Clinical feature, GALC variant spectrum, and genotype-phenotype correlation in Korean Krabbe disease patients: Multicenter experience over 13 years.

Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by deficiency of the galactocerebrosidase (GALC) due to variants in the GALC gene. Here, we provide the first and the largest comprehensive analysis of clinical and genetic characteristics, and genotype-phenotype correlations of KD in Korean in comparison with other ethnic groups. From June 2010 to June 2023, 10 patients were diagnosed with KD through sequencing of GALC. Clinical features, and results of GALC sequencing, biochemical test, neuroimaging, and neurophysiologic test were obtained from medical records. An additional nine previously reported Korean KD patients were included for review. In Korean KD patients, the median age of onset was 2 years (3 months-34 years) and the most common phenotype was adult-onset (33%, 6/18) KD, followed by infantile KD (28%, 5/18). The most frequent variants were c.683_694delinsCTC (23%) and c.1901T>C (23%), while the 30-kb deletion was absent. Having two heterozygous pathogenic missense variants was associated with later-onset phenotype. Clinical features were similar to those of other ethnic groups. In Korean KD patients, the most common phenotype was the adult-onset type and the GALC variant spectrum was different from that of the Caucasian population. This study would further our understanding of KD.

Women's experience of childbirth care in health facilities: a qualitative assessment of respectful maternity care in Afghanistan.

BACKGROUND: Respectful maternity care (RMC) remains a key challenge in Afghanistan, despite progress on improving maternal and newborn health during 2001-2021. A qualitative study was conducted in 2018 to provide evidence on the situation of RMC in health facilities in Afghanistan. The results are useful to inform strategies to provide RMC in Afghanistan in spite of the humanitarian crisis due to Taliban's takeover in 2021. METHODS: Focus group discussions were conducted with women (4 groups, 43 women) who had used health facilities for giving birth and with providers (4 groups, 21 providers) who worked in these health facilities. Twenty key informant interviews were conducted with health managers and health policy makers. Motivators for, deterrents from using, awareness about and experiences of maternity care in health facilities were explored. RESULTS: Women gave birth in facilities for availability of maternity care and skilled providers, while various verbal and physical forms of mistreatment were identified as deterrents from facility use by women, providers and key informants. Low awareness, lack of resources and excessive workload were identified among the reasons for violation of RMC. CONCLUSION: Violation of RMC is unacceptable. Awareness of women and providers about the rights of women to respectful maternity care, training of providers on the subject, monitoring of care to prevent mistreatment, and conditioning any future technical and financial assistance to commitments to RMC is recommended.

Preventive Effect of Ecklonia cava Extract on DSS-Induced Colitis by Elevating Intestinal Barrier Function and Improving Pathogenic Inflammation.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a complex gastrointestinal disorder with a multifactorial etiology, including environmental triggers, autoimmune mechanisms, and genetic predisposition. Despite advancements in therapeutic strategies for IBD, its associated mortality rate continues to rise, which is often attributed to unforeseen side effects of conventional treatments. In this context, we explored the potential of Ecklonia cava extract (ECE), derived from an edible marine alga known for its anti-inflammatory and antioxidant properties, in mitigating IBD. This study investigated the effectiveness of ECE as a preventive agent in a murine model of dextran sulfate sodium (DSS)-induced colitis. Our findings revealed that pretreatment with ECE significantly ameliorated colitis severity, as evidenced by increased colon length, reduced spleen weight, and histological improvements demonstrated by immunohistochemical analysis. Furthermore, ECE significantly attenuated the upregulation of inflammatory cytokines and mediators and the infiltration of immune cells known to be prominent features of colitis in mice. Notably, ECE alleviated dysbiosis of intestinal microflora and aided in the recovery of damaged intestinal mucosa. Mechanistically, ECE exhibited protective effects against pathogenic colitis by inhibiting the NLRP3/NF-κB pathways known to be pivotal regulators in the inflammatory signaling cascade. These compelling results suggest that ECE holds promise as a potential candidate for IBD prevention. It might be developed into a functional food for promoting gastrointestinal health. This research sheds light on the preventive potential of natural compounds like ECE in the management of IBD, offering a safer and more effective approach to combating this challenging disease.

CK2α-mediated phosphorylation of GRP94 facilitates the metastatic cascade in triple-negative breast cancer.

Distant metastasis is a significant hallmark affecting to the high death rate of patients with triple-negative breast cancer (TNBC). Thus, it is crucial to identify and develop new therapeutic strategies to hinder cancer metastasis. While emerging studies have hinted a pivotal role of glucose-regulated protein 94 (GRP94) in tumorigenesis, the exact biological functions and molecular mechanisms of GRP94 in modulating cancer metastasis remain to be elucidated. Our study demonstrated an increased expression of GRP94 in TNBC correlated with metastatic progression and unfavorable prognosis in patients. Functionally, we identified that GRP94 depletion significantly diminished TNBC tumorigenesis and subsequent lung metastasis. In contrast, GRP94 overexpression exacerbated the invasiveness, migration, and lung metastasis of non-TNBC cells. Mechanistically, we found that casein kinase 2 alpha (CK2α) active in advanced breast cancer phosphorylated GRP94 at a conserved serine 306 (S306) residue. This phosphorylation increased the stability of GRP94 and enhanced its interaction with LRP6, leading to activation of canonical Wnt signaling. From a therapeutic standpoint, we found that benzamidine, a novel CK2α inhibitor, effectively suppressed GRP94 phosphorylation, LRP6 stabilization, and metastasis of TNBC. Our results point to the critical role of CK2α-mediated GRP94 phosphorylation in TNBC metastasis through activation of Wnt signaling, highlighting GRP94 as a therapeutic target to impede TNBC metastasis.

The Role of Robotics in Meeting Institutional Goals: A Unified Strategy to Facilitate Program Excellence.

PURPOSE: The rapid expansion of robotic surgical equipment necessitates a review of the needs and challenges faced by hospitals introducing robots for the first time to compete with experienced institutions. The aim of this study was to analyze the impact of robotic surgery on our hospital compared to open and laparoscopic surgery, examine internal transformations, and assess regional, domestic, and international implications. METHODS: A retrospective review was conducted of electronic medical records (EMRs) from 2019 to 2022 at Inha University Hospital, including patients who underwent common robotic procedures and equivalent open and laparoscopic operations. The study investigated clinical and operational performance changes in the hospital after the introduction of robotic technology. It also evaluated the operational effectiveness of robot implementation in local, national, and international contexts. To facilitate comparison with other hospitals, the data were transmitted to Intuitive Surgical, Inc. for analysis. The study was conducted in compliance with domestic personal information regulations and received approval from our Institutional Review Board. RESULTS: We analyzed EMR data from 3,147 patients who underwent surgical treatment. Over a period of 3.5 years, the adoption of robotic technology in a hospital setting significantly enhanced the technical skills of all professors involved. The introduction of robotic systems led to increased patient utilization of conventional surgical techniques, as well as a rise in the number of patients choosing robotic surgery. This collective trend contributed to an overall increase in patient numbers. This favorable evaluation of the operational effectiveness of our hospital's robot implementation in the context of local, national, and global factors is expected to positively influence policy changes. CONCLUSION: Stakeholders should embrace data science and evidence-based techniques to generate valuable insights from objective data, assess the health of robot-assisted surgery programs, and identify opportunities for improvement and excellence.

The Influence of Family Adversities on Longitudinal Changes in Physical Inactivity Among Korean Adolescents During the COVID-19 Pandemic.

Objectives: Lack of physical activity has a critical effect on the physical and mental health of adolescents. This study examined the influence of family adversities on the longitudinal changes in physical inactivity among adolescents during the coronavirus disease 2019 (COVID-19) pandemic. Methods: The study used multi-wave data from the Korean Children and Youth Panel Survey, including 2590 Korean adolescents aged 12-14 years. The longitudinal trajectory of physical inactivity among adolescents and the effects of related factors were estimated using a latent growth modeling method. Results: Our results revealed a significant increase in physical inactivity among adolescents over time. At the onset of the pandemic, approximately one-seventh of Korean middle schoolers reported a lack of physical activity. However, 3 years later, during the quarantine, nearly one-fifth of these adolescents reported a significant increase in their physical inactivity. Initially, low level parental education was predictive of adolescents' physical inactivity, but this effect diminished over time, becoming statistically insignificant by the end of the 3-year period. Moreover, the increase in physical inactivity over the 3 years was significantly influenced by parental rejection. Conclusions: These findings suggest that adolescents who experience parental rejection are more likely to report an increase in sedentary behaviors in contexts such as the COVID-19 pandemic.

IL-10+ regulatory B cells mitigate atopic dermatitis by suppressing eosinophil activation.

Atopic dermatitis (AD) presents significant therapeutic challenges due to its poorly understood etiology. Eosinophilia, a hallmark of allergic inflammation, is implicated in AD pathogenesis. Interleukin-10 (IL-10)-producing regulatory B (Breg) cells exhibit potent anti-inflammatory effects. However, their role in controlling AD-related eosinophilia is not well understood. To investigate the impact of eosinophils on AD, we employed IL-5Rα-deficient (Il5ra-/-) mice, which lack functional eosinophils. Induction of AD in these mice resulted in attenuated disease symptoms, underscoring the critical role of eosinophils in AD development. Additionally, the adoptive transfer of purified Breg cells into mice with AD significantly alleviated disease severity. Mechanistic studies revealed that IL-10 produced by Breg cells directly inhibits eosinophil activation and infiltration into the skin. In vitro experiments further confirmed that Breg cells inhibited eosinophil peroxidase secretion in an IL-10-dependent manner. Our collective findings demonstrate that IL-10 from Breg cells alleviates AD by suppressing eosinophil activation and tissue infiltration. This study elucidates a novel regulatory mechanism of Breg cells, providing a foundation for future Breg-mediated therapeutic strategies for AD.

IL-27-induced PD-L1highSca-1+ innate lymphoid cells suppress contact hypersensitivity in an IL-10-dependent manner.

Innate lymphoid cells (ILCs) play an important role in maintaining tissue homeostasis and various inflammatory responses. ILCs are typically classified into three subsets, as is the case for T-cells. Recent studies have reported that IL-10-producing type 2 ILCs (ILC210s) have an immunoregulatory function dependent on IL-10. However, the surface markers of ILC210s and the role of ILC210s in contact hypersensitivity (CHS) are largely unknown. Our study revealed that splenic ILC210s are extensively included in PD-L1highSca-1+ ILCs and that IL-27 amplifies the development of PD-L1highSca-1+ ILCs and ILC210s. Adoptive transfer of PD-L1highSca-1+ ILCs suppressed oxazolone-induced CHS in an IL-10-dependent manner Taken together, our results demonstrate that ILC210s are critical for the control of CHS and suggest that ILC210s can be used as target cells for the treatment of CHS.

Clinical use of whole exome sequencing in children with developmental delay/intellectual disability.

BACKGROUND: Identifying the underlying etiology of developmental delay/intellectual disability (DD/ID) is challenging but important. The genetic diagnosis of unexplained DD/ID helps in the treatment and prognosis of the disability in patients. In this study, we reported our experience of using whole exome sequencing (WES) of children with unexplained DD/ID. METHODS: We conducted a retrospective analysis of WES results of children under 19 years of age with unexplained DD/ID between January 2020 and December 2021. The demographic data of all patients and variants identified through WES were evaluated. Furthermore, we evaluated the clinical characteristics that influenced the identification of genetic causes. RESULTS: Forty-one patients with DD/ID were included, of whom 21 (51.2 %) were male. The average age at symptom onset was 1.6 ± 1.3 years, and the duration from symptom onset to diagnosis was 3.1 ± 3.7 years. Hypotonia was the most common symptom (17 patients, 41.5 %), and epilepsy was confirmed in 10 patients (24.4 %). Twenty-two pathogenic/likely pathogenic variants were identified in 20 patients, and three variants of uncertain significance were identified in three patients. Family-based trio Sanger sequencing for candidate variants of 12 families was conducted; 10 variants were de novo, one variant paternally inherited, and two variants compound heterozygous. The diagnostic yield of WES for DD/ID was 48.8 % and was significantly high in patients with an early onset of DD/ID and facial dysmorphism. In contrast, patients with autism spectrum disorder (ASD) were more likely to have negative WES results compared with others without ASD. CONCLUSION: The diagnostic yield of WES was 48.8 %. We conclude that patients' characteristics, such as dysmorphic features and the age of symptom onset, can predict the likelihood that WES will identify a causal variant of a phenotype.

HIV seroconversion among female sex workers: retrospective cohort study from a large-scale HIV prevention and sexual and reproductive health program in Tanzania.

Introduction: In 2016, UNAIDS set ambitious targets to reduce global HIV infections by 75% by 2020 and 90% by 2030, based on the 2.1 million new infections reported in 2010. However, by 2022, new HIV infections had only decreased by 38%, from 2.1 million in 2010 to 1.3 million in 2022, raising concerns about reaching the 2030 goal. Female sex workers (FSWs) in sub-Saharan Africa face a disproportionately high risk of HIV acquisition, contributing 5%-20% of all new infections in several countries in the region. This analysis investigates HIV seroconversion and associated factors among FSWs, offering insights into critical interventions for preventing HIV transmission in this population and advancing the goal of ending the HIV pandemic by 2030. Methods: We conducted a retrospective cohort study involving 17,977 FSWs who initially tested HIV negative upon enrollment in the Sauti project between October 2016 and September 2018. HIV incidence rates were calculated by dividing the number of new HIV cases by observed person-time within the cohort. Cox regression analysis identified factors associated with seroconversion. Results: The study revealed an HIV incidence rate of 8.6 per 100 person-years among FSWs [95% confidence interval (CI): 8.1-9.1]. Factors independently associated with HIV seroconversion included age 35 years or older [adjusted hazard ratio (aHR): 2.53; 95% CI: 2.03-3.14], unprotected sex (aHR: 1.27; 95% CI: 1.13-1.42), STI symptoms (aHR: 1.99; 95% CI: 1.67-2.38), and alcohol consumption before sex (aHR: 1.20; 95% CI: 1.07-1.34). Conclusion: Targeted interventions are vital in curbing HIV transmission among FSWs, with a focus on expanding access to primary HIV prevention services, particularly for older FSWs who face heightened risk. Tailored sexual health education programs are imperative to encourage consistent condom use and enable informed decision-making. Accessible and timely STI screening and treatment services are crucial to mitigate HIV transmission risk. Collaborative partnerships between healthcare providers, community organizations, and government agencies are essential in implementing these interventions among FSWs.

Dihydrostilbenes and flavonoids from whole plants of Jacobaea vulgaris.

The isolation of previously undescribed 12 compounds from the MeOH extract of Jacobaea vulgaris whole plants is disclosed, comprising 11 dihydrostilbenes (1-11) and one flavanone (12), and eight known compounds (six flavonoids, one dihydrostilbene, and one caffeoylquinic acid). Structural elucidation employed spectroscopic methods, including 1D and 2D NMR spectroscopy, HRESIMS, and ECD calculations. Evaluation of the compounds' effects on PCSK9 and LDLR mRNA expression revealed that compounds 1 and 3 downregulated PCSK9 mRNA while increasing LDLR mRNA expression, suggesting potential cholesterol-lowering properties.

Coffin-Siris Syndrome: Case Series of Three Patients and a Novel ARID2 Variant.

Coffin-Siris syndrome (CSS) is a rare congenital disorder characterized by coarse facial features, intellectual disability or developmental delay, and aplasia or hypoplasia of the tips of the fifth finger and/or toes. Mutations in genes affecting the switch/sucrose non-fermenting ATP-dependent chromatin remodeling complex are reported to cause CSS. Here, we describe three CSS patients. Two girls aged 3 and 2 years old presented with global developmental delay, poor growth, and a dysmorphic face. Whole-exome sequencing (WES) was performed and they were diagnosed with CSS due to heterozygous frameshift variants (c.3443_3444del, p.Lys1148ArgfsTer9 and c.2869_2890del, p.Pro957CysfsTer20) in ARID1B A 2-year-old girl presented with gross motor delay and dysmorphic face. She was diagnosed with CSS due to a novel heterozygous frameshift variant (c.4942_4943del: p.Gln1648GlyfsTer8) in ARID2.