Exploring bleeding in oral anticoagulant users: assessing incidence by indications and risk factors in the entire nationwide cohort.

Background: Oral anticoagulants (OACs) are essential for the prevention and treatment of thromboembolic disorders, but bleeding, a major complication, can have a fatal impact on the patient's treatment. Objectives: We aimed to estimate the nationwide, real-world incidence rate of bleeding in patients taking OACs and confirm the incidence by indications and risk factors. Methods: This cross-sectional study identified OAC users from April 1 to December 31, in both 2019 and 2020, using the HIRA-NPS database. The primary outcome variables were the incidence rate of major bleeding events during OAC treatment and within 30 days of treatment discontinuation. We estimated the adjusted incidence rate ratio (aIRR) in subpopulations. Results: Among 18,822 OAC users, the incidence rate of major bleeding was 27.9 (95% CI: 24.6-31.5) per 1,000 person-years. The incidence rate of major bleeding was higher in patients with a bleeding history, with an aIRR of 11.51; those at high bleeding risk (HAS-BLED score ≥3), with an aIRR of 1.51; those with high CCI scores ≥3, with an aIRR of 1.88; and those with liver disease, with an aIRR of 1.41. For indications, compared to patients with nonvalvular atrial fibrillation (NVAF), the aIRR of major bleeding was significantly higher at an aIRR of 2.35 in patients undergoing VTE treatment. Patients with ischemic stroke showed a higher incidence of major bleeding with an aIRR of 2.13 than NVAF patients. The aIRR of major bleeding in the oral anticoagulant group, compared to the matched control group, was 2.25 (95% CI: 1.93-2.63). Conclusion: These findings may be useful for implementing strategies to improve the evaluation and management of anticoagulation-related bleeding.

Comparison of three approaches for treating the bony access window in lateral sinus floor elevation: a retrospective analysis.

The aim of this study was to retrospectively determine the effects of applying different treatment methods to the bony access window on the healing outcomes in lateral sinus floor elevation (SFE). Lateral SFE with implant placement was performed in 131 sinuses of 105 patients. The following three treatment methods were applied to the bony access window: application of a collagen barrier (group CB), repositioning the bone fragment (group RW) and untreated (group UT). Radiographic healing in the window area, augmented bone height changes and marginal bone level changes were examined. Mixed logistic and mixed linear models were analyzed. Over 4.3 ± 1.4 years of follow-up, the implant survival rate was 100% in groups CB and UT, and 96.9% in group RW. The treatment applied to the window did not significantly influence the radiographic healing in the window area, augmented bone height changes or marginal bone level changes (p > 0.05). The healed window areas had generally flat morphologies and were fully corticalized. The mean changes in the augmented bone were less than 1.5 mm in all groups. Marginal bone level changes were minimal. In conclusion, Healing outcomes were not different among three different methods to treat the bony access window in lateral SFE.

Causality of genetically determined serum metabolites on lower back pain or/and sciatica: a comprehensive Mendelian randomized study.

Background: There is an urgent need to confirm biomarkers reflecting the pathogenesis and targeted drugs of lower back pain or/and sciatica in clinical practice. This study aimed to conduct a two sample bidirectional Mendelian randomization (MR) analysis to explore the causal link between 486 serum metabolites and lower back pain or/and sciatica. Methods: All data come from two public shared databases of European ancestry and single nucleotide polymorphisms (SNPs) for lower back pain or/and sciatica acted as instrumental variables. The traditional inverse variance weighting (IVW) method, weighted-median method, MR-Egger methodand other methods were used to estimate causality. The horizontal pleiotropy, heterogeneities were also verified through the MR-Egger intercept test, Cochran's Q test, MR-PRESSO test and the leave-one-out sensitivity analysis. Reverse MR analysis was employed to evaluate the direct impact of metabolites on lower back pain or/and sciatica. Additionally, we conducted the colocalization analysis to reflect the causality deeply. Furthermore, metabolic pathway analysis was performed. Results: 28 metabolites (18 known metabolites, 1 identified metabolites and 9 unknown metabolites) relevant to the risk of sciatica or/and lower back pain after using genetic variants as probes at PIVW < 0.05 were identifed. Among them, 8 serum metabolites decreased risk of sciatica or/and lower back pain significantly (P < 0.05), and 14 serum metabolites increased risk of sciatica or/and lower back pain significantly (P < 0.05). No reverse causal association was found between 28 metabolites and sciatica or/and lower back pain. Colocalization analysis results showed that the associations between sciatica or/and lower back pain and the 28 identified metabolites were not due to shared causal variant sites. Moreover, pathway enrichment analysis identifed 11 signifcant metabolic pathways, which are mainly involved in the pathological mechanism of sciatica or/and lower back pain (P < 0.05). There was no horizontal pleiotropy or heterogeneity in the other analyses. Conclusion: Our analyses provided robust evidence of causal associations between blood metabolites on sciatica or/and lower back pain. However, the underlying mechanisms remain to be further investigated.

Genome-wide association study of subfoveal choroidal thickness in a longitudinal cohort of older adults.

To identify genetic influences on subfoveal choroidal thickness of older adults using a genome-wide association study (GWAS). We recruited 300 participants from the population-based Korean Longitudinal Study on Health and Aging (KLoSHA) and Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD) cohort studies and 500 participants from the Bundang age-related macular degeneration (AMD) cohort study dataset. We conducted a GWAS on older adult populations in the KLoSHA and KLOSCAD cohorts. Single nucleotide polymorphisms (SNPs) associated with choroidal thickness were identified with P values < 1.0 × 10-4 in both the right and left eyes, followed by validation using the Bundang AMD cohort dataset. This association was further confirmed by a functional in vitro study using human umbilical vein endothelial cells (HUVECs). The ages of the cohort participants in the discovery and validation datasets were 73.5 ± 3.3 and 71.3 ± 7.9 years, respectively. In the discovery dataset, three SNPs (rs1916762, rs7587019, and rs13320098) were significantly associated with choroidal thickness in both eyes. This association was confirmed for rs1916762 (genotypes GG, GA, and AA) and rs7587019 (genotypes GG, GA, and AA), but not for rs13320098. The mean choroidal thickness decreased by 56.7 µm (AA, 73.8%) and 31.1 µm (GA, 85.6%) compared with that of the GG genotype of rs1916762, and by 55.4 µm (AA, 74.2%) and 28.2 µm (GA, 86.7%) compared with that of the GG genotype of rs7587019. The SNPs rs1916762 and rs7587019 were located close to the FAM124B gene near its cis-regulatory region. Moreover, FAM124B was highly expressed in vascular endothelial cells. In vitro HUVEC experiments showed that the inhibition of FAM124B was associated with decreased vascular endothelial proliferation, suggesting a potential mechanism of choroidal thinning. FAM124B was identified as a susceptibility gene affecting subfoveal choroidal thickness in older adults. This gene may be involved in mechanisms underlying retinal diseases associated with altered choroidal thickness, such as age-related macular degeneration.

Planned Immediate Chemotherapy and Cryopreservation of Oocytes or Embryos for Fertility Preservation in Women with Malignancies.

Purpose: Oocyte and embryo cryopreservation before gonadotoxic treatment are established methods to increase the likelihood of live births. Although several sociodemographic factors were found to be associated with undergoing fertility preservation (FP) treatment, clinical characteristics such as planned immediate chemotherapy were not fully investigated. We aimed to investigate whether the planned immediate chemotherapy is related to the decision to undergo oocyte/embryo cryopreservation for FP with adjustment for other clinical characteristics. Methods: This institutional cohort study included 491 premenopausal women aged 19 years or older who visited the FP clinic at a tertiary medical center between 2006 and 2019. The primary outcome was whether the participants underwent oocyte/embryo cryopreservation. We evaluated the odds ratios (ORs) and corresponding 95% confidence intervals (CIs) of undergoing oocyte/embryo cryopreservation according to whether immediate chemotherapy was planned using univariable and multivariable logistic regression. Results: Women scheduled for immediate chemotherapy were much less likely to undergo oocyte/embryo cryopreservation than women not scheduled for immediate chemotherapy (OR = 0.46, 95% CI 0.27-0.76) in univariable logistic regression analysis. After adjustment for covariates such as marital status, type of malignancies, and calendar year period, women scheduled for immediate chemotherapy were still less likely to undergo oocyte/embryo cryopreservation than women not scheduled for immediate chemotherapy (OR = 0.31, 95% CI: 0.17-0.56). The association was not different according to the type of malignancies (p for interaction = 0.13). Regarding breast cancer, the OR for undergoing oocyte/embryo cryopreservation in women scheduled for immediate chemotherapy was robust compared with those not planned for immediate chemotherapy (OR = 0.25, 95% CI: 0.12-0.53). Conclusion: The present study demonstrated that planned immediate chemotherapy was negatively associated with undergoing oocyte/embryo cryopreservation. This information can be helpful for FP counseling.

Updated overall survival and ctDNA analysis in patients with EGFR T790M-positive advanced non-small cell lung cancer treated with lazertinib in the phase 1/2 LASER201 study.

BACKGROUND: Lazertinib is a potent, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with significant efficacy in patients with EGFR T790M-mutated non-small cell lung cancer (NSCLC). This is the final overall survival (OS) report from the phase 1/2 LASER201 study in patients with advanced NSCLC with disease progression on or after prior EGFR TKI therapy. METHODS: Eligible patients were aged ≥ 20 years, with advanced EGFR-mutated NSCLC and previous therapy with EGFR TKI. Patients in this integrated analysis received oral lazertinib 240 mg/day. Endpoints included efficacy and safety; exploratory analyses included associations between circulating EGFR-mutant tumor DNA (ctDNA) and efficacy parameters. RESULTS: This integrated analysis included 78 patients in Korea who received second- or later-line lazertinib. The median OS was 38.9 months; estimated survival rates at 12, 24, and 36 months were 89.5%, 73.9%, and 52.8%, respectively. The cumulative 12-month incidence of central nervous system progression was 9.4%. EGFR-mutant ctDNA was detected in 46 patients (62.2%) at baseline. The presence of ctDNA at baseline significantly predicted progression-free survival (PFS), disease control rate (DCR), and OS. PFS, response rate, and DCR were significantly associated with EGFR-mutant ctDNA clearance at cycle 3; PFS and OS were significantly associated with ctDNA clearance at cycle 5. The safety profile of lazertinib 240 mg/day was consistent with previous findings. CONCLUSIONS: Lazertinib is a promising treatment option for patients with EGFR T790M-positive NSCLC following disease progression on prior EGFR-directed TKIs. Patients in LASER201 experienced prolonged OS, regardless of their EGFR mutation, brain metastases, or prior brain radiation status. Clearance of plasma EGFR mutations after lazertinib was associated with patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03046992.

Capmatinib in MET exon 14-mutated non-small-cell lung cancer: final results from the open-label, phase 2 GEOMETRY mono-1 trial.

BACKGROUND: Capmatinib has previously shown activity in treatment-naive and previously treated patients with non-small-cell lung cancer (NSCLC) and a MET exon 14-skipping mutation (METex14). Here, we report the final outcomes from the phase 2 GEOMETRY mono-1 study with an aim to provide further evidence for the activity of capmatinib. METHODS: In this non-randomised, multi-cohort, open-label, phase 2 trial conducted in 152 centres and hospitals in 25 countries, with patients treated in 95 centres in 20 countries, eligible patients (aged ≥18 years) with MET-dysregulated, EGFR wild-type, and ALK rearrangement-negative advanced NSCLC (stage IIIB/IV) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were assigned to cohorts (1a, 1b, 2, 3, 4, 5a, 5b, 6 and 7) based on their MET status (METex14 or MET amplification) and previous therapy lines. Patients received capmatinib (400 mg orally twice daily) in 21-day treatment cycles. The primary endpoint was overall response rate by blinded independent central review per Response Evaluation Criteria in Solid Tumours version 1.1 and was performed on the full analysis set (all patients who received at least one dose of capmatinib). Previous reports of this study had published interim or primary data for cohorts 1-7. Here, we report the final clinical outcomes from all METex14 cohorts (4, 5b, 6, and 7) and safety from all study cohorts (1-7). The trial is registered with ClinicalTrials.gov, NCT02414139, and has been completed. FINDINGS: Of 373 treated patients enrolled from June 11, 2015, to March 12, 2020, 160 (97 [61%] female) patients had METex14 NSCLC and were enrolled in four cohorts: 60 treatment-naive (cohorts 5b and 7) and 100 previously treated (cohorts 4 and 6). The overall median study follow-up was 46·4 months (IQR 41·8-65·4) for the treatment-naïve patients and 66·9 months (56·7-73·9) for previously treated patients, respectively. Overall responses were recorded in 41 (68%; 95% CI 55·0-79·7) of 60 treatment-naive patients and 44 (44%; 95% CI 34·1-54·3) of 100 previously treated patients. In all 373 treated patients, the most common treatment-related adverse events were peripheral oedema (n=174; 47%), nausea (n=130; 35%), increased blood creatinine (n=78; 21%), and vomiting (n=74; 20%). Grade 3-4 serious adverse events occurred in 164 (44%) patients, dyspnoea being the most common (18 patients [5%]). Treatment-related deaths occurred in four (1%) patients (one each of cardiac arrest, hepatitis, organising pneumonia, and pneumonitis). No new safety signals were reported. INTERPRETATION: These long-term results support METex14 as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for treatment-naive and previously treated patients with METex14 NSCLC. FUNDING: Novartis Pharmaceuticals.

HM-chromanone attenuates obesity and adipose tissue inflammation by downregulating SREBP-1c and NF-κb pathway in high-fat diet-fed mice.

Background: Obese adipose tissue produces various pro-inflammatory cytokines that are major contributors to adipose tissue inflammation.Objective: The present study aimed to determine the effects of HM-chromanone (HMC) against obesity and adipose tissue inflammation in high-fat diet-fed mice.Materials and methods: Twenty-four C57BL/6J male mice were divided into three groups: ND (normal diet), HFD (high-fat diet), and HFD + HMC. The ND group was fed a normal diet, whereas the HFD and HFD + HMC groups were fed a high-fat diet. After 10 weeks of feeding, the animals were orally administered the treatments daily for 9 weeks. The ND and HFD group received distilled water as treatment. The HFD+HMC group was treated with HM-chromaone (50 mg/kg).Results: HM-chromanone administration decreased body weight, fat mass, and adipocyte diameter. HM-chromanone also improved plasma lipid profiles, decreased leptin levels, and increased adiponectin levels. The inhibiting effect of HM-chromanone on SREBP-1c, PPARγ, C/EBPα, and FAS decreased adipogenesis, thereby alleviating lipid accumulation. Furthermore, HM-chromanone administration exhibited a reduction in macrophage infiltration and the expression of pro-inflammatory cytokines. HM-chromanone suppressed the phosphorylation of IκBα and NF-κB, leading to the inhibition of iNOS and COX2 expressions, resulting in decreased inflammation in adipose tissue.Discussion and conclusion: These results highlight the anti-obesity and anti-inflammatory properties of HM-chromanone, achieved through the downregulation of the SREBP-1c and NF-κB pathway in high-fat diet-fed mice.

ctDNA dynamics and mechanisms of acquired resistance in patients treated with osimertinib with or without bevacizumab from the randomised phase II ETOP-BOOSTER trial.

BACKGROUND: ETOP 10-16 BOOSTER study was a randomised phase II trial of osimertinib and bevacizumab versus osimertinib in patients with an acquired EGFR T790M mutation. The mechanisms of acquired resistance to osimertinib and bevacizumab have not been described previously. METHODS: Next generation sequencing (Guardant360®) was conducted in serial plasma samples. The association between ctDNA and efficacy outcomes was explored and molecular alterations at progression were described. RESULTS: 136 patients (88% of 155 randomised) had plasma samples at baseline (68 per arm), 110 (71%) at week 9 and 65 (42%) at progression. In a multivariable model for progression-free survival (PFS), the treatment effect was found different by smoking status (interaction p=0.046), with the effect of smoking also different by baseline EGFR T790M (interaction p=0.033), while both TP53 at baseline and tissue EGFR Exon 21 L858R mutation were significantly associated with worse PFS outcome. Smokers (current/former) without baseline EGFR T790M showed a significant improvement in PFS under combination treatment, albeit with small numbers (p=0.015). Week-9 EGFR T790M clearance was associated with improved PFS in the osimertinib arm (p=0.0097). Acquired EGFR C797S mutations were detected in 22% and 13% of patients in the combination and osimertinib arm, respectively. CONCLUSIONS: The differential effect of treatment by smoking was not explained by TP53 mutation or other molecular alterations examined. Molecular mechanisms of acquired resistance were detected but no novel molecular alterations were identified in the combination arm.

Association of Compensatory Mechanisms in Prefrontal Cortex and Impaired Anatomical Correlates in Semantic Verbal Fluency: A Functional Near-Infrared Spectroscopy Study.

OBJECTIVE: Semantic verbal fluency (SVF) engages cognitive functions such as executive function, mental flexibility, and semantic memory. Left frontal and temporal lobes, particularly the left inferior frontal gyrus (IFG), are crucial for SVF. This study investigates SVF and associated neural processing in older adults with mild SVF impairment and the relationship between structural abnormalities in the left IFG and functional activation during SVF in those individuals. METHODS: Fifty-four elderly individuals with modest level of mild cognitive impairment whose global cognition were preserved to normal but exhibited mild SVF impairment were participated. Prefrontal oxyhemoglobin (HbO2) activation and frontal cortical thickness were collected from the participants using functional near-infrared spectroscopy (fNIRS) and brain MRI, respectively. We calculated the ß coefficient of HbO2 activation induced by tasks, and performed correlation analysis between SVF induced HbO2 activation and cortical thickness in frontal areas. RESULTS: We observed increased prefrontal activation during SVF task compared to the resting and control task. The activation distinct to SVF was identified in the midline superior and left superior prefrontal regions (p<0.05). Correlation analysis revealed an inverse relationship between SVF-specific activation and cortical thickness in the left IFG, particularly in pars triangularis (r(54)=-0.304, p=0.025). CONCLUSION: The study contributes to understanding the relationship between reduced cortical thickness in left IFG and increased functional activity in cognitively normal individuals with mild SVF impairment, providing implications on potential compensatory mechanisms for cognitive preservation.

Blood metabolites, neurocognition and psychiatric disorders: a Mendelian randomization analysis to investigate causal pathways.

BACKGROUND: Neurocognitive dysfunction is observationally associated with the risk of psychiatric disorders. Blood metabolites, which are readily accessible, may become highly promising biomarkers for brain disorders. However, the causal role of blood metabolites in neurocognitive function, and the biological pathways underlying their association with psychiatric disorders remain unclear. METHODS: To explore their putative causalities, we conducted bidirectional two-sample Mendelian randomization (MR) using genetic variants associated with 317 human blood metabolites (nmax = 215,551), g-Factor (an integrated index of multiple neurocognitive tests with nmax = 332,050), and 10 different psychiatric disorders (n = 9,725 to 807,553) from the large-scale genome-wide association studies of European ancestry. Mediation analysis was used to assess the potential causal pathway among the candidate metabolite, neurocognitive trait and corresponding psychiatric disorder. RESULTS: MR evidence indicated that genetically predicted acetylornithine was positively associated with g-Factor (0.035 standard deviation units increase in g-Factor per one standard deviation increase in acetylornithine level; 95% confidence interval, 0.021 to 0.049; P = 1.15 × 10-6). Genetically predicted butyrylcarnitine was negatively associated with g-Factor (0.028 standard deviation units decrease in g-Factor per one standard deviation increase in genetically proxied butyrylcarnitine; 95% confidence interval, -0.041 to -0.015; P = 1.31 × 10-5). There was no evidence of associations between genetically proxied g-Factor and metabolites. Furthermore, the mediation analysis via two-step MR revealed that the causal pathway from acetylornithine to bipolar disorder was partly mediated by g-Factor, with a mediated proportion of 37.1%. Besides, g-Factor mediated the causal pathway from butyrylcarnitine to schizophrenia, with a mediated proportion of 37.5%. Other neurocognitive traits from different sources provided consistent findings. CONCLUSION: Our results provide genetic evidence that acetylornithine protects against bipolar disorder through neurocognitive abilities, while butyrylcarnitine has an adverse effect on schizophrenia through neurocognition. These findings may provide insight into interventions at the metabolic level for risk of neurocognitive and related disorders.

Construction of Metal/Zeolite Hybrid Nanoframe Reactors via in-Situ-Kinetics Transformations.

Metal/zeolite hybrid nanoframes featuring highly accessible compartmental environments, abundant heterogeneous interfaces, and diverse chemical compositions are expected to possess significant potential for heterogeneous catalysis, yet their general synthetic methodology has not yet been established. In this study, we developed a two-step in-situ-kinetics transformation approach to prepare metal/ZSM-5 hybrid nanoframes with exceptionally open nanostructures, tunable metal compositions, and abundant accessible active sites. Initially, the process involved the formation of single-crystalline ZSM-5 nanoframes through an anisotropic etching and recrystallization kinetic transformation process. Subsequently, through an in situ reaction of the Ni2+ ions and the silica species etched from ZSM-5 nanoframes, layered nickel silicate emerged on both the inner and outer surfaces of the zeolite nanoframes. Upon reduction under a hydrogen atmosphere, well-dispersed Ni nanoparticles were produced and immobilized onto the ZSM-5 nanoframes. Strikingly, this strategy can be extended to immobilize a variety of ultrasmall monometallic and bimetallic alloy nanoparticles on zeolite nanoframes. Benefiting from the structural and compositional advantages, the resultant hybrid nanoframes with a high loading of discrete Ni nanoparticles exhibited enhanced performance in the hydrodeoxygenation of stearic acid into liquid fuels. Overall, the methodology shares fresh insights into the rational construction of intricate frame-like metal/zeolite hybrid nanoreactors for many potential catalytic applications.

Promising Approach for Optimizing In Vivo Fluorescence Imaging in a Tumor Mouse Model: Precision in Cancer Research.

BACKGROUND/AIM: Cancer remains a major global health concern due to its high mortality rates. Advanced diagnostic imaging, such as in vivo near-infrared (NIR) fluorescence imaging, enhances early detection by reducing autofluorescence and enabling deeper tissue penetration, addressing some limitations of conventional methods. Understanding the underlying causes of autofluorescence, even in mouse model fluorescence imaging, is crucial for accurate interpretation. This study investigated the origins of autofluorescence observed in experimental animals under NIR wavelengths, achieving successful fluorescence imaging in a clinically relevant tumor mouse model. MATERIALS AND METHODS: Both fasting and non-fasting groups were evaluated to assess the dietary impact on autofluorescence, with various feeds tested. Subcutaneous and lung tumor models were established in C57BL/6 and BALB/c nude mice using LL/2-iRFP cells. Cryo-sectioning and lung tissue imaging were conducted to confirm tumor presence and assess fluorescence signals. RESULTS: It was found that autofluorescence, notably common in the abdomen, is attributed to dietary factors. By selecting feed that lacks autofluorescence, the impact of dietary fluorescence on imaging was evaluated, leading to the establishment of optimized imaging conditions suited to the presence or absence of autofluorescence. Subsequently, utilizing lung cancer cells expressing near-infrared proteins (LL/2-iRFP), intratracheal, and subcutaneous tumor mouse models were developed, and successful in vivo imaging was achieved using the optimized imaging protocols, effectively bypassing autofluorescence. CONCLUSION: This study emphasizes the importance of understanding and addressing autofluorescence in fluorescence imaging, presenting valuable insights for enhancing the reliability and accuracy of diagnostic imaging techniques in cancer research and clinical practice.

Masticatory Function, Sex, and Risk of Dementia Among Older Adults: A Population-Based Cohort Study.

BACKGROUND: A decline in masticatory function may indicate brain dysfunction related to dementia, but the relationship between masticatory function and dementia risk remains unclear. This study aimed to investigate whether masticatory function is associated with the risk of cognitive decline and dementia. METHODS: Data were obtained from the nationwide prospective cohort study of randomly sampled community-dwelling Koreans aged ≥ 60 years. The 5,064 non-demented participants, whose number of chewing cycles per bite was assessed by clinical interview, were followed for 8 years with biennial assessments of cognitive performance and clinical diagnoses of all-cause dementia and Alzheimer's disease (AD). Structural brain magnetic resonance imaging was collected from a subset of cohort participants and their spouses for imaging analyses. RESULTS: Males who chewed ≥ 30 cycles/bite had faster decline in global cognition and memory function and were at higher risk for incident all-cause dementia (hazard ratio [HR], 2.91; 95% confidence interval [CI], 1.18-7.18) and AD (HR, 3.22; 95% CI, 1.14-9.11) compared to males with less than 10 cycles/bite. Additionally, increased chewing cycles in males were associated with reduced brain volume, particularly in regions involved in compensatory cognitive control of mastication. There was no significant association between chewing cycles and the risk of dementia or brain volume in females. CONCLUSION: Older men who frequently chew their meals could be considered a notable population at risk for dementia who should be carefully assessed for their cognitive trajectories.

A Korean Family Presenting with Renal Cysts and Maturity-Onset Diabetes of the Young Caused by a Novel In-Frame Deletion of HNF1B.

Maturity-onset diabetes of the young (MODY; OMIM # 606391) comprises a cluster of inherited disorders within non-autoimmune diabetes mellitus (DM), typically emerging during adolescence or young adulthood. We report a novel in-frame deletion of HNF1B in a family with renal cysts and MODY, furthering our understanding of HNF1B-related phenotypes. We conducted sequential genetic testing to investigate the glucose intolerance, renal cysts, hepatic cysts, and agenesis of the dorsal pancreas observed in the proband. A comprehensive clinical exome sequencing approach using a Celemics G-Mendeliome Clinical Exome Sequencing Panel was employed. Considering the clinical manifestations observed in the proband, gene panel sequencing identified a heterozygous HNF1B variant, c.36_38delCCT/p.(Leu13del) (reference transcript ID: NM_000458.4), as the most likely cause of MODY in the proband. The patient's clinical presentation was consistent with MODY caused by the HNF1B variant, showing signs of glucose intolerance, renal cysts, hepatic cysts, and agenesis of the dorsal pancreas. Sanger sequencing confirmed the same HNF1B variant and established the paternally inherited autosomal dominant status of the heterozygous variant in the patient, as well as in his father and sister. The presence of early-onset diabetes, renal cysts, a family history of the condition, and nephropathy appearing before or after the diagnosis of diabetes mellitus (DM) suggests a diagnosis of HNF1B-MODY5. Early diagnosis is crucial for preventing complications of DM, enabling family screening, providing pre-conceptional genetic counseling, and monitoring kidney function decline.

Wet Mechanochemical Synthesis of BH4-Substituted Lithium Argyrodites.

In all-solid-state batteries, a solid electrolyte with high ionic conductivity is required for fast charging, uniform lithium deposition, and increased cathode capacity. Lithium argyrodite with BH4 - substitution has promising potential due to its higher ionic conductivity compared to argyrodites substituted with halides. In this study, Li5.25PS4.25(BH4)1.75, characterized by a high ionic conductivity of 13.8 mS cm-1 at 25 °C, is synthesized via wet ball-milling employing o-xylene. The investigation focused on optimizing wet ball-milling parameters such as ball size, xylene content, drying temperature, as well as the amount of BH4 - substitution in argyrodite. An all-solid-state battery prepared using Li5.25PS4.25(BH4)1.75 as the electrolyte and LiNbO3 coated NCM811 as the cathode exhibits an initial coulombic efficiency of 90.2% and maintains 93.9% of its initial capacity after 100 cycles at fast charging rate (5C). It is anticipated that the application of this wet mechanochemical synthesis will contribute further to the commercialization of all-solid-state batteries using BH4-substituted argyrodites.

Proteogenomic characterization identifies clinical subgroups in EGFR and ALK wild-type never-smoker lung adenocarcinoma.

Patients with lung adenocarcinoma who have never smoked (NSLA) and lack key driver mutations, such as those in the EGFR and ALK genes, face limited options for targeted therapies. They also tend to have poorer outcomes with immune checkpoint inhibitors than lung cancer patients who have a history of smoking. The proteogenomic profile of nonsmoking lung adenocarcinoma patients without these oncogenic driver mutations is poorly understood, which complicates the precise molecular classification of these cancers and highlights a significant area of unmet clinical need. This study analyzed the genome, transcriptome, and LC‒MS/MS-TMT-driven proteome data of tumors obtained from 99 Korean never-smoker lung adenocarcinoma patients. NSLA tumors without EGFR or ALK driver oncogenes were classified into four proteogenomic subgroups: proliferation, angiogenesis, immune, and metabolism subgroups. These 4 molecular subgroups were strongly associated with distinct clinical outcomes. The proliferation and angiogenesis subtypes were associated with a poorer prognosis, while the immune subtype was associated with the most favorable outcome, which was validated in an external lung cancer dataset. Genomic-wide impacts were analyzed, and significant correlations were found between copy number alterations and both the transcriptome and proteome for several genes, with enrichment in the ERBB, neurotrophin, insulin, and MAPK signaling pathways. Proteogenomic analyses suggested several targetable genes and proteins, including CDKs and ATR, as potential therapeutic targets in the proliferation subgroup. Upregulated cytokines, such as CCL5 and CXCL13, in the immune subgroup may serve as potential targets for combination immunotherapy. Our comprehensive proteogenomic analysis revealed the molecular subtypes of EGFR- and ALK-wild-type NSLA with significant unmet clinical needs.

Multiple remotely sensed datasets and machine learning models to predict chlorophyll-a concentration in the Nakdong River, South Korea.

The Nakdong River is a crucial water resource in South Korea, supplying water for various purposes such as potable water, irrigation, and recreation. However, the river is vulnerable to algal blooms due to the inflow of pollutants from multiple points and non-point sources. Monitoring chlorophyll-a (Chl-a) concentrations, a proxy for algal biomass is essential for assessing the trophic status of the river and managing its ecological health. This study aimed to improve the accuracy and reliability of Chl-a estimation in the Nakdong River using machine learning models (MLMs) and simultaneous use of multiple remotely sensed datasets. This study compared the performances of four MLMs: multi-layer perceptron (MLP), support vector machine (SVM), random forest (RF), and eXetreme Gradient Boosting (XGB) using three different input datasets: (1) two remotely sensed datasets (Sentinel-2 and Landsat-8), (2) standalone Sentinel-2, and (3) standalone Landsat-8. The results showed that the MLP model with multiple remotely sensed datasets outperformed other MLMs with 0.43 - 0.86 greater in R2 and 0.36 - 5.88 lower in RMSE. The MLP model demonstrated the highest performance across the range of Chl-a concentrations and predicted peaks above 20 mg/m3 relatively well compared to other models. This was likely due to the capacity of MLP to handle imbalanced datasets. The predictive map of the spatial distribution of Chl-a generated by MLP well captured the areas with high and low Chl-a concentrations. This study pointed out the impacts of imbalanced Chl-a concentration observations (dominated by low Chl-a concentrations) on the performance of MLMs. The data imbalance likely led to MLMs poorly trained for high Chl-a values, producing low prediction accuracy. In conclusion, this study demonstrated the value of multiple remotely sensed datasets in enhancing the accuracy and reliability of Chl-a estimation, mainly when using the MLP model. These findings would provide valuable insights into utilizing MLMs effectively for Chl-a monitoring.

A sensorineural hearing loss harboring novel compound heterozygous variant in the TRIOBP gene: A case report.

Background: Autosomal recessive non-syndromic deafness-28 (DFNB28; OMIM #609823) specifically refers to prelingual sensorineural hearing loss (SNHL) resulting from homozygous or compound heterozygous mutations in the TRIO- and F-actin-binding protein, TRIOBP gene. In this report, we present a pediatric patient exhibiting novel compound heterozygous deleterious variants in the TRIOBP gene. Methods: The auditory brainstem response result revealed both left- and right-sided deafness with a threshold of 20 dB normal hearing level in the proband. A comprehensive trio whole exome sequencing (WES) using the Celemics G-Mendeliome Whole Exome Sequencing Panel was employed. Results: The WES analysis revealed compound heterozygous TRIOBP variants in the proband, namely c.1192_1195delCAACinsT/p.Gln398* classified as pathogenic and c.3661C > T/p.Arg1221Trp categorized as a variant of uncertain significance according to American College of Medical Genetics and Genomics guidelines. These variants are considered the most probable cause of the proband's SNHL. Conclusion: TRIOBP isoforms are predominantly expressed in the inner ear, contributing to the formation of stereocilia rootlets. Further investigations are required to fully understand the phenotypic variability and establish the pathogenicity of the identified variant in relation to the TRIOBP gene and SNHL.

Construction and Preparation of the Novel ADN/CL-20 Cocrystal via Directional Hydrogen Bonding Design for Turning Hygroscopicity.

Ammonium dinitramide (ADN), as a novel and environmentally friendly oxidizer, has strong hygroscopicity when exposed to high-humidity air, which seriously hinders its application in solid propellants. Modification of oxidizers by cocrystallization is an effective strategy to improve the hygroscopicity of energetic components. In this paper, the theoretical simulation of ADN/CL-20 cocrystals was developed via a directional hydrogen bonding design to establish a cocrystal with improved hygroscopicity. Intermolecular interaction analyses reveal that hydrogen bonds and van der Waals interactions synergistically lead to the formation of cocrystals. The ADN/CL-20 cocrystal was prepared experimentally by the spray drying self-assembly technique, and the corresponding thermal analysis and sensitivity properties were conducted to illustrate the thermal stability and high safety. Furthermore, the critical relative humidity (CRH) measurement was carried out to evaluate the hygroscopicity of the cocrystal, exhibiting a certain degree of antihygroscopic effect with a CRH of 65%. The hydrogen bonds formed between ADN and CL-20 saturate the ammonium ions of ADN, further preventing ADN from absorbing water molecules in the air. The ADN/CL-20 cocrystal has high specific impulse characteristics (Isp: 272.6 s). Accordingly, this work clearly demonstrates that the ADN/CL-20 cocrystal is expected to be used in a solid propellant to make up for the deficiency of the ADN oxidizer.