Role of the STING→IRF3 Pathway in Ambient GABA Homeostasis and Cognitive Function.

Targeting altered expression and/or activity of GABA (γ-aminobutyric acid) transporters (GATs) provide therapeutic benefit for age-related impairments, including cognitive dysfunction. However, the mechanisms underlying the transcriptional regulation of GATs are unknown. In the present study, we demonstrated that the stimulator of interferon genes (STING) upregulates GAT1 and GAT3 expression in the brain, which resulted in cognitive dysfunction. Genetic and pharmacological intervention of STING suppressed the expression of both GAT1 and GAT3, increased the ambient GABA concentration, and therefore, enhanced tonic GABAA inhibition of principal hippocampal neurons, resulting in spatial learning and working memory deficits in mice in a type I interferon-independent manner. Stimulation of the STING→GAT pathway efficiently restored cognitive dysfunction in STING-deficient mice models. Our study uncovered for the first time that the STING signaling pathway regulates GAT expression in a cell autonomous manner and therefore could be a novel target for GABAergic cognitive deficits.

Machine Learning-Based Models for Advanced Fibrosis and Cirrhosis Diagnosis in Chronic Hepatitis B Patients With Hepatic Steatosis.

BACKGROUND AND AIMS: The global rise of chronic hepatitis B (CHB) superimposed on hepatic steatosis (HS) warrants noninvasive, precise tools for assessing fibrosis progression. This study leveraged machine learning (ML) to develop diagnostic models for advanced fibrosis and cirrhosis in this patient population. METHODS: Treatment-naive CHB patients with concurrent HS who underwent liver biopsy in 10 medical centers were enrolled as a training cohort and an independent external validation cohort (NCT05766449). Six ML models were implemented to predict advanced fibrosis and cirrhosis. The final models, derived from SHAP (Shapley Additive exPlanations), were compared with Fibrosis-4 Index, nonalcoholic fatty liver disease Fibrosis Score, and aspartate aminotransferase-to-platelet ratio index using the area under receiver-operating characteristic curve (AUROC) and decision curve analysis (DCA). RESULTS: Of 1,198 eligible patients, the random forest model achieved AUROCs of 0.778 (95% confidence interval [CI], 0.749-0.807) for diagnosing advanced fibrosis (random forest advanced fibrosis model) and 0.777 (95% CI, 0.748-0.806) for diagnosing cirrhosis (random forest cirrhosis model) in the training cohort, and maintained high AUROCs in the validation cohort. In the training cohort, the random forest advanced fibrosis model obtained an AUROC of 0.825 (95% CI, 0.787-0.862) in patients with hepatitis B virus DNA ≥105 IU/mL, and the random forest cirrhosis model had an AUROC of 0.828 (95% CI, 0.774-0.883) in female patients. The 2 models outperformed Fibrosis-4 Index, nonalcoholic fatty liver disease Fibrosis Score, and aspartate aminotransferase-to-platelet ratio index in the training cohort, and also performed well in the validation cohort. CONCLUSIONS: The random forest models provide reliable, noninvasive tools for identifying advanced fibrosis and cirrhosis in CHB patients with concurrent HS, offering a significant advancement in the comanagement of the 2 diseases. CLINICALTRIALS: gov, Number: NCT05766449.

Effects of Glucagon-Like Peptide-1 Receptor Agonist on Bone Mineral Density and Bone Turnover Markers: A Meta-Analysis.

AIMS: Glucagon-like peptide-1 receptor agonist (GLP-1RA) may promote bone formation, but conversely, they could also weaken bones due to the reduction in mechanical load associated with weight loss. However, the clinical effects in humans have not been clearly demonstrated. This meta-analysis aimed to evaluate whether GLP-1RAs affect BMD and bone turnover markers. MATERIAL AND METHODS: PubMed, Embase, and Scopus were searched on June 13, 2024. The eligibility criteria were: (1) human studies, (2) receiving a GLP-1RA for more than 4 weeks, (3) an untreated control group or a placebo group, (4) reporting of at least one BMD or bone turnover marker, and (5) an RCT design. The risk of bias was assessed using the Cochrane risk of bias 2 tool. Fixed- or random-effects meta-analysis was performed according to heterogeneity. RESULTS: Seven studies were included in the meta-analysis. GLP-1RAs did not significantly change BMD in the femoral neck (mean difference [MD], 0.01 g/cm2; 95% CI, -0.01-0.04 g/cm2), in the total hip (MD, -0.01 g/cm2; 95% CI, -0.02-0.01 g/cm2), and in the lumbar spine (MD, 0 g/cm2; 95% CI, -0.02-0.02 g/cm2). C-terminal telopeptide of type 1 collagen (CTX), a bone resorption marker, significantly increased after GLP-1RA treatment (MD, 0.04 µg/L; 95% CI, 0.01-0.07 µg/L). GLP-1RAs did not significantly change bone formation markers such as procollagen type 1 N-terminal propeptide, bone-specific alkaline phosphatase, osteocalcin. CONCLUSIONS: GLP-1RA did not affect BMD and bone formation markers. However, GLP-1RAs led to a significant increase in CTX.

Burden and preparedness of care partners of people living with amyotrophic lateral sclerosis at home in Korea: A care partner survey.

INTRODUCTION/AIMS: The care burden of people living with amyotrophic lateral sclerosis (pALS) increases with disease progression. This study aimed to investigate the home care status and preparedness of care partners of pALS (cALS) in Korea. METHODS: An online survey was conducted with family care partners of patients diagnosed with ALS for over 1 year in 2022. The data collected included care time, depression evaluated using the patient health questionnaire-9 (PHQ-9), preparedness for caregiving scale (PCS), and caregiver competence scale (CCS). Results were compared based on whether the pALS underwent a tracheostomy or not. RESULTS: Ninety-eight cALS of 98 pALS participated in the study, of whom 59 pALS had undergone tracheostomy. Among the cALS, 60.2% were spouses, and 34.7% were children. The cALS took care of the patients for 13 (8-20) hours/day (median, interquartile range [IQR]) on weekdays and 15 (10-24) h/day on weekends. Among the cALS, 91.8% were depressed, and 28.6% had severe depression. The median (IQR) PCS and CCS scores were low (11/32 (8-15) and 8/20 (8-11), respectively), and both were lower in those caring for patients without than with tracheostomy (p < .001 and p < .02, respectively). Most cALS (77.6%) wished to continue caring for their pALS at home. DISCUSSION: Family care partners of pALS spend more than half of each day caring for patients and are often depressed. Most cALS preferred providing care at home, but felt ill-prepared. Designing home-based medical care is necessary for pALS to thrive at home.

Efficacy on symptoms and mortality day vs. night administration of EGFR-TKIs for advanced non-small cell lung cancer.

PURPOSE: This study has a purpose to investigate the side effects of three EGFR-TKIs targeted therapeutic agents (gefitinib, erlotinib, and afatinib) and all-cause mortality in patients with metastatic lung cancer. METHODS: We performed a prospective cohort study. We selected all patients with newly diagnosed metastatic lung cancer between January and November 2019. Main exposure was daytime versus nighttime use of targeted EGFR TKIs. The study outcome was a symptom change using the mobile application, and all-cause mortality between January 2019 and March 2023. RESULTS: Among the 87 study participants, 35 (40%) took their medication at night. Among the 87 study participants, 35 (40%) took their medication at night. At 6 weeks of treatment, acne (1.36; 95% confidence interval [CI] 1.09, 1.64; p for interaction = 0.04) and dry skin (1.35; 95% CI 1.09, 1.61, p for interaction = 0.01) in the day group showed a much increase from baseline compared to the night group. In contrast, the night group reported greater reductions in lung cancer-related symptoms from baseline compared to the day. During follow-up (median 43 months), the night group had a lower risk of all-cause death than the day group, especially in younger patients (adjusted hazard ratio = 0.34; 95% CI 0.13, 0.87). CONCLUSIONS: The group taking EGFR-TKIs at night experienced fewer side effects and had longer overall survival compared to the day group. Clinicians should consider recommending that lung cancer patients take their once-daily oral anticancer drugs in the evening rather than the morning to improve treatment outcomes.

Usefulness of cardiopulmonary exercise test combined with exercise stress echocardiography in mild chronic thromboembolic pulmonary disease.

PURPOSE: Chronic thromboembolic pulmonary disease (CTEPD) can lead to exercise limitations even without right ventricular (RV) dysfunction or pulmonary hypertension at rest. Combining exercise stress echocardiography with cardiopulmonary exercise testing (ESE-CPET) for RV function and pressure changes combined measuring overall function may be useful for CTEPD evaluation. This study aims to investigate CPET and ESE results to elucidate the mechanisms of exercise limitation in mild CTEPD cases. METHODS: Among our CTEPD registry, 50 patients who performed both right heart catheterization data of mild disease (less than 30 mm Hg of mean pulmonary arterial pressure (mPAP)) and ESE-CPET were enrolled. Echocardiography and CPET-derived parameters were compared with hemodynamic parameters measured through right heart catheterization. RESULTS: Peak VO2 (maximal oxygen consumption) was decreased in overall population (71.3 ± 16.3% of predictive value). Peak VO2 during exercise was negatively correlate with mPAP and pulmonary vascular resistance at rest. A substantial increase in RV systolic pressure (RVSP) was observed during exercise (RVSP: pre-exercise 37.2 ± 11.8 mm Hg, postexercise 64.3 ± 24.9 mm Hg, p-value < .001). Furthermore, RV function deteriorated during exercise when compared to the baseline (RV fractional area change: 31.5 ± 10.0% to 37.8 ± 7.0%, p-value < .001; RV global longitudinal strain: -17.1 ± 4.2% to -17.7 ± 3.3%, p-value < .001) even though basal RV function was normal. While an excessive increase in RVSP during exercise was noticed in both groups, dilated RV and RV dysfunction during exercise were demonstrated only in the impaired exercise capacity group. CONCLUSION: CTEPD patients with mild PH or without PH exhibited limited exercise capacity alongside an excessive increase in RVSP during exercise. Importantly, RV dysfunction during exercise was significantly associated with exercise capacity. ESE-CPET could aid in comprehending the primary cause of exercise limitation in these patients.

The trend of dental check-up and prevalence of dental complications following the use of bone modifying agents in patients with metastatic breast and prostate cancer: analysis of data from the Korean National Health Insurance Service.

BACKGROUND: Bone-modifying agents (BMA) are key components in the management of cancer patients with bone metastasis. Despite their clinical benefits, the use of BMA is associated with dental adverse events (AEs) including medication-related osteonecrosis of the jaw (MRONJ). This study investigated the frequency of dental surveillance before BMA treatment and the prevalence of dental AEs including MRONJ, after BMA treatment in patients with bone metastasis from breast and prostate cancer using data from the national health insurance system. METHODS: Data, including age, cancer diagnosis, administered BMA, and dental AEs during cancer treatment, of patients with bone metastasis from breast and prostate cancer who received at least one infusion of BMA between 2007 and 2019 were extracted from the Korean National Health Insurance Service (KNHIS) dataset. RESULTS: Of the 15,357 patients who received BMA, 1,706 patients (11.1%) underwent dental check-ups before BMA treatment. The proportion of patients receiving dental check-up increased from 4.4% in 2007 to 16.7% in 2019. Referral to dentists for a dental check-up was more active in clinics/primary hospitals than general/tertiary hospitals, and medical doctors and urologists actively consulted to dentists than general surgeons, regardless of the patient's health insurance status. After BMA treatment, 508 patients (3.8%) developed dental AEs, including abscess (42.9%), acute periodontitis (29.7%), acute pericoronitis (14.9%), and MRONJ (12.5% of dental AEs cases, 0.5% of total BMA treated patients). CONCLUSIONS: Considering the long treatment period in patients with metastatic cancer, coordination between dentists and oncologists is necessary to ensure appropriate dental management before the initiation of BMA.

The impact of specialized pediatric palliative care on advance care planning and healthcare utilization in children and young adults: a retrospective analysis of medical records of in-hospital deaths.

BACKGROUND: Pediatric palliative care supports children and young adults with life-limiting conditions and their families, seeking to minimize suffering and enhance quality of life. This study evaluates the impact of specialized palliative care (SPC) on advance care planning (ACP) and patterns of end-of-life care for patients who died in the hospital. METHODS: This is a retrospective cohort study of medical records extracted from a clinical data warehouse, covering patients who died aged 0-24 in an academic tertiary children's hospital in South Korea. Participants were categorized into before (2011-2013; pre-period) and after (2017-2019; post-period) the introduction of an SPC service. Within the post-period, patients were further categorized into SPC recipients and non-recipients. RESULTS: We identified 274 and 205 patients in the pre-period and post-period, respectively. ACP was conducted more and earlier in the post-period than in the pre-period, and in patients who received palliative care than in those who did not. Patients who received SPC were likely to receive less mechanical ventilation or cardiopulmonary resuscitation and more opioids. A multivariable regression model showed that earlier ACP was associated with not being an infant, receiving SPC, and having a neurological or neuromuscular disease. CONCLUSIONS: SPC involvement was associated with more and earlier ACP and less intense end-of-life care for children and young adults who died in the hospital. Integrating palliative care into routine care can improve the quality of end-of-life care by reflecting patients' and their families' values and preferences.

Public and Clinician Perspectives on Ventilator Withdrawal in Vegetative State Following Severe Acute Brain Injury: A Vignette Survey.

BACKGROUND: The vegetative state (VS) after severe acute brain injury (SABI) is associated with significant prognostic uncertainty and poor long-term functional outcomes. However, it is generally distinguished from imminent death and is exempt from the Life-Sustaining Treatment (LST) Decisions Act in Korea. Here, we aimed to examine the perspectives of the general population (GP) and clinicians regarding decisions on mechanical ventilator withdrawal in patients in a VS after SABI. METHODS: A cross-sectional survey was undertaken, utilizing a self-reported online questionnaire based on a case vignette. Nationally selected by quota sampling, the GP comprised 500 individuals aged 20 to 69 years. There were 200 doctors from a tertiary university hospital in the clinician sample. Participants were asked what they thought about mechanical ventilator withdrawal in patients in VS 2 months and 3 years after SABI. RESULTS: Two months after SABI in the case, 79% of the GP and 83.5% of clinicians had positive attitudes toward mechanical ventilator withdrawal. In the GP, attitudes were associated with spirituality, household income, religion, the number of household members. On the other hand, clinicians' attitudes were related to their experience of completing advance directives (AD) and making decisions about LST. In this case, 3 years after SABI, 92% of the GP and 94% of clinicians were more accepting of ventilator withdrawal compared to previous responses, based on the assumption that the patient had written AD. However, it appeared that the proportion of positive responses to ventilator withdrawal decreased when the patients had only verbal expressions (82% of the GP; 75.5% of clinicians) or had not previously expressed an opinion regarding LST (58% of the GP; 39.5% of clinicians). CONCLUSION: More than three quarters of both the GP and clinicians had positive opinions regarding ventilator withdrawal in patients in a VS after SABI, which was reinforced with time and the presence of AD. Legislative adjustments are needed to ensure that previous wishes for those patients are more respected and reflected in treatment decisions.

Beyond Legal Boundaries: Public and Clinician Perspectives on Treatment Withdrawal in Infants With Poor Neurological Prognosis.

BACKGROUND: Despite medical advancements in neonatal survival rates, many children have poor neurological outcomes. Because the law in Korea restricts the withdrawal of life-sustaining treatment to only cases of imminent death, treatment discontinuation may not be an option, even in patients with poor neurological prognosis. This study investigated the opinions of the general population and clinicians regarding life-sustaining treatment withdrawal in such cases using hypothetical scenarios. METHODS: We conducted a cross-sectional study on the general population and clinicians using a web-based questionnaire. The sample of the general population from an online panel comprised 500 individuals aged 20-69 years selected by quota sampling. The clinician sample comprised 200 clinicians from a tertiary university hospital. We created hypothetical vignettes and questionnaire items to assess attitudes regarding mechanical ventilation withdrawal for an infant at risk of poor neurological prognosis due to birth asphyxia at 2 months and 3 years after the incidence. RESULTS: Overall, 73% of the general population and 74% of clinicians had positive attitudes toward mechanical ventilator withdrawal at 2 months after birth asphyxia. The proportion of positive attitudes toward mechanical ventilator withdrawal was increased in the general population (84%, P < 0.001) and clinicians (80.5%, P = 0.02) at 3 years after birth asphyxia. Religion, spirituality, the presence of a person with a disability in the household, and household income were associated with the attitudes of the general population. In the multivariable logistic regression analysis of the general population, respondents living with a person with a disability or having a disability were more likely to find the withdrawal of the ventilator at 2 months and 3 years after birth asphyxia not permissible. Regarding religion, respondents who identified as Christians were more likely to find the ventilator withdrawal at 2 months after birth asphyxia unacceptable. CONCLUSION: The general population and clinicians shared the perspective that the decision to withdraw life-sustaining treatment in infants with a poor neurological prognosis should be considered before the end of life. A societal discussion about making decisions centered around the best interest of pediatric patients is warranted.

Challenges to decarbonizing medication prescribing and use practices: A call to action.

Climate change undeniably impacts the social and environmental determinants of one's health. The healthcare sector, encompassing medications and the pharmaceutical industry supply chain, accounts for a significant portion of global health care contributions to greenhouse gas (GHG) and waste production. Despite these realities, healthcare professionals - physicians, pharmacists, nurses, and others - may be unaware of GHG emissions and the long-term environmental effects of the medications they prescribe, dispense, and administer daily. In this commentary, we identify existing challenges and explore potential strategies to recognize and reduce the climate change impacts associated with medication use.

Optimal microneedle length for hair regrowth in hair cycle arrest (alopecia X) in six dogs.

BACKGROUND: Hair cycle arrest (HCA) is a chronic alopecic disorder in dogs. Clinical responses vary and are often insufficient. Microneedling (MN) has been used as a successful treatment for HCA in dogs; ideal protocols have not yet been established. OBJECTIVES: The objective of the study was to compare the efficacy and safety of three needle lengths for MN in dogs with HCA. ANIMALS: Six unrelated client-owned dogs, including five Pomeranians and one mixed-breed dog, diagnosed with HCA. MATERIALS AND METHODS: Individual alopecic sites were divided into three sections. For each section, different lengths of needles (1, 2 and 3 mm) were used. Efficacy and safety were evaluated at 1, 3 and 6 months. Treated sections were monitored for 20 months. RESULTS: Three months after treatment with 3 mm needles, all sections showed hair regrowth. There was no hair regrowth in two of six sections treated with 2 mm needles, and four of six sections did not show a response to treatment with 1 mm needles. Two dogs developed transient pruritus. Five of six dogs had recurrent hair loss between 5 and 16 months of follow-up. CONCLUSION AND CLINICAL RELEVANCE: Microneedling using longer needles stimulated better hair regrowth in dogs with HCA. Alopecia relapsed in most dogs and minor pruritus occurred in some dogs.

Investigating the effects of Carpesii fructus extract on the liver transcriptome of olive flounder (Paralichthys olivaceus) as a potential antiparasitic agent.

Olive flounder (Paralichthys olivaceus), a popular aquaculture species, is plagued by the disease scuticociliatosis caused by Miamiensis avidus, which has a high mortality rate and is typically treated with chemicals such as formalin and hydrogen peroxide. However, Carpesii fructus extract has shown potential as a natural therapeutic agent by reducing the motility of M. avidus. However, despite its potential importance, the effect of the extract on fish metabolism remains unknown. In this study, the effect of Carpesii fructus extract and formalin on fish metabolism was analysed by whole transcriptome analysis in the liver of P. olivaceus. A total of 37,796 transcripts were generated and differential expression genes (DEGs) were identified in the liver of P. olivaceus treated with Carpesii fructus extract or formalin. In addition, functional analysis of DEGs between treatment groups was presented using Gene Ontology. These results will be crucial for the study of scuticociliatosis in various fish species, including P. olivaceus, and for the development of therapeutic agents for other diseases.

The prognostic value of a combined immune score in tumor and immune cells assessed by immunohistochemistry in triple-negative breast cancer.

BACKGROUND: This study aimed to develop a novel combined immune score (CIS)-based model assessing prognosis in triple-negative breast cancer (TNBC). METHODS: The expression of eight immune markers (PD-1, PD-L1, PD-L2, IDO, TIM3, OX40, OX40L, and H7-H2) was assessed with immunohistochemistry on the tumor cells (TCs) and immune cells (ICs) of 227 TNBC cases, respectively, and subsequently associated with selected clinicopathological parameters and survival. Data retrieved from The Cancer Genome Atlas (TCGA) were further examined to validate our findings. RESULTS: All immune markers were often expressed in TCs and ICs, except for PD-1 which was not expressed in TCs. In ICs, the expression of all immune markers was positively correlated between one another, except between PD-L1 and OX40, also TIM3 and OX40. In ICs, PD-1, PD-L1, and OX40L positive expression was associated with a longer progression-free survival (PFS; p = 0.040, p = 0.020, and p = 0.020, respectively). In TCs, OX40 positive expression was associated with a shorter PFS (p = 0.025). Subsequently, the TNBC patients were classified into high and low combined immune score groups (CIS-H and CIS-L), based on the expression levels of a selection of biomarkers in TCs (TCIS-H or TCIS-L) and ICs (ICIS-H or ICIS-L). The TCIS-H group was significantly associated with a longer PFS (p < 0.001). Furthermore, the ICIS-H group was additionally associated with a longer PFS (p < 0.001) and overall survival (OS; p = 0.001), at significant levels. In the multivariate analysis, both TCIS-H and ICIS-H groups were identified as independent predictors of favorable PFS (p = 0.012 and p = 0.001, respectively). ICIS-H was also shown to be an independent predictor of favorable OS (p = 0.003). The analysis of the mRNA expression data from TCGA also validated our findings regarding TNBC. CONCLUSION: Our novel TCIS and ICIS exhibited a significant prognostic value in TNBC. Additional research would be needed to strengthen our findings and identify the most efficient prognostic and predictive biomarkers for TNBC patients.

DS86760016, a Leucyl-tRNA Synthetase Inhibitor, Is Active against Mycobacterium abscessus.

Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. Epetraborole, a benzoxaborole, is a clinical candidate developed for Gram-negative infections and has been confirmed to exhibit favorable activity against a well known pulmonary pathogen, Mycobacterium abscessus. However, according to ClinicalTrials.gov, in 2017, a clinical phase II study on the use of epetraborole to treat complicated urinary tract and intra-abdominal infections was terminated due to the rapid emergence of drug resistance during treatment. Nevertheless, epetraborole is in clinical development for nontuberculous mycobacteria (NTM) disease especially for Mycobacterium avium complex-related pulmonary disease (MAC-PD). DS86760016, an epetraborole analog, was further demonstrated to have an improved pharmacokinetic profile, lower plasma clearance, longer plasma half-life, and higher renal excretion than epetraborole in animal models. In this study, DS86760016 was found to be similarly active against M. abscessus in vitro, intracellularly, and in zebrafish infection models with a low mutation frequency. These results expand the diversity of druggable compounds as new benzoxaborole-based candidates for treating M. abscessus diseases.

Dynamic Nuclear Polarization of Selectively 29Si-Enriched Core@shell Silica Nanoparticles.

29Si silica nanoparticles (SiO2 NPs) are promising magnetic resonance imaging (MRI) probes that possess advantageous properties for in vivo applications, including suitable biocompatibility, tailorable properties, and high water dispersibility. Dynamic nuclear polarization (DNP) is used to enhance 29Si MR signals via enhanced nuclear spin alignment; to date, there has been limited success employing DNP for SiO2 NPs due to the lack of endogenous electronic defects that are required for the process. To create opportunities for SiO2-based 29Si MRI probes, we synthesized variously featured SiO2 NPs with selective 29Si isotope enrichment on homogeneous and core@shell structures (shell thickness: 10 nm, core size: 40 nm), and identified the critical factors for optimal DNP signal enhancement as well as the effective hyperpolarization depth when using an exogenous radical. Based on the synthetic design, this critical factor is the proportion of 29Si in the shell layer regardless of core enrichment. Furthermore, the effective depth of hyperpolarization is less than 10 nm between the surface and core, which demonstrates an approximately 40% elongated diffusion length for the shell-enriched NPs compared to the natural abundance NPs. This improved regulation of surface properties facilitates the development of isotopically enriched SiO2 NPs as hyperpolarized contrast agents for in vivo MRI.

Strumpellin/WASHC5 regulates the structural plasticity of cortical neurons involved in gait coordination.

Strumpellin/Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex subunit 5 (WASHC5) is a core component of the WASH complex, and its mutations confer pathogenicity for hereditary spastic paraplegia (HSP) type SPG8, a rare neurodegenerative gait disorder. WASH complex activates actin-related protein-2/3-mediated actin polymerization and plays a pivotal role in intracellular membrane trafficking in endosomes. In this study, we examined the role of strumpellin in the regulation of structural plasticity of cortical neurons involved in gait coordination. Administration of a lentivirus containing a strumpellin-targeting short hairpin RNA (shRNA) to cortical motor neurons lead to abnormal motor coordination in mice. Strumpellin knockdown using shRNA attenuated dendritic arborization and synapse formation in cultured cortical neurons, and this effect was rescued by wild-type strumpellin expression. Compared with the wild-type, strumpellin mutants N471D or V626F identified in patients with SPG8 exhibited no differences in rescuing the defects. Moreover, the number of F-actin clusters in neuronal dendrites was decreased by strumpellin knockdown and rescued by strumpellin expression. In conclusion, our results indicate that strumpellin regulates the structural plasticity of cortical neurons via actin polymerization.

Naturally occurring substitution in one amino acid in VHSV phosphoprotein enhances viral virulence in flounder.

Viral hemorrhagic septicemia virus (VHSV) is a rhabdovirus that causes high mortality in cultured flounder. Naturally occurring VHSV strains vary greatly in virulence. Until now, little has been known about genetic alterations that affect the virulence of VHSV in flounder. We recently reported the full-genome sequences of 18 VHSV strains. In this study, we determined the virulence of these 18 VHSV strains in flounder and then the assessed relationships between differences in the amino acid sequences of the 18 VHSV strains and their virulence to flounder. We identified one amino acid substitution in the phosphoprotein (P) (Pro55-to-Leu substitution in the P protein; PP55L) that is specific to highly virulent strains. This PP55L substitution was maintained stably after 30 cell passages. To investigate the effects of the PP55L substitution on VHSV virulence in flounder, we generated a recombinant VHSV carrying PP55L (rVHSV-P) from rVHSV carrying P55 in the P protein (rVHSV-wild). The rVHSV-P produced high level of viral RNA in cells and showed increased growth in cultured cells and virulence in flounder compared to the rVHSV-wild. In addition, rVHSV-P significantly inhibited the induction of the IFN1 gene in both cells and fish at 6 h post-infection. An RNA-seq analysis confirmed that rVHSV-P infection blocked the induction of several IFN-related genes in virus-infected cells at 6 h post-infection compared to rVHSV-wild. Ectopic expression of PP55L protein resulted in a decrease in IFN induction and an increase in viral RNA synthesis in rVHSV-wild-infected cells. Taken together, our results are the first to identify that the P55L substitution in the P protein enhances VHSV virulence in flounder. The data from this study add to the knowledge of VHSV virulence in flounder and could benefit VHSV surveillance efforts and the generation of a VHSV vaccine.

Longitudinal analysis of annual national hemovigilance data to assess pathogen reduced platelet transfusion trends during conversion to routine universal clinical use and 7-day storage.

BACKGROUND: France converted to universal pathogen reduced (PR; amotosalen/UVA) platelets in 2017 and extended platelet component (PC) shelf-life from 5- to 7-days in 2018 and 2019. Annual national hemovigilance (HV) reports characterized longitudinal PC utilization and safety over 11 years, including several years prior to PR adoption as the national standard of care. METHODS: Data were extracted from published annual HV reports. Apheresis and pooled buffy coat [BC] PC use was compared. Transfusion reactions (TRs) were stratified by type, severity, and causality. Trends were assessed for three periods: Baseline (2010-14; ~7% PR), Period 1 ([P1] 2015-17; 8%-21% PR), and Period 2 ([P2] 2018-20; 100% PR). RESULTS: PC use increased by 19.1% between 2010 and 2020. Pooled BC PC production increased from 38.8% to 68.2% of total PCs. Annual changes in PCs issued averaged 2.4% per year at baseline, -0.02% (P1) and 2.8% (P2). The increase in P2 coincided with a reduction in the target platelet dose and extension to 7-day storage. Allergic reactions, alloimmunization, febrile non-hemolytic TRs, immunologic incompatibility, and ineffective transfusions accounted for >90% of TRs. Overall, TR incidence per 100,000 PCs issued declined from 527.9 (2010) to 345.7 (2020). Severe TR rates declined 34.8% between P1-P2. Forty-six transfusion-transmitted bacterial infections (TTBI) were associated with conventional PCs during baseline and P1. No TTBI were associated with amotosalen/UVA PCs. Infections with Hepatitis E (HEV) a non-enveloped virus resistant to PR, were reported in all periods. DISCUSSION: Longitudinal HV analysis demonstrated stable PC utilization trends with reduced patient risk during conversion to universal 7-day amotosalen/UVA PCs.

Development and validation of a convolutional neural network model for diagnosing Helicobacter pylori infections with endoscopic images: a multicenter study.

BACKGROUND AND AIMS: Insufficient validation limits the generalizability of deep learning in diagnosing Helicobacter pylori infection with endoscopic images. The aim of this study was to develop a deep learning model for the diagnosis of H pylori infection using endoscopic images and validate the model with internal and external datasets. METHODS: A convolutional neural network (CNN) model was developed based on a training dataset comprising 13,403 endoscopic images from 952 patients who underwent endoscopy at Seoul National University Hospital Gangnam Center. Internal validation was performed using a separate dataset comprised of images of 411 individuals of Korean descent and 131 of non-Korean descent. External validation was performed with the images of 160 patients in Gangnam Severance Hospital. Gradient-weighted class activation mapping was performed to visually explain the model. RESULTS: In predicting H pylori ever-infected status, the sensitivity, specificity, and accuracy of internal validation for people of Korean descent were .96 (95% confidence interval [CI], .93-.98), .90 (95% CI, .85-.95), and .94 (95% CI, .91-.96), respectively. In the internal validation for people of non-Korean descent, the sensitivity, specificity, and accuracy in predicting H pylori ever-infected status were .92 (95% CI, .86-.98), .79 (95% CI, .67-.91), and .88 (95% CI, .82-.93), respectively. In the external validation cohort, sensitivity, specificity, and accuracy were .86 (95% CI, .80-.93), .88 (95% CI, .79-.96), and .87 (95% CI, .82-.92), respectively, when performing 2-group categorization. Gradient-weighted class activation mapping showed that the CNN model captured the characteristic findings of each group. CONCLUSIONS: This CNN model for diagnosing H pylori infection showed good overall performance in internal and external validation datasets, particularly in categorizing patients into the never- versus ever-infected groups.