Efficacy and Safety of Oral Administration of Wine Lees Extract (WLE)-Derived Ceramides and Glucosylceramides in Enhancing Skin Barrier Function: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: Our search for plant-derived ceramides from sustainable sources led to the discovery of ceramides and glucosylceramides in wine lees. OBJECTIVE: This study evaluated the efficacy and safety of wine lees extract (WLE)-derived ceramides and glucosylceramides in enhancing skin barrier function. METHODS: A randomized, double-blind, placebo-controlled study was conducted with 30 healthy Japanese subjects aged 20-64. Subjects were allocated to receive either the WLE-derived ceramides and glucosylceramides (test group) or placebo for 12 weeks. The primary outcome was transepidermal water loss (TEWL), and secondary outcomes included skin hydration, visual analog scale (VAS) of itching sensation, and the Japanese Skindex-29. RESULTS: One participant withdrew for personal reasons, resulting in 29 subjects for data analysis (placebo n = 15; test n = 14). The test group showed a tendency of lower TEWL compared to the placebo after 8 weeks (p = 0.07). Furthermore, after 12 weeks of administration, the test group had significantly lower TEWL than the placebo (p = 0.04). On the other hand, no significant differences were observed in the secondary outcome parameters. No adverse events related to the supplements were reported. CONCLUSIONS: Oral supplementation of WLE-derived ceramides and glucosylceramides is a prominent and safe approach to enhancing skin barrier function and health. TRIAL REGISTRATION: (UMIN000050422).

Magnetic field control device for transplantation of corneal endothelial tissue with magnetic filaments.

The corneal endothelial transplantation involves the transfer and attachment of a single-layered corneal endothelial tissue to the narrow space between the cornea and iris. Given the high risk of damage to the endothelial tissue and surrounding corneal tissues when using sharp instruments inserted externally to apply force during the process, the development of a device capable of transferring corneal endothelial tissue using a magnetic field became necessary. This study aims to develop a magnetic control device for transferring corneal endothelial tissue with attached magnetic particles to the transplant site, validate its appropriate transfer capabilities, and assess its applicability to corneal endothelial transplantation. For this purpose, a magnetic field-generating manipulation device equipped with four electromagnets controlled by a joystick and microcomputer was developed. Through simulated experiments, the strength of the magnetic field and the attraction force on the tissue were predicted, and the actual magnetic field strength was measured for validation. To measure the magnetic transfer force, experiments were conducted by towing corneal endothelial tissue fixed with 6 mg, 12 mg, and 18 mg plastic weights. Subsequently, the tissue's transfer speed was measured after applying continuous and pulsed magnetic fields. The results confirmed the feasibility of tissue transfer using the magnetic control device, and it was observed that pulsed magnetic fields led to faster transfer speeds and easier control compared to continuous magnetic fields. Exploratory animal experiments using rabbits were conducted to simulate real surgical conditions, confirming the feasibility of corneal endothelial tissue transfer and attachment.

Spatiotemporal variation of sterols in sediment as markers of primary production and ocean sewage dumping in the southwestern East Sea (Japan Sea).

The sedimentation of organic carbon in the Ulleung Basin, in the southwestern East Sea (Japan Sea) was investigated using radiocarbon and sterols. The accumulation rates of organic carbon and the contents of brassicasterol and dinosterol were higher on the slope than in the central basin, reflecting the surface water productivity, whereas cholesterol showed similar or higher contents in the central basin. The coprostanol concentration in surface sediments reflected the dispersion of sewage dumped in this region. The vertical distribution showed that the coprostanol concentration was the highest in the top 5-cm layer near the Korea Strait, close to one of the two dumping sites. A high coprostanol concentration was also found near the coast further north, where the content peaked at ∼10 cm depth. The vertical distribution of coprostanol helped to estimate the sediment accumulation rate at sites where radiocarbon gradient was too small or the values were too variable.

Small Extracellular Vesicle Signaling and Mitochondrial Transfer Reprograms T Helper Cell Function in Human Asthma.

RATIONALE: Asthma is a chronic inflammatory disease of the airways that involves crosstalk between myeloid-derived regulatory cells (MDRCs) and CD4+ T cells. Although small extracellular vesicles (sEVs) are known to mediate cell-cell communication, the role of sEV signaling via mitochondria in perpetuating asthmatic airway inflammation is unknown. OBJECTIVES: We investigated the effects of MDRC-derived exosomes on dysregulated T cell responses in asthmatics. METHODS: Small extracellular vesicles isolated from bronchoalveolar lavage fluid or airway MDRCs of mild to moderate asthmatics or healthy controls were co-cultured with autologous peripheral and airway CD4+ T lymphocytes. sEV internalization, sEV-mediated transfer of mitochondria targeted GFP to T cells, sEV mitochondrial signaling, and subsequent activation, proliferation and polarization of CD4+ T lymphocytes to Th1, Th2 and Th17 subsets were assessed. MEASUREMENTS AND MAIN RESULTS: Airway MDRC-derived sEVs from asthmatics mediated T cell receptor engagement and transfer of mitochondria that induced antigen-specific activation and polarization into Th17 and Th2 cells, drivers of chronic airway inflammation in asthma. CD4+ T cells internalized sEVs containing mitochondria predominantly by membrane fusion, and blocking mitochondrial oxidant signaling in MDRC-derived exosomes mitigated T cell activation. Reactive oxygen species-mediated signaling that elicited T cell activation in asthmatics was sEV-dependent. A Drp1-dependent mitochondrial fission in pro-inflammatory MDRCs promoted mitochondrial packaging within sEVs, which then co-localized with the polarized actin cytoskeleton and mitochondrial networks in the organized immune synapse of recipient T cells. CONCLUSIONS: Our studies indicate a previously unrecognized role for mitochondrial fission and exosomal mitochondrial transfer in dysregulated T cell activation and Th cell differentiation in asthma which could constitute a novel therapeutic target.

Dietary mercury intake, the IL23R rs10889677 polymorphism, and the risk of gastric cancer: a hospital-based case-control study.

Objectives: Mercury can stimulate immune responses through T helper 17 (Th17). The gene IL23R is a key factor in Th17 function, which may also contribute to digestive tract diseases. The aim of this study was to observe the associations between dietary mercury and gastric cancer (GC) and to investigate whether the IL23R rs10889677 polymorphism modifies those associations. Methods: This case-control study included 377 patients with GC and 756 healthy controls. Dietary mercury intake (total mercury and methylmercury) was assessed using a dietary heavy metal database incorporated into the food frequency questionnaire. IL23R genetic polymorphism rs10889677 (A>C) was genotyped. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression models with adjustments for potential confounders. Results: A higher dietary methylmercury intake was associated with an elevated risk of GC (OR for the highest versus lowest tertile [T3 vs. T1]=2.02; 95% CI, 1.41-2.91; p for trend <0.001). The IL23R rs10889677 reduced the risk of GC in individuals who carried at least 1 minor allele (OR=0.62; 95% CI, 0.46-0.83; p=0.001; AC/CC vs. AA). Individuals with a C allele exhibited a lower susceptibility to GC through methylmercury intake than those with the AA genotype (OR for the T3 of methylmercury and AA carriers=2.93; 95% CI, 1.77-4.87; and OR for the T3 of methylmercury and AC/CC genotype=1.30; 95% CI, 0.76-2.21; p-interaction=0.013). Conclusion: Our findings suggest that a genetic polymorphism, rs10889677 in IL23R, plays a role in modifying the association between dietary methylmercury intake and the risk of GC.

Evolutional dynamics of highly pathogenic avian influenza H5N8 genotypes in wintering bird habitats: Insights from South Korea's 2020-2021 season.

The winter of 2020-2021 in South Korea witnessed severe outbreaks of Highly Pathogenic Avian Influenza (HPAI) viruses, specifically multiple genotypes of the H5N8 subtype. These outbreaks prompted an extensive investigation into the genetic characteristics and evolutionary dynamics of these viruses. Under the auspices of the National Institute of Wildlife Disease Control and Prevention (NIWDC), we conducted a nationwide surveillance program, collecting 7588 specimens from diverse wild bird habitats. Influenza A viruses were isolated at a rate of 5.0%, with HPAI H5N8 viruses accounting for 38.5% of isolates, predominantly found in wild bird carcasses (97.3%). Genetic analysis revealed the emergence of novel HPAI genotypes due to genetic reassortment events. G1 and G2 viruses were separately introduced into Korea, with G1 viruses displaying dynamic behavior, resulting in diverse sub-genotypes (G1-1 to G1-5) and mainly isolated from clinical specimens. Conversely, the G2 virus, introduced later, became the dominant strain consistently isolated mainly from bird carcasses (88.9%). These findings underscore the emergence of numerous novel HPAI genotypes shaped by multiple reassortment events in high-density wintering grounds of migratory birds. These sites act as hotspots for genetic exchanges, significantly influencing avian ecology, including resident bird species, and contributing to HPAI H5N8 evolution. The genetic diversity and ongoing evolution of these viruses highlight the need for vigilant surveillance and adaptive control measures. Recognizing the potential spillover to human populations, a One Health approach is essential to mitigate the evolving threats posed by avian influenza.

A Modified eCura System to Stratify the Risk of Lymph Node Metastasis in Undifferentiated-Type Early Gastric Cancer After Endoscopic Resection.

PURPOSE: The original eCura system was designed to stratify the risk of lymph node metastasis (LNM) after endoscopic resection (ER) in patients with early gastric cancer (EGC). We assessed the effectiveness of a modified eCura system for reflecting the characteristics of undifferentiated-type (UD)-EGC. MATERIALS AND METHODS: Six hundred thirty-four patients who underwent non-curative ER for UD-EGC and received either additional surgery (radical surgery group; n=270) or no further treatment (no additional treatment group; n=364) from 18 institutions between 2005 and 2015 were retrospectively included in this study. The eCuraU system assigned 1 point each for tumors >20 mm in size, ulceration, positive vertical margin, and submucosal invasion <500 µm; 2 points for submucosal invasion ≥500 µm; and 3 points for lymphovascular invasion. RESULTS: LNM rates in the radical surgery group were 1.1%, 5.4%, and 13.3% for the low- (0-1 point), intermediate- (2-3 points), and high-risk (4-8 points), respectively (P-for-trend<0.001). The eCuraU system showed a significantly higher probability of identifying patients with LNM as high-risk than the eCura system (66.7% vs. 22.2%; McNemar P<0.001). In the no additional treatment group, overall survival (93.4%, 87.2%, and 67.6% at 5 years) and cancer-specific survival (99.6%, 98.9%, and 92.9% at 5 years) differed significantly among the low-, intermediate-, and high-risk categories, respectively (both P<0.001). In the high-risk category, surgery outperformed no treatment in terms of overall mortality (hazard ratio, 3.26; P=0.015). CONCLUSIONS: The eCuraU system stratified the risk of LNM in patients with UD-EGC after ER. It is strongly recommended that high-risk patients undergo additional surgery.

Assessment and validation of glottic motion using cone-beam CT and real-time cine MRI.

PURPOSE: This study aimed to assess the margin for the planning target volume (PTV) using the Van Herk formula. We then validated the proposed margin by real-time magnetic resonance imaging (MRI). METHODS: An analysis of cone-beam computed tomography (CBCT) data from early glottic cancer patients was performed to evaluate organ motion. Deformed clinical target volumes (CTV) after rigid registration were acquired using the Velocity program (Varian Medical Systems, Palo Alto, CA, USA). Systematic (Σ) and random errors (σ) were evaluated. The margin for the PTV was defined as 2.5 Σ + 0.7 σ according to the Van Herk formula. To validate this margin, we accrued healthy volunteers. Sagittal real-time cine MRI was conducted using the ViewRay system (ViewRay Inc., Oakwood Village, OH, USA). Within the obtained sagittal images, the vocal cord was delineated. The movement of the vocal cord was summed up and considered as the internal target volume (ITV). We then assessed the degree of overlap between the ITV and the PTV (vocal cord plus margins) by calculating the volume overlap ratio, represented as (ITV∩PTV)/ITV. RESULTS: CBCTs of 17 early glottic patients were analyzed. Σ and σ were 0.55 and 0.57 for left-right (LR), 0.70 and 0.60 for anterior-posterior (AP), and 1.84 and 1.04 for superior-inferior (SI), respectively. The calculated margin was 1.8 mm (LR), 2.2 mm (AP), and 5.3 mm (SI). Four healthy volunteers participated for validation. A margin of 3 mm (AP) and 5 mm (SI) was applied to the vocal cord as the PTV. The average volume overlap ratio between ITV and PTV was 0.92 (range 0.85-0.99) without swallowing and 0.77 (range 0.70-0.88) with swallowing. CONCLUSION: By evaluating organ motion by using CBCT, the margin was 1.8 (LR), 2.2 (AP), and 5.3 mm (SI). The margin acquired using CBCT fitted well in real-time cine MRI. Given that swallowing during radiotherapy can result in a substantial displacement, it is crucial to consider strategies aimed at minimizing swallowing and related motion.

Association of musculoskeletal involvement with lung function and mortality in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with high mortality. Low muscle mass, frailty and sarcopenia lead to functional impairment that negatively impact quality of life and survival but are not used in clinical practice. We aimed to determine the association of Fat-free mass index (FFMI) and frailty with lung function, exercise tolerance and survival in patients with IPF. In this study, 70 patients with IPF underwent assessment of body composition, lung function, 6-min walk distance (6MWD) testing, hand grip strength, quality of life (QoL) assessment by St. George's Respiratory questionnaire (SGRQ) and frailty assessment using the SHARE-FI tool. FFMI was calculated using pectoralis muscle cross-sectional area (PM-CSA) on CT chest images and the lowest quartile defined reduced muscle mass. Sarcopenia was defined as low FFMI and handgrip strength. Regression analyses were conducted to determine predictive value of frailty, low FFMI and sarcopenia on clinical outcomes. The Cox proportional hazards model was used to analyze the impact of FFMI and frailty score on survival. The mean age was 70 years with moderate impairment in lung function (mean ppFVC 68.5%, ppDLCO 45.6%). Baseline forced vital capacity (p < 0.001), diffusion capacity of lung for carbon monoxide (p = < 0.01), 6WMD (p < 0.05) were significantly lower in frail patients compared to non-frail patients. BMI was found to closely correlate with FFMI (r = 0.79, p < 0.001), but not with frailty score (r = - 0.2, p = 0.07). Frailty was a significant predictor of FVC, DLCO, 6MWD, SGRQ scores when adjusted for age and gender. Muscle mass and sarcopenia were significant predictors of FVC, DLCO, but not 6MWD or QoL scores. Multivariate cox-proportional hazards ratio model adjusting for age and gender showed that frailty was significantly associated with increased mortality (HR = 2.6, 95% CI 1.1-6.1). Low FFMI (HR = 1.3, 95% CI 0.6-2.8), and sarcopenia (HR = 2.1, 95% CI 0.8-5.3), though associated with a trend to increased mortality, were not statistically significant. Frailty is associated with lower lung function and higher mortality in patients with IPF. Longitudinal evaluations are necessary to further determine the associations between low FFMI, sarcopenia and frailty with outcomes in IPF.

The Neuromechanics of Inspiratory Muscles in Mechanical Ventilation Liberation Success and Failure.

BACKGROUND: Assessing the neuromechanical coupling of inspiratory muscles during mechanical ventilation (MV) could reveal the physiological mechanism of MV failure. This study examined the respiratory neuromechanical characteristics between MV liberation success and failure. METHODS: This is an observational prospective study that included patients during their ventilator liberation process. Assessment of surface electromyography (sEMG) of inspiratory muscles, including the diaphragm and extra-diaphragmatic (scalene, sternocleidomastoid, and parasternal) muscles, was performed 15 minutes after the initiation of spontaneous breathing trials. Neuromechanical efficiency of the diaphragm (NMEDia) and extra-diaphragmatic muscles (NMEExtra) were compared in patients who were successfully liberated from MV with those who failed MV liberation within 72 hours after extubation. RESULTS: A total of 45 patients were enrolled and 28 were female (67%). The sample median age was 63 (IQR 47, 69) years old. One-third of patients failed MV liberation within 72 hours of their spontaneous breathing trials (SBTs). NMEDia was significantly lower in patients who failed MV liberation with a root mean square of (M 0.27), (IQR 0.21, 0.37) compared with (M 0.371), (IQR 0.3, 0.631) for the success group (p=0.0222). The area under the curve for NMEDia was lower in the failure group (M 0.270), (IQR 0.160, 0.370) and (M 0.485), (IQR 0.280, 0.683) for the success group (p=0.024). However, NMEExtra was not statistically different between the two groups. CONCLUSION: Reduced NMEDia is a predictor of MV liberation failure. NMEExtra was not a major contributor to MV liberation outcomes. Further studies should assess the performance of inspiratory muscles NME indices to predict MV liberation outcomes.

HA N193D substitution in the HPAI H5N1 virus alters receptor binding affinity and enhances virulence in mammalian hosts.

During the 2021/2022 winter season, we isolated highly pathogenic avian influenza (HPAI) H5N1 viruses harbouring an amino acid substitution from Asparagine(N) to Aspartic acid (D) at residue 193 of the hemagglutinin (HA) receptor binding domain (RBD) from migratory birds in South Korea. Herein, we investigated the characteristics of the N193D HA-RBD substitution in the A/CommonTeal/Korea/W811/2021[CT/W811] virus by using recombinant viruses engineered via reverse genetics (RG). A receptor affinity assay revealed that the N193D HA-RBD substitution in CT/W811 increases α2,6 sialic acid receptor binding affinity. The rCT/W811-HA193N virus caused rapid lethality with high virus titres in chickens compared with the rCT/W811-HA193D virus, while the rCT/W811-HA193D virus exhibited enhanced virulence in mammalian hosts with multiple tissue tropism. Surprisingly, a ferret-to-ferret transmission assay revealed that rCT/W811-HA193D virus replicates well in the respiratory tract, at a rate about 10 times higher than that of rCT/W811-HA193N, and all rCT/W811-HA193D direct contact ferrets were seroconverted at 10 days post-contact. Further, competition transmission assay of the two viruses revealed that rCT/W811-HA193D has enhanced growth kinetics compared with the rCT/W811-HA193N, eventually becoming the dominant strain in nasal turbinates. Further, rCT/W811-HA193D exhibits high infectivity in primary human bronchial epithelial (HBE) cells, suggesting the potential for human infection. Taken together, the HA-193D containing HPAI H5N1 virus from migratory birds showed enhanced virulence in mammalian hosts, but not in avian hosts, with multi-organ replication and ferret-to-ferret transmission. Thus, this suggests that HA-193D change increases the probability of HPAI H5N1 infection and transmission in humans.

Ambulatory Endoscopic Submucosal Dissection for Gastrointestinal Neoplasms: Trends and Associated Factors in the United States.

Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for superficial gastrointestinal (GI) cancers.1,2 ESD practice is expanding significantly in the United States and Western countries. This is attributed to a shorter hospital stay, better quality of life, and fewer adverse events compared with surgery. In the United States, ESD usually is performed and managed in an outpatient setting (ambulatory ESD) or with an overnight hospital stay. This practice is in contrast to Eastern Asian countries, where 3 to 5 days of hospital stay is a routine process for observation after ESD. A Swedish study showed that patients with well-selected colorectal neoplasms (median tumor size, 37 mm) could be managed safely in an outpatient setting after ESD.3 A North American multicenter ESD study also reported that ambulatory ESD was safe and feasible in selected cases (noninvasive cancers, no adverse events, high-volume endoscopists with short procedure time).4 However, procedural and technical aspects that enable safe outpatient management of patients after ESD need to be investigated.

Identifying the external N and Hg inputs to the estuary ecosystem based on the triple isotopic information (δ15NNO3, Δ17ONO3 and δ18ONO3).

The supply and sources of N and Hg in the Geum estuary of the western coast of Korea were evaluated. Triple isotope proxies (δ15NNO3, Δ17ONO3 and δ18ONO3) of NO3- combined with conservative mixing between river and ocean waters were used to improve isotope finger-printing methods. The N pool in the Geum estuary was primarily influenced by the Yellow Sea water, followed by riverine discharge (821 × 106 mol yr-1) and atmospheric deposition (51 × 106 mol yr-1). The influence of the river was found to be greater for Hg than that of the atmosphere. The triple isotope proxies revealed that the riverine and atmospheric inputs of N have been affected by septic wastes and fossil fuel burning, respectively. From the inner estuary towards offshore region, the influence of the river diminishes, thus increasing the relative impact of the atmosphere. Moreover, the isotope proxies showed a significant influence of N assimilation in February and nitrification in May.

Functional Annotation and Gene Set Analysis of Gastric Cancer Risk Loci in a Korean Population.

PURPOSE: We aimed to identify the associated single nucleotide polymorphisms (SNPs) with gastric cancer (GC) risk by genome-wide association study (GWAS) and to explore the pathway enrichment of implicated genes and gene-sets with expression patterns. MATERIALS AND METHODS: The study population was comprised of 1,253 GC cases and 4,827 controls from National Cancer Center and an urban community of the Korean Genome Epidemiology Study and their genotyping was performed. SNPs were annotated, and mapped to genes to prioritize by three mapping approaches by functional mapping and annotation (FUMA). The gene-based analysis and gene-set analysis were conducted with full GWAS summary data using MAGMA. Gene-set pathway enrichment test with those prioritized genes were performed. RESULTS: In GWAS, rs2303771, a nonsynonymous variant of KLHDC4 gene was top SNP associated significantly with GC (odds ratio, 2.59; p=1.32×10-83). In post-GWAS, 71 genes were prioritized. In gene-based GWAS, seven genes were under significant p < 3.80×10-6 (0.05/13,114); DEFB108B had the lowest p=5.94×10-15, followed by FAM86C1 (p=1.74×10-14), PSCA (p=1.81×10-14), and KLHDC4 (p=5.00×10-10). In gene prioritizing, KLDHC4 was the only gene mapped with all three gene-mapping approaches. In pathway enrichment test with prioritized genes, FOLR2, PSCA, LY6K, LYPD2, and LY6E showed strong enrichment related to cellular component of membrane; a post-translation modification by synthesis of glycosylphosphatidylinositol (GPI)-anchored proteins pathway. CONCLUSION: While 37 SNPs were significantly associated with the risk of GC, genes involved in signaling pathways related to purine metabolism and GPI-anchored protein in cell membrane are pinpointed to be playing important role in GC.

Acidity in rainwater and airborne suspended particles in the southwestern coast of the East Sea (Sea of Japan): Their potential impact on seawater total alkalinity.

Our understanding of the impact of atmospheric acid deposition on marine carbonate system remains limited, largely due to a lack of data regarding acidity present in atmospheric particles and precipitation. Previous research has relied on the electroneutrality-based ion balance method for indirect estimation of atmospheric acidity. In this study, atmospheric samples collected at a coastal site of South Korea were mixed with seawater to measure the change in seawater total alkalinity (ΔTAAPL) associated with atmospheric proton loading. For the precipitation samples, the measured ΔTAAPL and electroneutrality-based estimates showed a significant correlation. However, we did not observe similar results for the atmospheric particle samples. Furthermore, the decrease in oceanic TA due to ΔTAAPL was substantially smaller than that in dissolved inorganic carbon from concurrent nitrogen fertilization. Consequently, the adverse impact of acid deposition on ocean acidification or air-sea exchange of CO2 appears to be insignificant on a short-term scale.

Short- and Long-Term Survival of Metastatic Biliary Tract Cancer in the United States From 2000 to 2018.

INTRODUCTION: Information about survival outcomes in metastatic biliary tract cancer (BTC) is sparse, and the numbers often quoted are based on reports of clinical trials data that may not be representative of patients treated in the real world. Furthermore, the impact of more widespread adoption of a standardized combination chemotherapy regimen since 2010 on survival is unclear. METHODS: We performed an analysis of the Surveillance, Epidemiology, and End Results database to determine the real-world overall survival trends in a cohort of patients with metastatic BTC diagnosed between the years 2000 and 2017 with follow-up until 2018. We analyzed data for the entire cohort, evaluated short-term and long-term survival rates, and compared survival outcomes in the pre-2010 and post-2010 periods. Survival analysis was performed using the Kaplan-Meier method, and Cox proportional hazard models were used to evaluate factors associated with survival. RESULTS: Among 13, 287 patients, the median age was 68 years. There was a preponderance of female (57%) and white (77%) patients. Forty-one percent died within 3 months of diagnosis (short-term survivors) and 20% were long-term survivors (12 months or longer). The median overall survival (OS) for the entire cohort was 4.5 months. Median OS improved post-2010 (4.5 months) compared to pre-2010 (3.5 months) (P < .0001). On multivariate analysis, age <55 years, intrahepatic cholangiocarcinoma, surgical resection, and diagnosis post-2010 were associated with lower hazard of death. CONCLUSION: The real-world prognosis of metastatic BTC is remarkably poorer than described in clinical trials because a large proportion of patients survive less than three months. Over the last decade, the improvement in survival has been minimal.

SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility.

With the emergence of multiple predominant SARS-CoV-2 variants, it becomes important to have a comprehensive assessment of their viral fitness and transmissibility. Here, we demonstrate that natural temperature differences between the upper (33°C) and lower (37°C) respiratory tract have profound effects on SARS-CoV-2 replication and transmissibility. Specifically, SARS-CoV-2 variants containing the NSP12 mutations P323L or P323L/G671S exhibit enhanced RNA-dependent RNA polymerase (RdRp) activity at 33°C compared with 37°C and high transmissibility. Molecular dynamics simulations and microscale thermophoresis demonstrate that the NSP12 P323L and P323L/G671S mutations stabilize the NSP12-NSP7-NSP8 complex through hydrophobic effects, leading to increased viral RdRp activity. Furthermore, competitive transmissibility assay reveals that reverse genetic (RG)-P323L or RG-P323L/G671S NSP12 outcompetes RG-WT (wild-type) NSP12 for replication in the upper respiratory tract, allowing markedly rapid transmissibility. This suggests that NSP12 P323L or P323L/G671S mutation of SARS-CoV-2 is associated with increased RdRp complex stability and enzymatic activity, promoting efficient transmissibility.

Correcting biases in regional climate model boundary variables for improved simulation of high-impact compound events.

Although climate models have been used to assess compound events, the combination of multiple hazards or drivers poses uncertainties because of the systemic biases present. Here, we investigate multivariate bias correction for correcting systemic bias in the boundaries that form the inputs of regional climate models (RCMs). This improves the representation of physical relationships among variables, essential for accurate characterization of compound events. We address four types of compound events that result from eight different hazards. The results show that while the RCM simulations presented here exhibit similar performance for some event types, the multivariate bias correction broadly improves the RCM representation of compound events compared to no correction or univariate correction, particularly for coincident high temperature and high precipitation. The RCM with uncorrected boundaries tends to produce a negative bias in the return period of these events, suggesting a tendency to over-simulate compound events with respect to observed events.

Specialist Availability and Drug Adherence in Older Adults with Dementia Across Regions of the United States.

BACKGROUND: Access to specialists facilitates appropriate Alzheimer's disease and related dementia (ADRD) medication use and adherence. However, there is little information on the impact of specialists' availability on ADRD medication adherence, especially in regions of the United States (US) where specialists are scarce, e.g., the Deep South (DS). OBJECTIVE: To ascertain whether the availability of specialty physicians in the DS and other US regions predicts ADRD medication adherence among community-dwelling older adultsMethods:We conducted secondary analyses of claims data for 54,194 Medicare beneficiaries with ADRD in 2013-2015. Medication adherence was measured using the proportion of days covered (PDC). Multivariable-adjusted Modified Poisson regression was used to examine associations of adherence with physicians' availability by region. RESULTS: The race/ethnicity distribution was 81.44% white, 9.17% black, 6.24% Hispanic, 2.25% Asian, and 1% other; 71.81% were female, and 42.36% were older than 85 years. Beneficiaries across regions differed in all individual and contextual characteristics except sex and comorbidities. Neurologists and psychiatrists' availability was not significantly associated with adherence (DS = 1.00, 0.97-1.03 & non-DS = 1.01, 1.00-1.01). Race and having ≥1 specialist visits were associated with a lower risk of adherence in both regions (p < 0.0001). Advanced age, dual Medicare/Medicaid eligibility, and living in non-large metropolitan areas, were associated with adherence in the non-DS region. CONCLUSION: Among older Americans with ADRD, a context defined by specialist availability does not affect adherence, but other context characteristics related to socioeconomic status may. Research should further examine the influence of individual and contextual factors on ADRD treatment among older adults.