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A 21-year-old man presented with acute onset of jaundice, abdominal pain, ascites, and hepatomegaly, along with a history of Budd-Chiari syndrome previously treated with vena cava angioplasty. Investigations revealed rapidly worsening jaundice, coagulopathy, elevated creatinine levels, reactive hepatitis B serology, and positive antiphospholipid antibodies, with scores indicating a poor prognosis for liver transplant-free survival. Abdominal computed tomography demonstrated a narrowed intrahepatic vena cava and new thrombosis in the right and middle hepatic veins. Renal biopsy, prompted by nephritic range proteinuria, indicated mesangioproliferative glomerulonephritis (MPGN) with immune complex deposition. The described case involves acute-on-chronic liver failure with acute insults from new onset hepatic vein thrombosis and hepatitis B reactivation, in a patient at a non-transplant center, who also had underlying antiphospholipid antibody syndrome, and MPGN. The patient was successfully treated with antiviral, anticoagulation, and antiplatelet agents, along with a sodium-glucose cotransporter 2 inhibitor and a direct intrahepatic portosystemic shunt, despite having a Model for End-Stage Liver Disease score of 35.

Congenital anomalies of the biliary tree are rare and present challenges for endoscopists performing interventions such as endoscopic retrograde cholangiopancreatography (ERCP). The reported incidence of ectopic biliary drainage ranges from 2% to 20%, and the condition is often associated with pancreatobiliary complications, including choledocholithiasis (56%), cholangitis (39%), and acute pancreatitis (18.2%). These developmental abnormalities originate during embryogenesis. Uncommon sites for the ampullary opening include the third or fourth part of the duodenum, the stomach, and the pancreatic duct. We report a rare case of ectopic ampulla opening into the pylorus, which presented with cholangitis and was successfully managed with a modified ERCP technique.

Colon cancer is characterized during its history, by developing metastases in approximately 50% of patients. The organ most affected by this process is the liver and every year 900,000 new cases of colorectal cancer with liver metastases are recorded. In this disease setting, the therapeutic strategies include a combined treatment with loco-regional therapies and systemic chemotherapy treatments, with close collaboration between oncologists and surgeons. But the diversity of the clinical pictures that can present in patients with colorectal cancer liver metastases often makes it difficult to plan the sequence between surgery and chemotherapy, making it necessary to deal with these cases in a multidisciplinary team where the various professional figures discuss together individual cases to decide the best therapeutic strategy.

Background : Delayed post-polypectomy bleeding (DPPB) is a serious complication of polypectomy that is poorly understood. The aim of this study was to evaluate the effectiveness of endoscopic hemostasis in managing DPPB and to identify associated risk factors. Methods : We retrospectively analyzed 289 patients who experienced DPPB (≥ 24 hours after polypectomy) and underwent endoscopic hemostasis at five university hospitals between 2005 and 2018. Patient characteristics, polyp size, technical factors, rebleeding, complications, and length of hospitalization were assessed. Results : Endoscopic hemostasis was successful in all 289 cases of DPPB. The techniques and devices employed included epinephrine injection (24.9%), argon plasma coagulation (18.0%), hemostatic forceps (10.7%), and hemoclips (87.9%). Rebleeding occurred in 15 cases (5.2%) after initial endoscopic hemostasis. The incidence of rebleeding was significantly associated with polyp size (< 10 mm: 2.8%, 10 mm-19 mm: 5.6%, ≥ 20 mm: 13.5%, P = 0.030) and sedation status (yes: 1.8%, no: 7.3%, P = 0.040). However, hemostasis method, bleeding characteristics, and polyp location were not significantly linked to rebleeding. Multivariate analysis revealed that polyp size (odds ratio, 5.02; 95% confidence interval, 1.25-20.13; P = 0.023) was significantly associated with rebleeding after endoscopic hemostasis for DPPB. In all 15 cases of rebleeding, a second endoscopic hemostasis was successfully performed without the need for embolization or surgical intervention. No perforations occurred during the first or second endoscopic hemostatic procedures. Conclusion : Polyp size and sedation status were associated with rebleeding after endoscopic hemostasis for DPPB. As an intervention for DPPB, endoscopic hemostasis appears safe and effective.

We report a case of gallbladder cancer, which presented exclusively as tight pyloric stenosis. The patient had persistent vomiting, severe weight loss, and esophageal symptoms due to gastric reflux. Earlier, endoscopy had shown pyloric stenosis and computed tomography suggested gastric outlet obstruction. The result of endoscopic balloon dilation was poor, though a small caliber video scope could be passed over a guide wire distally into the duodenum. A positron emission tomography scan revealed a metabolically active lesion involving the pyloric canal and the patient was then subjected to surgery. Histopathology of the resected specimen identified the gallbladder cancer infiltrating the pylorus.

Background : Fecal incontinence (FI) results from damage to the external anal sphincter (EAS), significantly affecting quality of life. This clinical trial evaluated the impact of low-level laser (LLL) therapy on EAS repair and the treatment of FI. Methods : Thirty FI patients with EAS deficiency were divided into two groups (n = 15): a control group receiving sphincteroplasty alone and a laser group undergoing sphincteroplasty plus laser therapy. Following surgery, the laser group received daily laser therapy for 2 weeks. Outcomes were assessed using Wexner scores, electromyography (EMG), and endorectal sonography. Results : The laser group exhibited a significant increase in muscle bulk (P = 0.008) and a lower Wexner index (P < 0.0001) compared to the control group. EMG confirmed muscle contractility in the laser group. Conclusions: Two weeks of LLL therapy effectively increased muscle at the EAS injury site, leading to significant, lasting improvements in FI.

Introduction: Osteoarthritis (OA) is a prevalent chronic joint disorder. It is characterized by an immune response that maintains a low level of inflammation throughout its progression. During OA, cartilage degradation leads to the release of damage-associated molecular patterns (DAMPs), which intensify the inflammatory response. β-Amyloid is a well-recognized DAMP in OA, can interact with APOE isoforms. Methods: This study identified DAMPs-related genes in OA using bioinformatics techniques. Additionally, we examined the expression levels of β-amyloid and apolipoprotein E (ApoE) isoforms by enzyme-linked immunosorbent assay. Results: We identified 10 key genes by machine learning techniques. Immune infiltration analysis revealed upregulation of various immune cell types in OA cartilage, underscoring the critical role of inflammation in OA pathogenesis. In the validation study, elevated serum levels of β-amyloid in knee osteoarthritis (KOA) patients were confirmed, showing positive correlations with ApoE2 and ApoE4. Notably, ApoE3 was identified as an independent protective factor against KOA. Conclusion: In this bioinformatics analysis, we identified the DAMPs-related genes of KOA and explored their potential functions and regulatory networks. The high expression of β-amyloid in KOA was confirmed by experiments, and the correlation between β-amyloid and ApoE2, ApoE4 in KOA was revealed for the first time, this provides a new way to explore the pathogenesis of KOA and to study the therapeutic targets of KOA.

Aim: Atmospheric pressure cold plasma is the fourth state of matter obtained at low temperature with atmospheric pressure, which has antimicrobial, anti-inflammatory, sterilization, disinfection and surface modification enhancing properties. The aim of this study is to investigate the effectiveness of plasma activated medium (PAM) obtained from atmospheric pressure cold plasma on hand disinfection. Methods and Materials: The study was carried out on 15 individuals aged between 18 and 65 with healthy hand structures (no wounds, no pathology). Of the 15 individuals, 5 were selected as cleaning staff, 5 as office stuff, and 5 as academics. Samples were first taken from individuals using swap for bacterial identification. Afterwards, they were asked to wash their hands for 5 minutes in 250 ml PAM. At the end of the period, samples were taken from the individuals in the same way for bacterial identification using swap. The effectiveness of PAM in terms of hand disinfection was determined by comparing these two samples. Results: As a result of our study, it was found that bacterial colonies decreased in 3 of the samples taken from the hands of 5 cleaning personnel, remained stable in 2, a decrease in bacterial colonies in 4 of 5 office stuff, remained constant in 1, a decrease in bacterial colonies in 3 of 5 academicians, and remained stable in 2 of them. Staphylococcus aureus, Staphylococcus epidermidis, Bacillus megaterium, Staphylococcus capitis, Streptococcus mitis, Staphylococcus warneri bacteria were identified on the hands of individuals. Conclusion: As a result of our study, it was found that PAM, which has no side effects in the literature, can be an effective tool for hand disinfection.

Aim: This paper examines the predictors of all-cause mortality among hospitalized HIV-positive patients in Kazakhstan. Material and methods: The study uses baseline data from patient hospital discharge records derived from the Unified Electronic Healthcare System of Kazakhstan (UNEHS) between 2014 and 2019. Artificial intelligence technology was utilized to extract data from the discharge records. Patients were included based on their first hospitalization, and they were subsequently monitored until their discharge or occurrence of death. Results: The study revealed that females had a 2.06-fold higher risk of all-cause mortality compared to males. After adjustments in the Cox proportional hazard model, age, intravenous drug use (IDU), and anemia were observed as independent predictors of mortality within the patient cohort. Conclusions: Findings of this study emphasize the need to enhance efforts to prevent late HIV diagnosis by improving access to testing and treatment for those affected, and to strengthen potential for developing risk factors reduction strategies.

Aims: The case study evaluates the efficacy of Cognitive Behavioral Therapy in optimizing counseling outcomes for social anxiety and panic attacks within an academic setting. Counseling sessions were conducted with a 23-year-old female client over a four-month period at T.S Government College. Method: The study utilized a single case study design A-B-A. The client presented with symptoms of social anxiety and panic attacks, impacting various aspects of her life including academic performance, interpersonal relationships, social interactions and family dynamics. Results: Cognitive Behavioral Therapy techniques including Cognitive Restructuring, Social Skills Training, Role Play and Role Reversal, and Systematic Desensitization through Gradual Exposure, were implemented over 8 sessions. Assessment tools including pre-post ratings, behavioral observations and therapy blueprints were utilized to assess the severity of social anxiety. Conclusion: A significant decrease in the severity of social anxiety and panic attacks based on both subjective self-reporting and objective observations suggesting Cognitive Behavioral Therapy as an approach of counseling for individuals with social anxiety with panic attacks in educational setting. Keywords: Cognitive Behavioral Therapy, case study, case report, social anxiety, panic attacks, cognitive restructuring, systematic desensitization, role play, role reversal, social skills training

Severe respiratory failure, resulting from a wide range of acute and chronic diseases such as chronic obstructive pulmonary diseases, obstructive sleep apnoea, obesity hypoventilation syndrome (Pickwickian syndrome), COVID-19, bilateral pneumonitis, kyphoscoliosis, acute respiratory distress syndrome, amyotrophic lateral sclerosis, Guillain-Barré syndrome, and others, poses a significant challenge for healthcare systems worldwide. Treating severe respiratory failure often requires long-term or lifelong respiratory support, which places a heavy burden on both patients and healthcare systems. Despite the availability of free comprehensive care for patients with chronic kidney failure and heart failure, those requiring long-term respiratory support are often deprived of adequate medical and social assistance. This gap in care leads to frequent hospitalizations, disability, and premature death of patients with severe respiratory failure, further straining healthcare resources and increasing social tension. The solution of the problem is an organisation of ambulatory centre for homecare respiratory support for patients with severe chronic respiratory failure. Homecare respiratory support demonstrated worldwide cost-effectiveness by significantly enhancing patients clinical and social outcomes, restoring their work capacity, and reducing the need for hospitalizations. This article emphasizes the necessity of a comprehensive homecare respiratory support system and highlights how inadequate assistance can result in frequent hospitalizations, increased disability, and premature death, thereby imposing an additional strain on the healthcare system.

Aplastic anemia, mental retardation, and dwarfism (AMeD) syndrome, also known as aldehyde degradation deficiency (ADD) syndrome, is an autosomal recessive disorder caused by mutations in the ALDH2 and ADH5 genes, leading to decreased activity of the aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 5 (ADH5) enzymes, subsequently triggering enhanced cellular levels of formaldehyde and diverse multisystem manifestations. Herein, we present the case of a 7-year-old girl with AMeD syndrome, characterized by pancytopenia, developmental delay, microcephaly, epilepsy, and myelodysplastic syndrome. Whole-exome sequencing revealed compound heterozygous variants (c.832G>C and c.678delA) in the ADH5 gene and a heterozygous pathogenic variant (c.1510G>A) in the ALDH2 gene. This case underscores the complexity of AMeD syndrome, emphasizing the importance of genetic testing to ensure diagnosis and aid in the development of potential targeted therapeutic approaches.

Esthesioneuroblastoma (ENB) is a slow growing malignant tumour of olfactory neuro-epithelium that is locally aggressive with a tendency to recur years later. Infrequently, it can be associated with paraneoplastic syndrome. Here, we a report a pediatric case of ENB in whom syndrome of inappropriate ADH secretion (SIADH) was detected during ongoing primary treatment which reflected disease progression after initial response to chemotherapy, that was substantiated radiologically. SIADH has been reported in only a few cases of ENB.

Background: Primary malignancies of the thyroid gland are less frequent in the first two decades of life and accounts for only 0.5-3% of all malignant neoplasms in children and adolescents.Methods: A retrospective analysis was undertaken on children less than 18 years of age who were diagnosed with thyroid malignancy from 1st June 2018 to 31st May 2022. The electronic health records were reviewed to determine patient demographics, pathological characteristics, interventions (surgery and radioactive iodine therapy [RAI]) and follow up.Results: Eighteen patients were less than 18 years of age at the time of diagnosis. Mean age at diagnosis was 14.7 years (6-18 years). Majority were females and in post pubertal age group. Among our cohort 83.4% had stage 1 disease, whereas 16.6% had stage II disease. Lung involvement was noted in 16.6%. Risk stratification revealed that 44.6% of the children were in the high-risk group and 38.8% in the intermediate- risk group. Fifteen patients (83.3%) underwent I-131 therapy. Follow up period ranged from 2-51.7 months with a median follow up period of 22.15 months. Complete remission was noted in 15 patients (83.3%). Out of the children with metastatic lung disease, 1 had progressive disease, 2 had stable disease. Overall survival was 100%.Conclusion: Majority of our children in our retrospective data presented with nodal and distant metastasis. With the current advances in the treatment of thyroid malignancies, a good survival was noted even in children with pulmonary metastasis.

Pediatric acute leukemia presenting with osteolytic lesions and hypercalcemia is an unusual and rare occurrence. We are reporting two such cases with atypical presentations. The first case involved a 10-year-old boy who complained of progressively worsening lower back pain. Physical examination revealed restricted flexion and extension of the back due to pain, while complete blood count and peripheral blood smear were normal. CT and MRI spine indicated osteolytic lesions in all vertebrae and pelvic bones. Biopsies from the bone marrow and vertebrae confirmed the presence of lymphoblasts, with flow cytometry results positive for B-ALL. The second case involved a 2-year-old boy who presented with chronic fever, cough, and pain in the left hip region. Physical examination was unremarkable, but chest X-ray and CT thorax revealed mediastinal widening and an anterior mediastinal mass. Skeletal X-rays showed osteolytic lesions in the humerus and femur. Peripheral blood smear was suggestive of acute leukemia. Upon presentation, the child had a serum calcium level of 17 mg/dL, initially managed with fluids and furosemide, but also required zoledronate and calcitonin. Both these cases highlight that osteolytic lesions alone or combined with hypercalcemia can be the sole presentation of leukemia in children. Such cases require a high index of suspicion to diagnose this life-threatening condition promptly and initiate timely treatment for optimal outcomes.

Juvenile xanthogranuloma (JXG) is a rare histiocytic disorder primarily affecting children, typically presenting as self-limiting skin lesions. However, extracutaneous JXG (extra-JXG) or systemic JXG (sJXG) can involve various organs, including the central nervous system (CNS), leading to high morbidity and mortality, especially in cases of CNS involvement. Treatment approaches for CNS–JXG, including surgical resection, chemotherapy, and radiation therapy, lack consensus, with reports of relapsed or refractory cases being rare. Here, we present the case of a 2-year-old girl with refractory extra-JXG involving the CNS, characterized by multiple intracranial lesions. Initial chemotherapy with prednisolone and vinblastine showed no response, and second-line therapy, including cytarabine and vincristine combined with surgical resection, was also ineffective. However, a 6-cycle third-line chemotherapy regimen incorporating vincristine and carboplatin led to a positive response, with stable disease status, and normal growth and neurodevelopment observed. Our findings suggest that combined chemotherapy with carboplatin and vincristine is a feasible and well-tolerated treatment strategy for patients with CNS–JXG.

Background: Pediatric malignant bone tumors constitute an important subgroup of solid tumors and need comprehensive multidisciplinary care for optimal management. We aimed to review our local practice of managing malignant bone tumors and identify gaps to improve service.Methods: We retrospectively reviewed disease characteristics and management of twenty-five pediatric patients with malignant bone tumors from Jan 2000 to Dec 2020.Results: Median age at diagnosis was 8.75 years, male to female ratio of 0.8:1, and median follow-up was 3.6 years. Pain and swelling were the predominant symptoms at presentation, while lung was the most common metastatic site in Osteosarcoma (OS) and Ewing’s Sarcoma Family Tumors (ESFT). Metastatic disease was not associated with developing an event in OS (P=0.26) but was significantly associated with developing an event in the ESFT subgroup (P=0.002). There was no association of tumor necrosis of

Non-Down syndrome pediatric acute megakaryoblastic leukemia (AMKL) may be classified according to the presence of recurrent genetic abnormalities with prognostic relevance. In this case study, we report on a girl with AMKL, 32 months old at the time of diagnosis, in whom we confirmed the presence of the cryptic, poor prognosis NUP98::KDM5A fusion. The patient achieved complete remission (CR) with the first course of chemotherapy, underwent haploidentical family donor hematopoietic stem cell transplantation (HSCT) without event, but relapsed 5 months after HSCT. Through this case report, we emphasize the good initial response to chemotherapy, and the early relapse despite undergoing HSCT in first CR. We review the limited literature on NUP98::KDM5A (+) pediatric AML, and underscore the need for further study to improve the outcome of patients with this rare AML subtype.

Abstract Postoperative abdominal adhesion is one of the most common complications after abdominal surgery. The Toll-like receptor 4 (TLR4) signaling pathway is one of the most common inflammation-related pathways, and it has been demonstrated that TLR4 is highly expressed in adhesive tissues; however, the function of TLR4 in adhesion formation has not yet been studied. In the present study, the expression of TLR4 was first detected by immunohistochemical (IHC) and double-immunofluorescence staining in 40 mice, which were randomly divided into four groups, and sacrificed at 1, 3, 5 and 7 days after surgery. Subsequently, another 40 mice were randomly divided into five groups; with the exception of the sham group, the other groups were modeled and treated with saline that contained DMSO, sodium hyaluronate (HA), TAK-242 or TAK-242 + HA (applied to damaged peritoneal wounds). A total of 7 days after surgery, the mice were sacrificed and specimens were collected. Inflammation was detected by hematoxylin and eosin staining, and ELISA of transforming growth factor- β1 (TGF-β1) and interleukin-6 (IL-6); collagen deposition was examined by Masson staining and IHC staining of α-SMA; and reactive oxygen species (ROS) were detected by ROS staining and malondialdehyde (MDA) assay. The results revealed that TLR4 was highly expressed in the adhesive tissues at 3, 5 and 7 days after surgery. In addition, TAK-242 + HA treatment could reduce abdominal adhesion formation, exhibiting lower Nair’s score and inflammation scores, lower TGF-β1 and IL-6 levels, and lower collagen thickness and α-SMA levels compared with those in the control group. In addition, the TAK-242 + HA group had lower levels of ROS and MDA compared with those in the control group. The present study revealed that TLR4 was highly expressed in the process of adhesion formation and its inhibitor, TAK-242, combined with HA, could reduce adhesion formation by reducing inflammation and ROS, and alleviating collagen deposition.

Abstract Background New diagnostic tools are needed to improve the diagnosis and risk stratification of cutaneous melanoma. Disease-specific microRNA signatures have been previously described via NanoString profiling of solid biopsy tissue and plasma. This study validated these signatures via next-generation sequencing technology and compared their performance against clinical metrics and other published melanoma signatures. Methods RNA from 64 plasma and 60 FFPE biopsy samples from individuals with invasive melanoma or related benign/control phenotypes was extracted and enriched for microRNA. RNA sequencing was performed to compute MEL38/MEL12 signature scores. The results were evaluated with published NanoString and RNA sequencing datasets, comprising 548 solid tissue samples and 217 plasma samples, to predict disease status and patient outcome. Results The MEL38 diagnostic signature classifies patients into discrete diagnostic groups via RNA sequencing in either solid tissue or plasma (P

Abstract The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase approximately 50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.

Embryologically, the left brachiocephalic vein (LBV) originates as an anastomotic channel between the right and left anterior cardinal veins. This positions the LBV between the manubrium sterni anteriorly and the innominate artery posteriorly. This pattern of adjacency of the aorta to the LBV is unique to mammals and results from a quirk of evolution. With age, the ascending aorta unfolds, elongates and dilates. Simultaneously, there is a change in the thoracic geometry that reduces the thoracic volume primarily from disc height loss and kyphosis. These transitions progressively compress the LBV. Normally, this compression is circumvented via collateral pathways and “Blood finds a way”. However, traversing these circuitous pathways comes at a cost and can result in delayed transit times and venous congestion. While it is possible that compression of the LBV in the setting of adequate collateral channels may fail to provoke any pathologic sequelae, we propose a phenomenon in which such compression in the setting of inadequate collateral circulation may lead to a state of pathologic venous congestion. This anatomic anomaly and its associated clinical features, if identified, can offer a new avenue for treatment options for some of the hitherto unexplained neurologic disorders.

Background: The lateral antebrachial cutaneous nerve (LACN) is the terminal sensory branch of the musculocutaneous nerve and is rarely entrapped or injured. This study describes the electrodiagnostic (EDX) findings and etiologies of LACN neuropathy. Methods: This is a review of 49 patients with pain and/or paresthesia of the forearm who underwent EDX studies. The diagnosis of LACN neuropathy was based on clinical and sensory conduction abnormalities. Results: The most common etiology of LACN neuropathy was iatrogenic injury in 30 (61.2%) patients, primarily due to biceps tendon repair at the elbow (11 [36.7%]) and phlebotomy (5 [16.7%]). Fifteen (30.6%) patients sustained a non-iatrogenic injury at the proximal forearm/elbow, consisting of six (60%) laceration injuries and five (33.3%) stretch injuries. Four (8.2%) patients comprised the “other” etiology category, including two mass lesions causing LACN compression. Pain, paresthesia, and/or numbness in the LACN distribution were reported in 33 (67.3%), 27 (55.1%), and 23 (46.9%) patients, respectively. Hypoesthesia was detected in 45 (91.8%) patients, and dysesthesia in 7 (14.3%). The sensory nerve action potentials (SNAPs) of the LACN on the symptomatic side were absent in 44 (89.8%) patients. Of the five patients whose SNAPs of the LACN were detected, all had a decreased amplitude, and two had increased sensory latency. Conclusions: The most common etiology for LACN neuropathy in this series was iatrogenic injury; repair of biceps tendon at the elbow was the most frequent provoking cause. Protection of the LACN during surgical procedures at the elbow and forearm is vital to prevent iatrogenic injury.

We describe the case of a 63-year-old man with pontocerebellar hypoplasia without the claustrum (CL). The patient had a history of cerebral palsy, intelligent disability, cerebellar atrophy, and seizures since birth. At age 61, brain computed tomography (CT) revealed significant cerebellar and brainstem atrophy. At age 63, he was admitted to our hospital for aspiration pneumonia. Although he was treated with medications, including antibiotics, he died one month after admission. The autopsy revealed a total brain weight of 815 g, with the small-sized frontal lobe, cerebellum, and pons. The cross-section of the fourth ventricle had a slit-like appearance, rather than the typical diamond shape. In addition, bilateral CLs were not observed. Apart from CL, no other missing brain tissue or cells could be identified. Microscopic examinations disclosed neurofibrillary tangles in the hippocampus but not in the cortex; however, neither senile plaques nor Lewy bodies were detected. No acquired lesions, including cerebral infarction, hemorrhage, or necrosis, were noted. We pathologically diagnosed the patient with pontocerebellar hypoplasia without CL. As there have been no prior reports of pontocerebellar hypoplasia lacking CL in adults, this case may represent a new subtype. Congenital CL deficiency is likely associated with abnormalities in brain development. CL may play a role in seizure activity, and the loss of bilateral CLs does not necessarily result in immediate death. Further studies are needed to clarify the functions of CL.

Background/Objectives: Small-vessel occlusion, previously referred to as lacunar infarcts, accounts for approximately one-third of all ischemic strokes, using an axial diameter of less than 20 mm on diffusion-weighted imaging. However, this threshold may not adequately differentiate small-vessel occlusion from other pathologies, such as branch atheromatous disease (BAD) and embolism. This study aimed to assess the clinical significance and pathological implications of acute small subcortical infarctions (SSIs) based on infarct diameter. Methods: We conducted a retrospective case–control study using data from stroke patients recorded between 2016 and 2021 of the Stroke Registry in Chang Gung Healthcare System. Patients with acute SSIs in penetrating artery territories were included. Key variables such as patient demographics, stroke severity, and medical history were collected. Infarcts were categorized based on size, and the presence of early neurological deterioration (END) and favorable functional outcomes were assessed. Results: Among the 855 patients with acute SSIs, the median age was 70 years and the median National Institutes of Health Stroke Scale (NIHSS) score at arrival was four. END occurred in 97 patients (11.3%). Those who experienced END were significantly less likely to achieve a favorable functional outcome compared to those who did not (18.6% vs. 59.9%, p < 0.001). The incidence of END increased progressively with infarct sizes of 15 mm or larger, with the optimal threshold for predicting END identified as 15.5 mm and for BAD, it was 12.1 mm. A multiple logistic regression analysis revealed that motor tract involvement [adjusted odds ratio (aOR) 2.3; 95% confidence interval (CI) 1.1–4.7], an initial heart rate greater than 90 beats per minute (aOR 2.3; 95% CI 1.2–4.3), and a larger infarct size (15 mm to less than 20 mm vs. 10 mm to less than 15 mm; aOR 3.0; 95% CI 1.4–6.3) were significantly associated with END. Conclusions: Our findings suggest that setting the upper limit for small-vessel occlusion at 15 mm would be more effective in distinguishing it from BAD. However, these findings should be interpreted in the context of the retrospective design and study population. Further multi-center research utilizing high-resolution vessel wall imaging is necessary to refine this threshold and enhance diagnostic accuracy.

Introduction: Patients with acute mountain sickness (AMS) due to hypoxia at high altitudes often exhibit abnormal water metabolism. Hypoxia-inducible factors (HIFs) are major regulators of adaptive responses to hypoxia. As transcription factors, HIFs are involved in the regulation of erythropoiesis, iron metabolism, angiogenesis, energy metabolism, and cell survival by promoting the transcriptional expression of hundreds of target genes. Roxadustat, a novel drug for the treatment of anemia associated with chronic kidney disease, acts by inhibiting the degradation of HIFs to increase their protein levels. However, the clinical use of roxadustat is frequently associated with peripheral edema, suggesting the involvement of HIFs in regulating the body's water balance possibly by modulating water reabsorption in the kidney. Methods: we first evaluated the effect of hypoxia (8% O2) on mouse urine output. We then performed in vitro experiments using hypoxia (1% O2) and roxadustat on mouse primary proximal tubular cells (mPTCs). The qPCR, western blot, and immunofluorescence were used to assess AQP1 mRNA and protein expression levels. Luciferase, CHIP, and EMSA were used to investigate the transcriptional regulation of AQP1 by HIF1α. Results: We found that mice exposed to hypoxia (8% O2) had significantly reduced urine volume compared to mice exposed to normoxia (21% O2). Hypoxia significantly elevated AQP1 expression at both mRNA and protein levels. In vitro experiments using mouse primary cultured proximal tubular cells (mPTCs) revealed that both hypoxia and roxadustat increased AQP1 expression. Mechanistically, overexpression of HIF1α, but not HIF2α, markedly increased AQP1 protein expression. Furthermore, the up-regulation of AQP1 by hypoxia and roxadustat can be blocked by the HIF1α inhibitor PX-478 in mPTCs. Finally, we found that the AQP1 gene promoter contains a putative hypoxia response element (HRE) and confirmed that AQP1 is a target gene of HIF1α using Luciferase reporter, CHIP, and EMSA assays. Conclusion: This study demonstrates that hypoxia can reduce the urine volume of mice via upregulating AQP1 expression by HIF1α in the proximal tubular epithelial cells. Our findings also suggest a potential mechanism involved in water metabolism disorders in patients with AMS and in patients with chronic kidney disease (CKD) receiving roxadustat treatment.

Abstract Background Diabetic ketoacidosis (DKA) is a life-threatening condition as a complication of diabetes and represents a significant healthcare global burden. The current study goal was to determine factors affecting time to recovery from DKA in Alexandria Main University Hospital. Patients and methods One hundred fifty patients who had been admitted with DKA were included in this study. All patients were managed with hospitalization for IV fluids, continuous intravenous insulin infusion, electrolyte correction, as well as detection and treatment of the predisposing factor until the full resolution of DKA. Results Males contributed to 58.7% of the total patients in this study with a mean age of 32.16 ± 15.06 years. DKA mean time of resolution was 18.76 ± 14.07 h. The majority of patients were with T1DM (86%), while T2DM were 14%. Missed insulin dose was the leading precipitating factor (60.7%) followed by infections (38.7%). There was a statistically significant relationship between DKA resolution time with age, time of presentation, type of diabetes, initial pH, initial serum K+ level, initial HCO3 − level, initial anion gap, initial base excess, and initial RBS (p value

Abstract Background X-linked recessive chondrodysplasia punctata 1 (CDPX1) is a rare congenital skeletal dysplasia characterized by stippled epiphyses, nasal hypoplasia, and brachytelephalangy. ARSL (formerly known as ARSE), a member of the sulfatase gene family located on Xp22.3, has been identified as the causative gene for CDPX1. The high clinical and genetic heterogeneity of CDPX1 presents a challenge to prenatal diagnosis. Case presentation A G1P0 woman in her 30s with an unremarkable prenatal course presented in the second trimester. Maternal diseases, tobacco, alcohol, and drug history during pregnancy were denied. Obstetrical ultrasound examination revealed a flattened nose and a flattened midface with echogenic alterations of lumbar spinous process in the fetus. Amniocentesis was performed for genetic testing. A normal karyotype and a negative result of CNV-seq were obtained. However, Whole exome sequencing (WES) in trios revealed a hemizygous ARSL variant [NM_000047.3:c.1108del p.(Trp370Glyfs*35)] in the fetus, which was maternally inherited as confirmed by Sanger sequencing. This variant was absent from the genomAD and HGMD databases. According to the ACMG guidelines, this variant was interpreted as likely pathogenic (PVS1 + PM2_Supporting). The couple decided to terminate the pregnancy. After induction of labour, a severe nasal hypoplasia was noted; and brachytelephalangy was not remarkable. Postmortem digital X-ray imaging revealed symmetrical stippled epiphyses of the vertebrae in all spine regions and enlargement of spinous process of L1-L4 vertebrae. Conclusion A novel frameshift deletion variant of ARSL and the associated fetal phenotype have been identified. This study provides useful information for prenatal diagnosis and genetic counseling of CDPX1.

Abstract Over 700 syndromes associated with hearing loss (HL) have been identified. Labyrinthine aplasia, microtia, and microdontia (LAMM syndrome, OMIM: 610706) is a rare HL syndrome characterized by congenital sensorineural HL, labyrinthine aplasia, type I microtia and microdontia, which is caused by biallelic variants in the FGF3 gene. Using Whole-exome sequencing (WES), we identified a novel missense FGF3 variant (c.137G > C, p. Arg46Pro (NM_005247.4) in three unrelated Uyghur ethnic families. This variant is classified as a variant of uncertain significance according to ACMG guidelines, with the applied criteria of PM3, PM2_Supporting, PP3 and PP4. Patients from the three families revealed variable clinical features. We found a novel phenotype, sparse hair, in one of the proband. Our findings expanded the variant and phenotype spectrum of LAMM syndrome and provided new insights to the diagnose and pathogenesis investigation of the disease.

Upper tract urothelial cancer (UTUC) are rare subsets of urothelial cancer, which typically present with more aggressive course. Molecular markers stratifying urothelial tumors as luminal subtype and non-luminal subtype tumors have been proposed to select patients who may have greater or lesser benefit from neoadjuvant systemic therapy in bladder cancer, though not yet evaluated in UTUC. Here, a single-institution study retrospectively obtained clinical and genomic information in patients with UTUC and evaluated four patient tumors using the Decipher Bladder® assay and Foundation Medicine® test. All four patients had non-luminal molecular subtype including basal (N = 4) and mixed basal/claudin-low (N = 2) subtypes. The best clinical response achieved was stable disease in a patient who had basal/claudin-low subtype with residual ypT3 after neoadjuvant chemotherapy. For the remaining three patients, all were treated with platinum-based chemotherapy for eventual metastatic disease but all three showed progressive disease with limited overall survival, highlighting their aggressive course. The non-luminal subtype and lack of FGFR alteration may partly explain the poor overall outcomes while the real-world benefit of next generation sequencing for clinical use in UTUC patients require further clarification in a larger cohort study.

Aim: The present study aims to evaluate the efficacy of rechallenge with immune checkpoint inhibitors (ICIs) compared to chemotherapy and the predictive role of clinical parameters in non-small cell lung cancer (NSCLC) patients who were rechallenged. Methods: The study included 113 metastatic NSCLC patients who had initially responded to ICIs and platinum-based chemotherapy, either in combination in the first line or sequentially in the first and second line, but later experienced disease progression. Of those patients, 52 later received ICI rechallenge and 61 were exposed to chemotherapy. Results: In the rechallenge cohort, the median age was 67 years, 38 patients were men (73.1%), 26 (50.0%) had squamous cell carcinoma. Patients who underwent ICI rechallenge had longer overall survival (OS) compared to those who received chemotherapy (12.9 months vs. 9.6 months, P = 0.008). Multivariate analysis for progression-free survival (PFS) and OS revealed that poor Eastern Cooperative Oncology Group Performance Status (ECOG PS; PFS: P = 0.013 and OS: P = 0.037), absence of objective response during initial ICI therapy (PFS: P = 0.014 and OS: P = 0.028), and baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3.8 (PFS: P = 0.001 and OS: P = 0.003) were negative predictive factors of ICI rechallenge. The three parameters were included in a risk model named as the NEO score, which stratified patients who received ICI rechallenge into two predictive groups. Patients with ECOG PS 0-1, objective response during initial ICI treatment, and NLR < 3.8 (favorable group) had longer PFS (8.6 months vs. 3.0 months, P < 0.001) and OS (16.6 months vs. 5.5 months, P < 0.001) compared to those with absence of all three markers (poor group). There was no association between the NEO score and survival outcomes in patients who did not undergo rechallenge. Conclusions: ICI rechallenge showed a survival benefit, particularly in NSCLC patients with NLR < 3.8, good ECOG PS, and objective response.

Introduction Escherichia coli (E. coli) is a significant commensal gram-negative bacterium that can give rise to various diseases. The roles of Toll-like receptor 2 (TLR2) and the NLR pyrin domain-containing 3 (NLRP3) inflammasome in sepsis induced by E. coli infection remain unclear. Methods In vivo, we investigated differences in mortality, production of inflammatory mediators, organ damage, neutrophil count, and bacterial load during E. coli infection in C57BL/6J mice, as well as in mice deficient in TLR2 or NLRP3. In vitro, we investigated the impact of E. coli on the activation of TLR2 and NLRP3 in macrophages and the influence of TLR2 and NLRP3 on the activation of inflammatory signaling pathways and the secretion of inflammatory mediators in macrophages induced by E. coli infection. Results TLR2-deficient (TLR2-/-) and NLRP3-deficient (NLRP3-/-) mice exhibit significantly increased mortality and organ damage after E. coli infection. These mice also show elevated levels of TNF-α and IL-10 in serum and peritoneal lavage fluid (PLF). Additionally, TLR2-/- and NLRP3-/- mice display heightened neutrophil recruitment, increased bacterial load in the blood. Furthermore, macrophages from these mice demonstrate a significant reduction in the activation of the MAPK signaling pathway. Conclusion TLR2 and NLRP3 play crucial roles in modulating inflammatory mediator expression, immune cell recruitment, and bactericidal activity, thereby preventing excessive tissue damage and reducing mortality in E. coli-induced sepsis.

Introduction: Despite the pivotal role of hepcidin in the development of anemia among the patients with chronic kidney disease (CKD), the association between serum hepcidin levels and CKD progression has been never investigated. We here hypothesized that elevation in serum hepcidin levels might be associated with the risk of incident end-stage kidney disease (ESKD) among the patients with pre-dialysis CKD. Methods: A total of 2,109 patients with pre-dialysis CKD at stages 1 to pre-dialysis 5 were categorized into the quartiles by serum hepcidin levels. The study outcome was incident ESKD. The median duration of follow-up was 7.9 years. Results: The analysis of the baseline characteristics revealed that unfavorable clinical features were in general associated with higher serum hepcidin levels. The cumulative incidence of ESKD was significantly differed by serum hepcidin levels, with the highest incidence in the 4th quartile (P < 0.001, by log-rank test). Cox regression analysis demonstrated that, compared to the 1st quartile, the risk of incident ESKD is significantly increased in the 4th quartile (adjusted hazard ratio 1.372, 95% confidence interval 1.070 to 1.759). Penalized spline curve analysis illustrated a linear, positive correlation between serum hepcidin levels and the risk of incident ESKD. Subgroup analyses revealed that the association is significantly more prominent in the patients with advanced CKD (i.e., estimated glomerular filtration rate < 45 mL/min/1.73 m2). Conclusion: Elevation in serum hepcidin levels is significantly associated with the risk of incident ESKD among the patients with pre-dialysis CKD.

Muhammad Haroon Stanikzai,1 Mohammad Nasim Zafar,2 Khalid Akbari,3 Ahmad Haroon Baray,1 Hadia Sayam1 1Department of Public Health, Faculty of Medicine, Kandahar University, Kandahar, Afghanistan; 2Department of Para-Clinic, Faculty of Medicine, Kandahar University, Kandahar, Afghanistan; 3Department of Internal Medicine, Faculty of Medicine, Paktia University, Gardez, Paktia, AfghanistanCorrespondence: Muhammad Haroon Stanikzai, Department of Public Health, Faculty of Medicine, Kandahar University, District &num; 10, 3801, Kandahar, Afghanistan, Tel +93704775578, Email haroonstanikzai1@gmail.comBackground: Although depression is a frequently occurring mental disorder in patients with hypertension, little is known about the symptoms of depression among Afghan hypertensive patients.Objective: This study aimed to analyze the prevalence and predictors of depression symptoms among Afghan hypertensive patients.Methods: This was a secondary analysis of a multi-center cross-sectional study conducted between August and December 2022 across three major provinces in Afghanistan. Socio-demographic and clinical characteristics of the eligible participants were used in the analysis. A score of ≥ 5 on the PHQ-9 (Patient Health Questionnaire) was considered the cut-off point for labeling hypertensive patients as screening positive for depressive symptoms. We performed binary logistic regression to determine the predictors of depression symptoms among hypertensive patients.Results: Out of 853 hypertensive patients, 51.8% (95% CI: 48.4– 55.2%) had depressive symptoms. Binary logistic regression revealed that low monthly household income [AOR=1.42, 95% CI (1.01– 1.97), low education level [2.41 (1.57– 3.71)], physical inactivity [1.81 (1.22– 2.71)], poor blood pressure control [2.41 (1.57– 3.71)], and the presence of medical comorbidity [1.59 (1.15– 2.19)] were the predictors of depression symptoms.Conclusion: This study showed a high prevalence of depressive symptoms among Afghan hypertensive patients. Moreover, we found that low monthly household income, physical inactivity, low education level, poor blood pressure control, and the presence of medical comorbidity were the predictors of depression symptoms. Our findings suggest that hypertensive patients should be screened for mental health symptoms, and those most at risk for depression should seek supportive counseling.Keywords: hypertension, depression, determinants, Afghanistan

Abstract Background The complete circulating long non-coding RNAs (lncRNAs) signature of rheumatoid arthritis (RA) and osteoarthritis (OA) is still uncovered. The lncRNA integrin subunit beta 2 (ITGB2)-anti-sense RNA 1 (ITGB2-AS1) affects ITGB2 expression; however, there is a gap in knowledge regarding its expression and clinical usefulness in RA and OA. This study investigated the potential of serum ITGB2-AS1 as a novel diagnostic biomarker and its correlation with ITGB2 expression and its ligand intercellular adhesion molecule-1 (ICAM-1), disease activity, and severity in RA and primary knee OA patients. Subjects Forty-three RA patients, 35 knee OA patients, and 22 healthy volunteers were included. Results Compared with healthy controls, serum ITGB2-AS1 expression was upregulated in RA patients but wasn’t significantly altered in knee OA patients, whereas serum ICAM-1 protein levels were elevated in both diseases. ITGB2-AS1 showed discriminative potential for RA versus controls (AUC = 0.772), while ICAM-1 displayed diagnostic potential for both RA and knee OA versus controls (AUC = 0.804, 0.914, respectively) in receiver-operating characteristic analysis. In the multivariate analysis, serum ITGB2-AS1 and ICAM-1 were associated with the risk of developing RA, while only ICAM-1 was associated with the risk of developing knee OA. A panel combining ITGB2-AS1 and ICAM-1 showed profound diagnostic power for RA (AUC = 0.9, sensitivity = 86.05%, and specificity = 91.67%). Interestingly, serum ITGB2-AS1 positively correlated with disease activity (DAS28) in RA patients and with ITGB2 mRNA expression in both diseases, while ICAM-1 positively correlated with ITGB2 expression in knee OA patients. Conclusion Our study portrays serum ITGB2-AS1 as a novel potential diagnostic biomarker of RA that correlates with disease activity. A predictive panel combining ITGB2-AS1 and ICAM-1 could have clinical utility in RA diagnosis. We also spotlight the association of ICAM-1 with knee OA diagnosis. The correlation of serum ITGB2-AS1 with ITGB2 expression in both diseases may be insightful for further mechanistic studies.

Abstract N 6-methyladenosine (m6A) is involved in most biological processes and actively participates in the regulation of reproduction. According to recent research, long non-coding RNAs (lncRNAs) and their m6A modifications are involved in reproductive diseases. In the present study, using m6A-modified RNA immunoprecipitation sequencing (m6A-seq), we established the m6A methylation transcription profiles in patients with recurrent implantation failure (RIF) for the first time. There were 1443 significantly upregulated m6A peaks and 425 significantly downregulated m6A peaks in RIF. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that genes associated with differentially methylated lncRNAs are involved in the p53 signalling pathway and amino acid metabolism. The competing endogenous RNA network revealed a regulatory relationship between lncRNAs, microRNAs and messenger RNAs. We verified the m6A methylation abundances of lncRNAs by using m6A-RNA immunoprecipitation (MeRIP)–real-time polymerase chain reaction. This study lays a foundation for further exploration of the potential role of m6A modification in the pathogenesis of RIF.

Abstract Background Fabry disease is an X-linked lysosomal storage disease caused by the impairment of α-galactosidase A. The complex intronic haplotype (CIH) variants, located in promoter and intronic regulatory lesions, has been found in patients with classical forms of Fabry disease. We present a case of Fabry disease in female monozygotic twins exhibiting the CIH mutation and classical manifestations. Case presentation A 61-year-old woman with a history of stroke, carotid artery occlusion, hypertrophic cardiomyopathy, and chronic kidney disease was referred to the nephrology clinic for management of her chronic kidney disease. Her monozygotic twin sister also presented with hypertrophic cardiomyopathy, atrial flutter, carotid stenosis, and proteinuria. Clinical symptoms and a comprehensive family history strongly suggested the presence of Fabry disease. Genetic analysis revealed the presence of 5 variants within a complex intronic haplotype (CIH): c.−10 C > T, c.369 + 990 C > A, c.370 − 81_370–77delCAGCC, c.640–16 A > G, and c.1000–22 C > T. We conducted a review of the patient’s previous kidney biopsy findings, which demonstrated the presence of lamellated inclusion bodies in electron microscopy. Remarkably, both the monozygotic twin sister and her son exhibited the same genetic mutation. Enzyme replacement therapy was initiated for the patient. Her kidney function decreased throughout a thorough 2-year follow-up period, while there was a slight decrease in the left ventricular mass index. Conclusions This is the first reported case of female monozygotic twins with the CIH variants representing cardiac, cerebrovascular, and renal manifestations suggestive of Fabry disease.

Abstract Congenital long QT syndrome (LQTS) is a genetic heart disorder, which may lead to life-threatening arrhythmias, especially in children. Here, we reported two children who were initially misdiagnosed with epilepsy and experienced Torsades de Pointes (TdP) cardiac electrical storm (ES). Through whole exome sequencing (WES), we identified two Potassium voltage-gated channel subfamily H member 2 (KCHN2) mutations (c.1841 C > T and c.1838 C > T) respectively in a 6-year-old boy and a 13-year-old girl. Clinical data indicated that the QT interval was significantly prolonged, the T-wave pattern of chest V5-V6 leads and limb leads were inverted. Our study suggests that patients with epilepsy, especially those refractory epilepsy with atypical features, need comprehensive evaluation of cardiovascular function. KCNH2 mutation in pore region, QT interval prolongation and T wave inversion are high risk factors for ES. For LQT2 patients with ES, Nadolol and left cardiac sympathetic denervation are indicated, sometimes with an ICD.

Abstract Background Diabetic nephropathy (DN) has been a major factor in the outbreak of end-stage renal disease for decades. As the underlying mechanisms of DN development remains unclear, there is no ideal methods for the diagnosis and therapy. Objective We aimed to explore the key genes and pathways that affect the rate progression of DN. Methods Nanopore-based full-length transcriptome sequencing was performed with serum samples from DN patients with slow progression (DNSP, n = 5) and rapid progression (DNRP, n = 6). Results Here, transcriptome proclaimed 22,682 novel transcripts and obtained 45,808 simple sequence repeats, 1,815 transcription factors, 5,993 complete open reading frames, and 1,050 novel lncRNA from the novel transcripts. Moreover, a total of 341 differentially expressed transcripts (DETs) and 456 differentially expressed genes (DEGs) between the DNSP and DNRP groups were identified. Functional analyses showed that DETs mainly involved in ferroptosis-related pathways such as oxidative phosphorylation, iron ion binding, and mitophagy. Moreover, Functional analyses revealed that DEGs mainly involved in oxidative phosphorylation, lipid metabolism, ferroptosis, autophagy/mitophagy, apoptosis/necroptosis pathway. Conclusion Collectively, our study provided a full-length transcriptome data source for the future DN research, and facilitate a deeper understanding of the molecular mechanisms underlying the differences in fast and slow progression of DN.

Abstract Background Chronic kidney disease (CKD) patients face the risk of rapid kidney function decline leading to adverse outcomes like dialysis and mortality. Lipid metabolism might contribute to acute kidney function decline in CKD patients. Here, we utilized the Mendelian Randomization approach to investigate potential causal relationships between drug target-mediated lipid phenotypes and rapid renal function decline. Methods In this study, we utilized two methodologies: summarized data-based Mendelian randomization (SMR) and inverse variance-weighted Mendelian randomization (IVW-MR), to approximate exposure to lipid-lowering drugs. This entailed leveraging expression quantitative trait loci (eQTL) for drug target genes and genetic variants proximal to drug target gene regions, which encode proteins associated with low-density lipoprotein (LDL) cholesterol, as identified in genome-wide association studies. The objective was to investigate causal associations with the progression of rapid kidney function decline. Results The SMR analysis revealed a potential association between high expression of PCSK9 and rapid kidney function decline (OR = 1.11, 95% CI= [1.001–1.23]; p = 0.044). Similarly, IVW-MR analysis demonstrated a negative association between LDL cholesterol mediated by HMGCR and kidney function decline (OR = 0.74, 95% CI = 0.60–0.90; p = 0.003). Conclusion Genetically predicted inhibition of HMGCR is linked with the progression of kidney function decline, while genetically predicted PCSK9 inhibition is negatively associated with kidney function decline. Future research should incorporate clinical trials to validate the relevance of PCSK9 in preventing kidney function decline.

Abstract Background Androgen insensitivity syndrome (AIS) is a rare genetic disorder characterized by resistance to androgens, mainly due to mutations in the androgen receptor (AR) gene. It can manifest as complete AIS, partial AIS and mild AIS. While there have been studies linking specific AR gene mutations to AIS phenotypes, different clinical AIS phenotypes are also reported in patients with the same AR gene mutation. So far, the precise correlations between phenotypes and genotypes remain incompletely understood. Methods We conducted a thorough investigation involving four patients diagnosed with different types of AIS from a single Chinese family. Clinical manifestations, laboratory examinations, and fertility outcomes were well-documented. Furthermore, we performed genetic sequencing to detect possible pathogenetic variants. Results Whole exome sequencing identified a hemizygous missense variant (c.2263T > C; p.Phe755Leu) of AR gene in all four affected patients with different degrees of undermasculinisation and heterogeneous spermatogenesis. The proband, diagnosed with partial AIS, opted for treatment with donated sperm due to non-obstructive azoospermia, while their older sibling, diagnosed with complete AIS, was raised as a girl. His two maternal uncles were both diagnosed with mild AIS, the older uncle fathered two girls naturally, whereas the younger uncle utilized assisted reproductive technology to conceive a boy because of severe oligoasthenozoospermia. Conclusion Our study first identified the same AR variant (c.2263T > C;p.Phe755Leu) in four affected patients displaying highly diverse phenotypes of AIS and fertility outcomes, thereby significantly expanding the phenotypic spectrum of AIS. Notably, we presented a clear insight into different fertility outcomes of AIS patients with identical AR (c.2263T > C;p.Phe755Leu) variant, which provided reliable evidence that males harboring this variant may obtain biological offspring naturally or in combination with assisted reproductive technology. Furthermore, our study underscored the potential role of androgen concentration in shaping the phenotypic diversity of AIS, warranting further investigation.

Background: Precise regulation of cell-cell communication is vital for cell survival and normal function during embryogenesis. The Wnt protein family, a highly conserved and extensively studied group, plays a crucial role in key cell-cell signaling events essential for development and regeneration. Congenital anomalies of the kidney and urinary tract (CAKUT) represent a leading cause of chronic kidney disease in children and young adults, and include a variety of birth abnormalities resulting from disrupted genitourinary tract development during embryonic development. The incidence and progression of CAKUT may be related to the Wnt signal transduction mechanism. Summary: This review provides a comprehensive overview of the classical Wnt signaling pathway’s role in CAKUT, explores related molecular mechanisms and provides new targets and intervention methods for the future treatment of the disease. Key Messages: The Wnt signal is intricately engaged in a variety of differentiation processes throughout kidney development.

Abstract Background Periodontal disease (PD) is a condition that can be treated and managed. This study aimed to determine if chronic PD status is associated with the risk of developing hypertension, utilizing data from the National Health Insurance Database of Korea. Methods Participants who received oral health examinations both in 2003 and in 2005–2006 were included. Those with a history of hypertension were excluded. Hypertension was defined as at least one outpatient or inpatient claim diagnosis (primary or secondary) of hypertension (International Classification of Diseases (ICD)-10 codes I10-I11) with prescription for antihypertensive medication or at least one incident of systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg during a health examination. Changes of PD status was determined during two oral examinations. Study participants were divided into 4 groups according to the changes of PD status: PD-free (those consistently free of disease in both exams), PD-recovered (individuals with disease initially but not in the second exam), PD-developed (no disease initially, but present in the second exam), and PD-chronic (disease throughout both exams). The incidence of hypertension after the second oral health examination (index date) was monitored. Participants were observed from the index date until the earliest occurrence of hypertension onset, mortality, or December 2020. Results The study comprised 706,584 participants: 253,003(35.8%) in the PD-free group, 140,143(19.8%) in the PD-recovered group, 132,397(18.7%) in the PD-developed group, and 181,041(25.6%) in the PD-chronic group. Over a median follow-up duration of 14.3 years, 239,937 (34.0%) cases of hypertension were recorded. The PD-recovered group had a lower risk of hypertension compared to the PD-chronic group, while the PD-developed group had a higher risk of hypertension compared to the PD-free group. Conclusion Chronic PD is associated with an increased risk of developing hypertension. Although the increase in risk is modest, recovery from PD may have beneficial effects in reducing hypertension risk. Further studies are needed to confirm the importance of regular dental examinations and effective management of PD to reduce hypertension risk.

Abstract Background The impact of socioeconomic status (SES) on arterial stiffness remains unclear. This study aimed to explore the association between both personal and household income, as well as education level, and estimated pulse wave velocity (ePWV). Methods A total of 13,539 participants (mean age 52.9 ± 16.7 years; 57.1% women) from the Korean National Health and Nutrition Survey database were analyzed. For SES variables, information on personal and household income and education level was collected using standardized questionnaires. Results The ePWV did not show significant differences across groups categorized by individual income levels (P = 0.183). However, there was a noticeable trend of decreasing ePWV with increasing household income levels (P

Abstract Background The antihypertensive efficacy of fimasartan was assessed based on the transition rate from a combination of calcium channel blockers (CCB) and angiotensin receptor blockers (ARB) to three-drug combination therapy, as compared to other ARBs. Methods This nationwide cohort study used data obtained from the Korean National Health Insurance Service database. Patients who had received national health checkups within 2 years prior to January 1, 2017, and were concurrently prescribed ARBs and CCBs for > 30 days during the 6 months from January 1, 2017, to June 30, 2017 were included in the study. Patients were categorized into the ‘fimasartan group’ (those prescribed fimasartan) and the ‘non-fimasartan group’ (those prescribed ARBs other than fimasartan). The index date was set as the last day of a 30-day prescription period for ARBs and CCBs, with a subsequent 2.5-year follow-up to observe the potential addition of a third drug, such as beta-blockers or diuretics. Results The study included 34,422 patients with a mean age of 60.3 years and 58.3% being male. The fimasartan group constituted 2.7% (n = 928) of the total, and the non-fimasartan group, 97.3% (n = 33,494). During the follow-up period, 38 patients in the fimasartan group (14.3 per 1,000 person-years) and 3,557 patients in the non-fimasartan group (42.8 per 1,000 person-years) required additional antihypertensive medications. After multivariate adjustment for age, sex, diabetes mellitus, dyslipidemia, cancer, heart failure, systolic blood pressure, and diastolic blood pressure, the fimasartan group showed a significantly lower rate of adding a third medication (hazard ratio 2.68, 95% confidence interval 1.95–3.69) compared to that of the non-fimasartan group. Conclusions Fimasartan is associated with a lower need for additional antihypertensive drugs compared to other ARBs. This implies its greater effectiveness in hypertension management, potentially enhancing cardiovascular outcomes, and minimizing polypharmacy.

Abstract Background Major surgeries are being carried for certain ailments. Surgeries can be major or minor depending on the extent of intervention. Major surgeries are prone to cause lots of complications such as shock, haemorrhage, wound infection, deep vein thrombosis, pulmonary complications, organ rejection, reactions to anaesthetics etc. Early identification of complications could reduce morbidity and mortality. Laboratory variables used in the assessment of hypovolemia include blood urea nitrogen, sodium, osmolality, hematocrit, and arterial blood gas. This study was undertaken to assess the utility of blood urea nitrogen: creatinine ratio (BCR) in the utility of assessment of hypovolemia in the first post-operative day in individuals who had major surgeries. Methods and materials The retrospective cross-sectional study included participants from the Departments of Orthopedic Surgery, Obstetrics and Gynecology, General Surgery and Cardiothoracic Surgery. Patients who underwent major surgeries between January 2019 and January 2020 were included. Study participants of 30 to 60 years of both genders were recruited into the study. Data were collected from the Medical Records of a tertiary care hospital in Chennai, India. Ethics approval was obtained, the institutional ethics committee (Ref: CSP/21/SEP/99/479 dated 30–12-2021). Waiver of consent was obtained since the patients were treated and discharged from the hospital. The data were analyzed by SPSS version 16. P value ≤ 0.05 was taken to be significant. Results BCR showed statistically significant difference across the groups with P = 0.02. BCR showed statistically significant difference between cardiac patients with total knee replacement and total abdominal hysterectomy surgeries. BCR showed positive correlation with age, fluids intake and negative correlation with pulse rate and respiratory rate. Conclusion BCR is a simple diagnostic tool for identifying hypovolemia in individuals who undergo major surgeries especially in the first postoperative day. It is significantly altered across the groups with highest value in individuals who have undergone knee replacement surgeries. BCR has high specificity and positive predictive value.

Abstract Background The mortality rate of COVID-19 patients with critical symptoms is reported to be 40.5%. Early identification of patients with poor progression in the critical cohort is essential to timely clinical intervention and reduction of mortality. Although older age, chronic diseases, have been recognized as risk factors for COVID-19 mortality, we still lack an accurate prediction method for every patient. This study aimed to delve into the cell-free DNA fragmentomics of critically ill patients, and develop new promising biomarkers for identifying the patients with high mortality risk. Methods We utilized whole genome sequencing on the plasma cell-free DNA (cfDNA) from 33 COVID-19 patients with critical symptoms, whose outcomes were classified as survival (n = 16) and death (n = 17). Mitochondrial DNA (mtDNA) abundance and fragmentomic properties of cfDNA, including size profiles, ends motif and promoter coverages were interrogated and compared between survival and death groups. Results Significantly decreased abundance (~ 76% reduction) and dramatically shorter fragment size of cell-free mtDNA were observed in deceased patients. Likewise, the deceased patients exhibited distinct end-motif patterns of cfDNA with an enhanced preference for “CC” started motifs, which are related to the activity of nuclease DNASE1L3. Several dysregulated genes involved in the COVID-19 progression-related pathways were further inferred from promoter coverages. These informative cfDNA features enabled a high PPV of 83.3% in predicting deceased patients in the critical cohort. Conclusion The dysregulated biological processes observed in COVID-19 patients with fatal outcomes may contribute to abnormal release and modifications of plasma cfDNA. Our findings provided the feasibility of plasma cfDNA as a promising biomarker in the prognosis prediction in critically ill COVID-19 patients in clinical practice.

Abstract Objective This study aims to assess the in vitro drug susceptibility of various Carbapenemase-Producing Enterobacteriaceae (CPE) genotypes and elucidate the underlying mechanisms of amikacin resistance. Methods A total of 72 unique CPE strains were collected from the Second Hospital of Jiaxing between 2019 and 2022, including 51 strains of Klebsiella pneumoniae, 11 strains of Escherichia coli, 6 strains of Enterobacter cloacae, 2 strains of Klebsiella aerogenes, 1 strain of Citrobacter freundii, and 1strain of Citrobacter werkmanii. Among these strains, 24 carried bla KPC gene, 20 carried bla NDM gene, 23 carried bla OXA−48−like gene, and 5 carried both bla KPC and bla NDM. We measured the in vitro activity of amikacin and other common antibiotics. Strains carrying bla OXA−48-like gene were selected for whole genome sequencing (WGS) via next-generation sequencing to identify genes related to antimicrobial resistance (AMR) and virulence factor (VF). Results Out of the 72 CPE strains tested, 41.7% exhibited resistance to amikacin. The drug resistance rates for K. pneumoniae, E. coli, and Enterobacter spp. were 51.0%, 27.3%, and 10.0%, respectively. The majority of the CPE strains (> 90%) displayed resistance to cephalosporins and carbapenems, while most of them were sensitive to polymyxin B and tigecycline (97.2% and 94.4%). The amikacin resistance rate was 100% for strains carrying bla OXA−48, 20.8% for those with bla KPC, 5.0% for those with bla NDM, and 20.0% for those with both bla KPC and bla NDM. These differences were statistically significant (P

Abstract Background EYA4 variants are responsible for DFNA10 deafness. Due to its insidious onset and slow progression, hearing loss in autosomal dominant non-syndromic hearing loss (ADNSHL) is usually challenging to detect early in clinical settings, with limited intervention options. Genetic testing can aid in early detection of hearing loss, enabling timely intervention to reduce disability rates and improve the quality of life. Methods In this study, we report the case of a Chinese family with postlingual and progressive hearing loss that was passed down for four generations. Whole-exome sequencing (WES) was performed on DNA samples from the proband. Candidate variants identified in the proband and family members were confirmed via Sanger sequencing. In silico prediction tools and co-segregation analyses were used to assess the pathogenicity of identified variants. A literature review of known EYA4 variants was performed, analysing variant frequency, distribution characteristics across different populations, and genotype-phenotype correlations. Results We identified a novel EYA4 variant, c.1745_1748del (p.Glu582ValfsTer6), in a Chinese family with ADNSHL, and co-segregation with the family’s phenotype was confirmed. The audiometry showed mid-to-high frequency downsloping hearing loss. To date, 52 pathogenic variants of EYA4 have been reported, with majority identified in Asian populations. Most observed are the missense and frameshift variants. Conclusions A novel variant of EYA4 was identified in a Chinese family with postlingual hearing loss, contributing to the expanding spectrum of EYA4 variants. The audiological features of EYA4 variants are highly heterogeneous and often challenging to detect early in clinical settings. Our findings highlight the significance of genetic testing in patients presenting with postlingual hearing loss.

Abstract Background Batten disease is a group of rare inherited neurodegenerative diseases. Juvenile CLN3 disease is the most prevalent type, and the most common pathogenic variant shared by most patients is the “1-kb” deletion which removes two internal coding exons (7 and 8) in CLN3. Previously, we identified two transcripts in patient fibroblasts homozygous for the 1-kb deletion: the ‘major’ and ‘minor’ transcripts. To understand the full variety of disease transcripts and their role in disease pathogenesis, it is necessary to first investigate CLN3 transcription in “healthy” samples without juvenile CLN3 disease. Methods We leveraged PacBio long-read RNA sequencing datasets from ENCODE to investigate the full range of CLN3 transcripts across various tissues and cell types in human control samples. Then we sought to validate their existence using data from different sources. Results We found that a readthrough gene affects the quantification and annotation of CLN3. After taking this into account, we detected over 100 novel CLN3 transcripts, with no dominantly expressed CLN3 transcript. The most abundant transcript has median usage of 42.9%. Surprisingly, the known disease-associated ‘major’ transcripts are detected. Together, they have median usage of 1.5% across 22 samples. Furthermore, we identified 48 CLN3 ORFs, of which 26 are novel. The predominant ORF that encodes the canonical CLN3 protein isoform has median usage of 66.7%, meaning around one-third of CLN3 transcripts encode protein isoforms with different stretches of amino acids. The same ORFs could be found with alternative UTRs. Moreover, we were able to validate the translational potential of certain transcripts using public mass spectrometry data. Conclusion Overall, these findings provide valuable insights into the complexity of CLN3 transcription, highlighting the importance of studying both canonical and non-canonical CLN3 protein isoforms as well as the regulatory role of UTRs to fully comprehend the regulation and function(s) of CLN3. This knowledge is essential for investigating the impact of the 1-kb deletion and rare pathogenic variants on CLN3 transcription and disease pathogenesis.