SCC is a common complication in MPS, but its risk and pathophysiology vary by MPS type. Therefore, an individualized approach is needed for early detection and appropriate intervention.

Preimplantation genetic testing for Cockayne syndrome with a novel ERCC6 variant in a Chinese family.

Cockayne syndrome (CS) is a rare, multisystem, autosomal recessive disorder characterized by cachectic dwarfism, nervous system abnormalities, and premature aging. Mutations in the ERCC6 and ERCC8 genes are the predominant causes of Cockayne syndrome, with ERCC6 gene mutations present in approximately 75% of cases. Trio-based whole-exome sequencing (trio-WES) was employed to identify potential pathogenic variants associated with CS. Preimplantation genetic testing for monogenic disorders (PGT-M) was conducted to prevent the transmission of the pathogenic variant. Two compound heterozygous mutations were identified in ERCC6-c.1297G>T (p. Glu433*) and c.1607T>G (p. Leu536Trp)-with c.1297G>T representing a novel mutation. Four blastocysts resulting from intracytoplasmic sperm injection were subjected to biopsy. Genetic analyses revealed that E1 harbored maternal mutations in diploid embryos, E2 and E3 carried both paternal and maternal mutations in non-diploid embryos, and E4 did not carry paternal or maternal mutations in diploid embryos. Following the transfer of the E4 embryos, a single successful pregnancy was achieved. The successful application of PGT-M in this family offers a potential approach for addressing other monogenic diseases. The findings of this study broaden the variant spectrum of ERCC6 and will contribute to the molecular diagnosis and genetic counseling of CS. This case highlights the feasibility and effectiveness of PGT-M in preventing CS and provides valuable insights for similarly affected families.

TcdB from Hypervirulent Clostridioides difficile Induces Neuronal Loss and Neurotransmitter Alterations in the Intrinsic Enteric Nervous System.

Clostridioides difficile infection (CDI) is a predominant cause of intestinal infections. The intrinsic enteric nervous system (ENS) occupies the intestinal tissue in large numbers and intricately regulates various aspects of intestinal function. Nonetheless, the specific effects of CDI on the intrinsic ENS remain underexplored. Herein, we employed the TcdB variant (TcdB2) derived from hypervirulent C. difficile to elucidate the impact of CDI on neurons located in colonic wall. We found that TcdB2 directly induced dose-dependent cytopathic effects on enteric neurons both in vitro and in adult mice colons. Notably, an increased expression of choline acetyltransferase (ChAT) and neural nitric oxide synthase (nNOS) in colonic neurons prior to the onset of cytopathic changes following treatment with TcdB2 were observed, both in vivo and in vitro. These findings suggest that during CDI, TcdB not only causes neuronal loss but also alters the composition of neurotransmitters in the ENS.

SMARCD1 is an essential expression-restricted metastasis modifier

Breast cancer is the most frequently diagnosed cancer worldwide, constituting 15% of cases in 2023. The predominant cause of breast cancer-related mortality is metastasis, and a lack of metastasis-targeted therapies perpetuates dismal outcomes for late-stage patients. By using meiotic genetics to study inherited transcriptional network regulation, we have identified, to the best of our knowledge, a new class of “essential expression-restricted” genes as potential candidates for metastasis-targeted therapeutics. Building upon previous work implicating the CCR4-NOT RNA deadenylase complex in metastasis, we demonstrate that RNA-binding proteins NANOS1, PUM2, and CPSF4 also regulate metastatic potential. Using various models and clinical data, we pinpoint Smarcd1 mRNA as a target of all three RNA-BPs. Strikingly, both high and low expression of Smarcd1 correlate with positive clinical outcomes, while intermediate expression significantly reduces the probability of survival. Applying the theory of “essential genes” from evolution, we identify 50 additional genes that require precise expression levels for metastasis to occur. Specifically, small perturbations in Smarcd1 expression significantly reduce metastasis in mouse models and alter splicing programs relevant to the ER+/HER2-enriched breast cancer. Identification subtype-specific essential expression-restricted metastasis modifiers introduces a novel class of genes that, when therapeutically “nudged” in either direction, may significantly improve late-stage breast cancer patients.

Assessing public trust in road traffic injuries prevention policies in Iran: a cross-sectional study.

Road Traffic Injuries (RTIs) represent the predominant cause of morbidity and mortality globally. Thus, impactful interventions and trustworthy authorities are imperative to mitigate traffic accidents. The present study seeks to assess public trust in traffic accident diminution policies and measures within the country of Iran. This cross-sectional study utilized a questionnaire comprising 31 questions distributed across eight dimensions. The questionnaire's design was informed by a literature review and semi-structured interviews with experts specializing in traffic accidents. The target population consisted of Tabriz city residents, who were selected via convenience sampling. The collected data were then analyzed using SPSS-16 software, employing the T-test, One-way ANOVA, and Pearson correlation coefficient to present the study's results. structural equation modeling (SEM) was conducted using R 4-4-2 programming language. A total of 681 participants completed the questionnaire, yielding a commendable response rate of 88.6%. The majority of participants were male (60.8%), and 86.2% identified as drivers, with 61.8% having experienced driving accidents. The overall score for public trust in RTIs policies was calculated to be 46.9%. The individual scores for specific domains of trust in traffic safety were as follows: safer roads (43.1%), safe vehicle (43.3%), safety laws (48.8%), safe user (51.1%), safe technology (51.5%), road safety management (46.8%). All the latent variables except education are significantly effective on public trust. The study findings indicate relatively low levels of public trust in RTIs policies among the Iranian population. These results emphasize the need for targeted interventions to enhance public confidence in specific aspects of traffic safety. Policymakers can use these insights to implement effective measures, thus contributing to the RTIs and the promotion of road safety in the country.

Impact of Kidney Function on Physiological Assessment of Coronary Circulation.

Diagnosing myocardial ischemia in chronic kidney disease (CKD) patients is crucial since coronary artery disease (CAD) forms the predominant cause of mortality in these patients. Thus, this study aimed to assess the impact of kidney function on the results of coronary circulation physiological assessment. Data were collected from 279 consecutive patients admitted to the Clinical Department of Cardiology and Cardiovascular Interventions at the University Hospital in Krakow. A total of 417 vessels were assessed for fractional flow reserve (FFR) and non-hyperemic resting pressure ratios, such as instantaneous wave-free ratio (iFR) and resting full-cycle ratio (RFR). Patients were categorized into two groups: glomerular filtration rate (GFR)-L (estimated GFR (eGFR) <70 mL/min/1.73 m2) and GFR-H (eGFR ≥70 mL/min/1.73 m2). A total of 118 patients (42.3%) were included in the GFR-L group, while 161 patients (57.7%) were in the GFR-H group. The left anterior descending branch of the left coronary artery (LAD) was the assessed vessel in approximately 60% of procedures, the frequency of which was very similar in both study groups. Focusing solely on LAD assessments, both FFR metrics (continuous and binary) were comparable between the groups. In contrast, for non-LAD vessels, the GFR-H group revealed substantially reduced FFR values, with more vessels displaying significant constriction. Patients in the GFR-H group showed higher instances of FFR+ iFR/RFR- discrepancies than their lower eGFR counterparts. An eGFR of 70 mL/min/1.73 m2 was the optimal cut-off to differentiate patients concerning the mentioned discrepancies. Kidney function influenced the coronary circulation physiological assessment results. Patients with reduced eGFR tended to have negative hyperemic assessments, especially in non-LAD vessels.

Post‐Mortem Analysis of Building‐Integrated Flexible Thin Film Modules

ABSTRACTFlexible, lightweight thin film (TF) photovoltaic (PV) modules offer a unique opportunity for integration into non‐planar surfaces unable to support heavy weights. While such applications increase the potential for PV in urban areas, the reliability implications are yet to be investigated. Here, prototypes of corrugated rooftiles with integrated Cu (In,Ga)Se2 (CIGS) modules were investigated after 3 years of outdoor operation. Their performance before and after the outdoor exposure was compared and defects were localized. An unpackaging method was developed, allowing access to the solar cells for more detailed characterization of present defects without causing additional damage or changes to existing defects. To our knowledge, this was the first time such an unpackaging method was successfully applied to flexible TF PV modules. The relative efficiency loss ranged from 17% to 43%, mostly due to short‐circuit current (ISC) loss and series resistance (RS) increase. The predominant cause of the RS increase was the delamination at the interconnects, ascribed to thermomechanical stresses caused by outdoor temperature fluctuations. The ISC loss was mainly caused by localized delamination of CIGS from the molybdenum (Mo) back‐contact. The occurrence of such delaminated areas pointed to presence of high local stresses during outdoor operation, possibly due to thermal fluctuations, applied deformation and/or mechanical impact. Two other types of delamination defects were found with no observable impact on performance. These results show the necessity for further optimization in the material choice and processing of TF flexible modules, to avoid mechanical stress related failures upon integration into curved surfaces.

Characterization of neurologic disease-associated Streptococcus suis strains within the United States swine herd and use of diagnostic tools.

Streptococcus suis negatively impacts swine health, posing diagnostic and preventative challenges. S. suis can induce disease and also quietly reside on mucosal surfaces. The limited use of diagnostic tools to identify disease-associated strains and rule out differential diagnoses, alongside the complex ecology of S. suis, poses significant challenges in comprehending this important pathogen and defining pathotypes. This study evaluated 2,379 S. suis central nervous system (CNS) isolates from diagnostic submissions between 2015 and 2019. Isolates originating from submissions with histologic evidence of CNS infection (n = 1,032) were further characterized by standard and advanced diagnostic techniques. We identified 29 S. suis serotypes and 4 reclassified serotypes as putative causes of CNS disease. Among these, serotypes 1 and 7 emerged as the predominant putative causes of CNS infection (32% of submissions). Furthermore, 51 sequence types (STs), of which 15 were novel, were detected with ST1 predominating. Through whole-genome sequencing of 145 isolates, we observed that five commonly used virulence-associated genes (VAGs; epf, mrp, sly, ofs, and srtF) were not present in most disease-associated isolates, and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) yielded false-positive results in 7% of isolates. These data indicate that (i) clinical signs and site of isolation alone are insufficient for defining a pathotype, (ii) S. suis serotypes and STs associated with CNS infection are more diverse than previously reported, (iii) MALDI-TOF MS may need to be supplemented with additional diagnostic tools for precise S. suis identification, and (iv) VAGs remain an unreliable means for identifying isolates associated with CNS disease.IMPORTANCEStreptococcus suis is an important and complex systemic bacterial pathogen of swine. Characterization of S. suis strains originating from pigs with histologic confirmation of neurologic disease is limited. Review of swine diagnostic submissions revealed that fewer than half of cases from which S. suis was isolated from the brain had histologic evidence of neurologic disease. This finding demonstrates that clinical signs and site of isolation alone are not sufficient for identifying a neurologic disease-associated strain. Characterization of strains originating from cases with evidence of disease using classic and advanced diagnostic techniques revealed that neurologic disease-associated strains are diverse and commonly lack genes previously associated with virulence.

12511 Rhabdomyolysis Related Acute Kidney Injury Presenting as First Manifestation of Autoimmune Hypothyroidism: A Case Report

Abstract Disclosure: A. Tiwari: None. S. Mantravadi: None. N. Doshi: None. A. Dabaja: None. C. Saad: None. Introduction: Autoimmune thyroiditis is the predominant cause of primary hypothyroidism, with an incidence of estimated 0.3-1.5 cases per 1000 people, with female to male predominance of 7-10[1]. Hypothyroid myopathy affects 79 % of the affected population. Its common presentation is fatigue and cramp but in rare instances rhabdomyolysis can occur with trivial triggers like alcohol, exercise2, Case Presentation: A 32-year-old male with no significant medical history, presented with generalized weakness, myalgia, and facial puffiness for last three months. The patient engaged in regular-intensity workouts and reported consuming 12 beers several times a week for past 5 years. Physical examination revealed facial puffiness and proximal muscle weakness. Initial Laboratory findings showed elevated creatinine (1.68 mg/dL, baseline 1.0 mg/dL in April 2020), CK (8113 U/L), AST (260 U/L), ALT (129 U/L). Urinalysis revealed hematuria and mild proteinuria. Serum electrolytes were unremarkable. Abdominal ultrasound showed diffuse hepatic steatosis with normal kidney appearance. This could not explain the reason for the Acute Kidney Injury and further workup showed TSH (&amp;gt;150 mIU/L) and TPO antibodies (197.9 U/mL). Autoimmune panel was unremarkable. Thyroid ultrasound done subsequently revealed a markedly heterogeneous gland. Treatment included parenteral crystalloids, low-dose prednisone which was empirically added for suspected autoimmune myositis and was later discontinued once the autoimmune panel was negative, and Levothyroxine at the recommended dose. At the time of discharge, his creatinine was reduced to 1.33 mg/dL and CK to 2,298 U/L. Discussion: Severe rhabdomyolysis is a rare but significant complication of autoimmune thyroiditis, potentially leading to acute kidney injury (AKI) if not promptly diagnosed and treated. Resident physicians often attribute symptoms like myalgia and generalized weakness in males to clear evident rhabdomyolysis if they find a cause like alcohol consumption and exercise, potentially overlooking the actual etiology. We recommend thyroid workup in such patients to promptly detect and manage underlying etiology predisposing to muscle damage and subsequent kidney injury. Our patient never had any Physician encounter as his prior medical history was unremarkable, however we suggest thorough family history and thyroid profile should be a part of outpatient workup as well for patients who show other risk factors for rhabdomyolysis like daily alcohol consumption, vigorous workout, consume medications like HMG CoA inhibitors, antipsychotics etc. Presentation: 6/3/2024

12599 Early Remission Of Chromosome 6 Q 24-related Neonatal Diabetes Mellitus

Abstract Disclosure: R. Pratibha: None. K. Dummula: None. Introduction: Chromosome 6q24 imprinting abnormalities represent the predominant cause of transient neonatal diabetes mellitus (TNDM), accounting for over two-thirds of cases with an estimated prevalence of 1 in 400,000. While remission typically manifests by 3 months of age, herein we detail a case of Chromosome 6q24-related TNDM exhibiting remission by 1.5 months of age. We share our clinical experience in managing this case without hypoglycemia and using C-Peptide levels as a monitoring tool to track the resolution. Case: A female infant, born at 36 weeks via elective C-section due to fetal growth restriction and oligohydramnios, was closely monitored in the nursery for potential hypoglycemia. Contrary to the expectation, she displayed escalating hyperglycemia, necessitating insulin infusion within 25 hours of birth. Apgar scores were 7 and 9, and the birth weight was 2095 g (6th percentile). Maternal history included impaired glucose tolerance in a previous pregnancy with borderline glucose tolerance during this gestation. The newborn physical exam was unremarkable except for mild macroglossia. Despite initial blood glucose (BG) of 52 mg/dl, it rose to 257 mg/dL by 16 hours. Insulin drip was started at 24 hours due to BG of 304 mg/dL. The monogenic diabetes panel obtained on day of life (DOL) #2 was negative; no acidosis was observed. The C- Peptide was low at 0.2 ng/ml. Insulin infusion was continued until DOL # 20. A trial of glyburide commenced on DOL #9 while on Insulin drip, yielded minimal response, prompting a transition to short-acting insulin for correction of hyperglycemia (&amp;gt;250 mg/dL). C-peptide level during sulfonylurea (SU) trial remained low (0.5 ng/mL). The infant required 2 to 3 corrections per day with 0.05 units of Lispro Insulin, with the last dose administered at 44 days. She did not receive any long-acting Insulin. As of her last follow-up at the endocrine clinic at 57 days of age, the infant is thriving well and has normal blood glucose levels. The 6q24 Methylation-MLPA study showed duplication of 6q24 on the paternally inherited chromosome 6. Significantly, she never encountered hypoglycemia during her hospital stay. The C-peptide increased to 0.8 ng/ml at DOL#37 and had normalized to 1.3 ng/mL by DOL#57 indicating remission of TNDM. Conclusion: 6q24-related TNDM may often be characterized by features such as small for gestational age (SGA), macroglossia, umbilical hernia, cardiac and renal abnormalities. Early presentation of hyperglycemia with this phenotype must prompt its diagnostic evaluation. Early resolution by 1.5 months as seen in our case is uncommon. Uniquely, we used C-peptide as a tracking tool to guide resolution and manage insulin therapy. Presentation: 6/3/2024

Impact of early continuous positive airway pressure in the delivery room (DR-CPAP) on neonates < 1500 g in a low-resource setting: a protocol for a pilot feasibility and acceptability randomized controlled trial

BackgroundPreterm birth is the leading cause of childhood mortality, and respiratory distress syndrome is the predominant cause of these deaths. Early continuous positive airway pressure is effective in high-resource settings, reducing the rate of continuous positive airway pressure failure, and the need for mechanical ventilation and surfactant. However, most deaths in preterm infants occur in low-resource settings without access to mechanical ventilation or surfactant. We hypothesize that in such settings, early continuous positive airway pressure will reduce the rate of failure and therefore preterm mortality.MethodsThis is a mixed methods feasibility and acceptability, single-center pilot randomized control trial of early continuous positive airway pressure among infants with birthweight 800–1500 g. There are two parallel arms: (i) application of continuous positive airway pressure; with optional oxygen when indicated; applied in the delivery room within 15 min of birth; transitioning to bubble continuous positive airway pressure after admission to the neonatal unit if Downes Score ≥ 4 (intervention), (ii) supplementary oxygen at delivery when indicated; transitioning to bubble continuous positive airways pressure after admission to the neonatal unit if Downes Score ≥ 4 (control). A two-stage consent process (verbal consent during labor, followed by full written consent within 24 h of birth) and a low-cost third-party allocation process for randomization will be piloted.We will use focus group discussions and key informant interviews to explore the acceptability of the intervention, two-stage consent process, and trial design. We will interview healthcare workers, mothers, and caregivers of preterm infants. Feasibility will be assessed by the proportion of infants randomized within 15 min of delivery; the proportion of infants in the intervention arm receiving CPAP within 15 min of delivery; and the proportion of infants with primary and secondary outcomes measured successfully.DiscussionThis pilot trial will enhance our understanding of methods and techniques that can enable emergency neonatal research to be carried out effectively, affordably, and acceptably in low-resource settings. This mixed-methods approach will allow a comprehensive exploration of parental and healthcare worker perceptions, experiences, and acceptance of the intervention and trial design.Trial registrationThe study is registered on the Pan African Clinical Trials Registry (PACTR) PACTR202208462613789. Registered 08 August 2022. https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=23888.

Computational quest, synthesis and anticancer profiling of 3-methyl quinoxaline-2-one-based active hits against the tyrosine kinase

BackgroundCancer is the predominant cause of mortality and a remarkable obstacle to elevating life anticipation in every nation on globe. Hepatocellular carcinoma (HCC), a hyper-vascular tumour, develops and progresses due to angiogenesis, a key feature of malignancy. HCC exhibits high neoangiogenic activity because of the need to generate new blood vessels for tumour growth.MethodsThe present work includes the construction of virtual library of ligands, virtual screening using the Dockthor-VS server, ADMET study using the SwissADME and Osiris property explorer. All the synthesized compounds were characterized by UV, IR, NMR and mass spectroscopic techniques. MTT assay was done to find the IC50 of the synthesized compounds against HepG2 cell line. The more active compound found is subjected to the molecular dynamics simulation study.ResultsThe ligands exhibited good docking scores, ADMET profile compared to the reference drugs. The target compounds were obtained with the satisfactory yields of 66–82%. The best activity against the HepG2 cancer cell line is observed with the compound SA-4 with IUPAC name (2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)-N-(5-(3-nitrophenyl)-5H-thiazolo[4,3-b] [1,3,4] thiadiazol-2-yl) acetamide). The experimental results obtained show correlation with the in silico results. MD simulation of the compound SA-4 indicates the moderate stability of the protein-ligand complex in real time environment.ConclusionThe results obtained suggest that the compound SA-4 has the potential to be a promising anticancer agent effective against the VEGFR-2 and FGFR-4.Graphical abstract

Single-component artificial urinary sphincter: Outcomes from one centre in Portugal.

Radical prostate cancer treatment is the predominant cause of iatrogenic stress urinary incontinence (SUI) in men, significantly impacting their quality of life (QoL). This prospective single-center study in Portugal aimed to evaluate the outcomes of men with moderate-to-severe SUI treated with a single-component artificial urinary sphincter (AUS). Male patients with iatrogenic moderate-to-severe SUI, determined by a 24-hour pad weight test, were included. The single-component device comprises a cuff linked to a pump unit through a kink-resistant tube. The implantation involved perineal incision for cuff placement and an inguinal incision for pump and tank positioning within the scrotum. Complications, pad usage, perioperative complications (Clavien-Dindo classification), and quality of life assessment using the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) questionnaire were documented. Between May 2021 and March 2023, 20 consecutive single-component AUS insertions were conducted at a Portuguese urology department. Follow-up concluded in July 2023, with a mean follow-up duration of 15 months (range: 5-27). Four patients experienced complications necessitating device revision or removal (erosion = 2, infection = 1, mechanical failure = 1). Social continence (0/1 pad/day) was achieved in 70% (14/20 patients), while 30% (6/20 patients) experienced incontinence. Perioperatively, one patient was classified as grade 2, while the remaining were grade 0/1 in the Clavien-Dindo classification. The mean ICIQ-SF score reduction was 10.5 points. The single-component AUS shows promising efficacy in managing moderate-to-severe male SUI, offering a good success rate, acceptable complications, improved QoL, and a straightforward surgical procedure.

GOLM1 promotes prostate cancer progression via interaction with PSMD1 and enhancing AR-driven transcriptional activation.

Aberrant transcriptional activation of the androgen receptor (AR) is a predominant cause of prostate cancer (PCa), including both in the initial and androgen-independent stages. Our study highlights Golgi membrane protein 1 (GOLM1) as a key regulator of AR-driven transcriptional activity in PCa progression. Utilizing local clinical data and TCGA data, we have established a robust association between GOLM1 and AR target genes, and further demonstrated that GOLM1 can enhance the expression of AR target genes. We discovered that GOLM1 interacts with PSMD1, a component of the 19S regulatory complex in the 26S proteasome, using mass spectrometry and Co-IP analysis. It is well known that ubiquitin-proteasome plays a vital role in AR expression and transcriptional regulation. Our findings demonstrate that GOLM1 enhances ubiquitin proteasome activity by binding to PSMD1, thereby facilitating AR-driven transcriptional activity and PCa progression. These results indicate that GOLM1 and its associated proteins may become potential therapeutic targets for PCa characterized by dysregulated AR-driven transcriptional activation.