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This study aims to investigate the effect of maternal nicotine exposure on the gene expression profiles in the liver of offspring mice. Pregnant mice were subcutaneously injected with either saline vehicle or nicotine twice a day on gestational days 11-21. Total RNA from the liver samples which collected from the offspring mice of postnatal day 7 and 21 was subjected to RNA sequencing. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis were conducted to identify the functions of differentially expressed genes (DEGs). Four genes were selected for further validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A total of 448 DEGs and 186 DEGs were identified on postnatal day 7 and 21, respectively. GO analysis revealed that the DEGs on postnatal day 7 mainly participated in the biological functions of cell growth and proliferation, and the DEGs on postnatal day 21 mainly participated in ion transport/activity. KEGG enrichment analysis showed that the DEGs on postnatal day 7 were mainly enriched in the cell cycle, cytokine-cytokine receptor interactions, hypertrophic cardiomyopathy, and the p53 signaling pathway, while the DEGs on postnatal day 21 were mainly enriched in neuroactive ligand-receptor interactions, the calcium signaling pathway, retinol metabolism, and axon guidance. The qRT-PCR results were consistent with the RNA sequencing data. The DEGs may affect the growth of liver in early postnatal period while may affect ion transport/activity in late postnatal period., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Purpose: To evaluate the association between the change in the number of PIMs in older adults during hospitalization and adverse outcomes., Methods: This retrospective cohort study was conducted in the internal medicine wards of a tertiary teaching hospital between May and December 2017. 3,460 patients (77.5±8.4 years, 60.4% male) were enrolled, and 206 patients died during hospitalization. PIMs were defined using the Beers Criteria as suggested by the American Geriatrics Society. Adverse outcomes studied were functional decline (a loss in 1 or more activities of daily living from admission to discharge), prolonged length of stay (LOS) (≥14 days), and mortality., Results: 2258 patients (65.3%) had increasing PIMs during hospitalization. They tended to be younger (77.0±8.3 versus 78.5±8.5 years, p<0.001) and had lower numbers of PIMs at admission (0.4±0.8 versus 0.8±1.1, p<0.001). Increasing PIM use was strongly associated with greater functional decline (aOR 1.36, 95%CI 1.01-1.67, p=0.005), prolonged LOS (aOR 3.47, 95%CI 2.71-4.44, p<0.001) and higher mortality rate (aOR 2.68, 95%CI 1.75-4.12, p<0.001), even after adjusting for all covariates. We observed a strong association between adverse outcomes and increasing PIMs in older adults during hospitalization (p for trend <0.001)., Conclusions: Older adults with increasing PIMs during hospitalization were at greater risk for functional decline, prolonged LOS, and mortality, especially in those with three or more PIMs. Further studies are needed to better understand the complex interactions and to evaluate the effectiveness of intervention programs to lower PIM number and improve discharge outcomes for patients who had increasing PIM use during hospitalization., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Open tibial fractures are frequently encountered in high-energy traumas and can result in significant complications such as nonunion, osteomyelitis, and even amputation. Among open tibial fractures, Gustilo type IIIC cases are particularly challenging due to the concomitant occurrence of neurovascular injuries and soft tissue defects. This study aimed to assess factors that affect union time and complications in Gustilo IIIC tibial fractures., Methods: Patients who presented at our center with IIIC open tibial fractures from January 2000 to October 2020 were eligible for this retrospective analysis. Patient demographics, fracture characteristics, and the timing, number, and type of surgical intervention were documented. Outcomes of interest included union time, occurrence of osteomyelitis, and amputation. We performed univariate analyses including chi-squared test, Fischer's exact test, analysis of variance, and Kruskal-Wallis test based on the normality of the data and multivariate analyses including Cox proportional hazards model and logistic regression analyses., Results: Fifty-eight patients were enrolled and grouped by fracture healing time; eight had timely union (13.8%); 27 had late union (46.6%); eight had delayed union (13.8%); three had nonunion (5.2%); and 12 underwent amputation (20.7%). Nine fractures (15.5%) were complicated by osteomyelitis. Union time was prolonged in cases of triple arterial injury, distal third fractures, multiple trauma with injury severity score (ISS) ≥ 16 points, and increased bone defect length. Additionally, a bone gap >50 mm, diabetes mellitus, low body mass index, and triple arterial injury in the lower leg were significant risk factors for amputation. A time from injury to definitive soft tissue coverage of more than 22 days was the major risk factor for osteomyelitis. A scoring system to predict union time was devised and the predicted probability of union within 2 years was stratified based on this score., Conclusion: IIIC tibial fractures involving the distal third of the tibia, fractures with bone defects, triple arterial injury, and multiple trauma with ISS ≥16 points demonstrated delayed union, and an effective prediction system for union time was introduced in this study. Early soft tissue coverage can reduce the risk of osteomyelitis. Finally, diabetes and severe bone and soft tissue defects pose a higher risk of amputation., (© 2023 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Purpose: The Blood First Assay Screening Trial (BFAST) is a prospective study using next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) in treatment-naïve advanced/metastatic non-small-cell lung cancer (NSCLC). We compared liquid biopsy to tissue testing and analyzed genomic alterations in Taiwanese patients with NSCLC using the BFAST database., Materials and Methods: A total of 269 patients underwent FoundationOne Liquid Companion Diagnostic (F1LCDx) assay at the National Taiwan University Hospital, of whom 264 underwent tissue-based genetic testing also. We analyzed the actionable mutations and the concordance between tissue-based genetic testing, which was limited to EGFR , ALK , ROS1 , and BRAF , in a real-life clinical setting and blood-based NGS in the clinical trial. Additionally, we analyzed the co-occurring genomic alterations from the blood-based ctDNA assay., Results: A total of 76.2% patients showed actionable mutations. Standard tissue testing did not detect known driver alterations in about 22.7% of the patients (sensitivity, 70.24%). Liquid NGS detected additional mutations ( RET , KRAS , MET , and ErbB2 ) in 14% of the patients, which went undetected by the standard-of-care testing. The complementary use of ctDNA NGS increased the detection rate by 42%. The F1LCDx assay had a sensitivity of 83.41%. Lower tumor and metastasis stages predicted nondetected blood-based NGS ctDNA results. Common co-occurring mutations in the blood-based NGS ctDNA assay were TP53 , DNMT3A , TET2 , PIK3CA , CTNNB1 , and RB1 . Among the patients with EGFR-mutated NSCLC, TET2 co-occurring alterations correlated with shorter progression-free survival of EGFR tyrosine kinase inhibitor treatment., Conclusion: NGS ctDNA analysis in comprehensive genetic testing improves actionable mutation identification, vital for treating Asian NSCLC cases with high actionable mutation rates. Lower stages correlated with undetected blood-based NGS ctDNA assay results.

Introduction: In real-world practice, most non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are exposed to short-course corticosteroids following immune checkpoint inhibitor (ICI) infusion to prevent chemotherapy-related adverse events. However, whether this early short-course corticosteroid use prevents immune-related adverse events (irAEs) remains unknown., Methods: Between January 1st, 2015, and December 31st, 2020, NSCLC patients who received at least one cycle of ICI with or without chemotherapy were enrolled. Early short-course corticosteroids were defined as corticosteroids administered following ICI injection and before chemotherapy on the same day and no longer than 3 days afterward. The patients were categorized as either "corticosteroid group" or "non-corticosteroid group" depending on their exposure to early short-course corticosteroid. The frequencies of irAEs requiring systemic corticosteroid use and irAEs leading to ICI discontinuation were compared between the two groups, and exploratory survival analyses were performed., Results: Among 252 eligible patients, 137 patients were categorized as "corticosteroid group" and 115 patients as "non-corticosteroid group." The corticosteroid group enriched patients in the first-line setting (n = 75, 54.7%), compared to the non-corticosteroid group (n = 28, 24.3%). Thirty patients (21.9%) in the corticosteroid group and 35 patients (30.4%) in the non-corticosteroid group developed irAEs requiring systemic corticosteroid use (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35-1.18; p = 0.15). Eight patients (5.8%) in the corticosteroid group, as compared with 18 patients (15.7%) in the non-corticosteroid group, permanently discontinued ICI due to irAEs (OR, 0.34; 95% CI, 0.12-0.85; p = 0.013)., Conclusion: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that lead to ICIs discontinuation, warranting further investigation of its prophylactic use to mitigate clinically significant irAEs., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50-64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis., (© 2023. The Author(s).)

Purpose: Accurate predictions of postoperative pain intensity are necessary for customizing analgesia plans. Insomnia is a risk factor for severe postoperative pain. Moreover, heart rate variability (HRV) can provide information on the sympathetic-parasympathetic balance in response to noxious stimuli. We developed a prediction model that uses the insomnia severity index (ISI), HRV, and other demographic factors to predict the odds of higher postoperative pain., Methods: We recruited gynecological surgery patients classified as American Society of Anesthesiologists class 1-3. An ISI questionnaire was completed 1 day before surgery. HRV was calculated offline using intraoperative electrocardiogram data. Pain severity at the postanesthesia care unit (PACU) was assessed with the 0-10 numerical rating scale (NRS). The primary outcome was the model's predictive ability for moderate-to-severe postoperative pain. The secondary outcome was the relationship between individual risk factors and opioid consumption in the PACU., Results: Our study enrolled 169 women. Higher ISI scores (p = 0.001), higher parasympathetic activity (rMSSD, pNN50, HF; p < 0.001, p < 0.001, p < 0.001), loss of fractal dynamics (SD2, alpha 1; p = 0.012, p = 0.039) in HRV analysis before the end of surgery were associated with higher NRS scores, while laparoscopic surgery (p = 0.031) was associated with lower NRS scores. We constructed a multiple logistic model (area under the curve = 0.852) to predict higher NRS scores at PACU arrival. The five selected predictors were age (OR: 0.94; p = 0.020), ISI score (OR: 1.14; p = 0.002), surgery type (laparoscopic or open; OR: 0.12; p < 0.001), total power (OR: 2.02; p < 0.001), and alpha 1 (OR: 0.03; p < 0.001)., Conclusion: We employed a multiple logistic regression model to determine the likelihood of moderate-to-severe postoperative pain upon arrival at the PACU. Physicians could personalize analgesic regimens based on a deeper comprehension of the factors that contribute to postoperative pain., (© 2023 World Institute of Pain.)

Introduction: According to current International Association for the Study of Lung Cancer guideline, physicians may first use plasma cell-free DNA (cfDNA) methods to identify epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-resistant mechanisms (liquid rebiopsy) for lung cancer. Tissue rebiopsy is recommended if the plasma result is negative. However, this approach has not been evaluated prospectively using next-generation sequencing (NGS)., Methods: We prospectively enrolled patients with lung cancer with first-line EGFR-TKI resistance who underwent tissue rebiopsy. The rebiopsied tissues and cfDNA were sequenced using targeted NGS, ACTDrug®+, and ACTMonitor®Lung simultaneously. The clinicopathological characteristics and treatment outcomes were analyzed., Results: Totally, 86 patients were enrolled. Twenty-six (30%) underwent tissue biopsy but the specimens were inadequate for NGS. Among the 60 patients with paired tissue and liquid rebiopsies, two-thirds (40/60) may still be targetable. T790M mutations were found in 29, including 14 (48%) only from tissue and 5 (17%) only from cfDNA. Twenty-four of them were treated with osimertinib, and progression-free survival was longer in patients without detectable T790M in cfDNA than in patients with detectable T790M in cfDNA (p = 0.02). For the 31 T790M-negative patients, there were six with mesenchymal-epithelial transition factor (MET) amplifications, four with ERBB2 amplifications, and one with CCDC6-RET fusion. One with MET amplification and one with ERBB2 amplification responded to subsequent MET and ERBB2 targeting agents respectively., Conclusions: NGS after EGFR-TKI resistance may detect targetable drivers besides T790M. To do either liquid or tissue NGS only could miss patients with T790M. To do tissue and liquid NGS in parallel after EGFR-TKI resistance may find more patients with targetable cancers., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The herbicide ioxynil (IOX) and the synthetic estrogen diethylstilbestrol (DES) are environmentally relevant contaminants that act as endocrine disruptors (EDCs) and have recently been shown to be cardiovascular disruptors in vertebrates. Mussels, Mytilus coruscus, were exposed to low doses of IOX (0.37, 0.037 and 0.0037 mg/L) and DES (0.27, 0.027 and 0.0027 mg/L) via the water and the effect monitored by generating whole animal transcriptomes and measuring cardiac performance and shell growth. One day after IOX (0.37 and 0.037 mg/L) and DES (0.27 and 0.027 mg/L) exposure heart rate frequency was decreased in both groups and 0.27 mg/L DES significantly reduced heart rate frequency with increasing time of exposure (P < 0.05) and no acclimatization occurred. The functional effects were coupled to significant differential expression of genes of the serotonergic synapse pathway and cardiac-related genes at 0.027 mg/L DES, which suggests that impaired heart function may be due to interference with neuroendocrine regulation and direct cardiac effect genes. Multiple genes related to detoxifying xenobiotic substances were up regulated and genes related to immune function were down regulated in the DES group (vs. control), indicating that detoxification processes were enhanced, and the immune response was depressed. In contrast, IOX had a minor disrupting effect at a molecular level. Of note was a significant suppression (P < 0.05) by DES of shell growth in juveniles and lower doses (< 0.0027 mg/L) had a more severe effect. The shell growth depression in 0.0027 mg/L DES-treated juveniles was not accompanied by abundant differential gene expression, suggesting that the effect of 0.0027 mg/L DES on shell growth may be direct. The results obtained in the present study reveal for the first time that IOX and DES may act as neuroendocrine disrupters with a broad spectrum of effects on cardiac performance and shell growth, and that DES exposure had a much more pronounced effect than IOX in a marine bivalve., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Codon usage bias (CUB) refers to different codons exhibiting varying frequencies of usage in the genome. Studying CUB is crucial for understanding genome structure, function, and evolutionary processes. Herein, we investigated the codon usage patterns and influencing factors of protein-coding genes in the chloroplast genomes of four sister genera (monophyletic Roscoea and Cautleya , and monophyletic Pommereschea and Rhynchanthus ) from the Zingiberaceae family with contrasting habitats in southwestern China. These genera exhibit distinct habitats, providing a unique opportunity to explore the adaptive evolution of codon usage. We conducted a comprehensive analysis of nucleotide composition and codon usage on protein-coding genes in the chloroplast genomes. The study focused on understanding the relationship between codon usage and environmental adaptation, with a particular emphasis on genes associated with photosynthesis. Nucleotide composition analysis revealed that the overall G/C content of the coding genes was ˂ 48%, indicating an enrichment of A/T bases. Additionally, synonymous and optimal codons were biased toward ending with A/U bases. Natural selection is the primary factor influencing CUB characteristics, particularly photosynthesis-associated genes. We observed differential gene expressions related to light adaptation among sister genera inhabiting different environments. Certain codons were favored under specific conditions, possibly contributing to gene expression regulation in particular environments. This study provides insights into the adaptive evolution of these sister genera by analyzing CUB and offers theoretical assistance for understanding gene expression and regulation. In addition, the data support the relationship between RNA editing and CUB, and the findings shed light on potential research directions for investigating adaptive evolution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Xin, Xiao, Lin, Li and Zhao.)

Mixed ionic-electronic conducting (MIEC) thermoelectric (TE) materials offer higher ionic conductivity and ionic Seebeck coefficient compared to those of purely ionic-conducting TE materials. These characteristics make them suitable for direct use in thermoelectric generators (TEGs) as the charge carriers can be effectively transported from one electrode to the other via the external circuit. In the present study, MIEC hydrogels are fabricated via the chemical cross-linking of polyacrylamide (PAAM) and polydopamine (PDA) to form a double network. In addition, electrically conducting carboxylated carbon nanotubes (CNT-COOH) are dispersed evenly within the hydrogel via sonication and interaction with the PDA. Moreover, the electrical properties of the hydrogel are further improved via the in situ polymerization of polyaniline (PANI). The presence of CNT-COOH facilitates the ionic conductivity and enhances the ionic Seebeck coefficient via ionic-electronic interactions between sodium ions and carboxyl groups on CNT-COOH, which can be observed in X-ray photoelectron spectroscopy results, thereby promoting the charge transport properties. As a result, the optimum device exhibits a remarkable ionic conductivity of 175.3 mS cm -1 and a high ionic Seebeck coefficient of 18.6 mV K -1 , giving an ionic power factor (PF i ) of 6.06 mW m -1 K -2 with a correspondingly impressive ionic figure of merit (ZT i ) of 2.65. These values represent significant achievements within the field of gel-state organic TE materials. Finally, a wearable module is fabricated by embedding the PAAM/PDA/CNT-COOH/PANI hydrogel into a poly(dimethylsiloxane) mold. This configuration yields a high power density of 171.4 mW m -2 , thus highlighting the considerable potential for manufacturing TEGs for wearable devices capable of harnessing waste heat.

Milkfish (Chanos chanos) are important euryhaline fish in Southeast Asian countries that can tolerate a wide range of salinity changes. Previous studies have revealed that milkfish have strong ion regulation and survival abilities under osmotic stress. In addition to ion regulation, water homeostasis in euryhaline teleosts is important during environmental salinity shifts. Aquaporins (AQP) are vital water channels in fish, and different AQPs can transport water influx or outflux from the body. AQP3 is one of the AQP channels, and the function of AQP3 in the gills of euryhaline milkfish is still unknown. The aim of this study was to investigate the expression and localization of AQP3 in the gills of euryhaline milkfish to contribute to our understanding of the physiological role and localization of AQP3 in fish. The AQP3 sequence was found in the milkfish next-generation sequencing (NGS) database and is mainly distributed in the gills of freshwater (FW)-acclimated milkfish. Under hypoosmotic and hyperosmotic stress, the osmolality of milkfish immediately shifted, similar to the aqp3 gene expression. Moreover, the abundance of AQP3 protein significantly decreased 3 h after transferring milkfish from FW to seawater (SW). However, there was no change within 7 days when the milkfish experienced hypoosmotic stress. Moreover, double immunofluorescence staining of milkfish gills showed that AQP3 colocalized with Na + /K + ATPase at the basolateral membrane of ionocytes. These results combined indicate that milkfish have a strong osmoregulation ability under acute osmotic stress because of the quick shift in the gene and protein expression of AQP3 in their gills., (© 2023 Wiley Periodicals LLC.)

Purpose: This retrospective cohort study was to assess the prognostic value of preoperative geriatric nutritional risk index (GNRI) on survival outcomes for patients with locally advanced oral squamous cell carcinoma (LAOSCC)., Methods: Patients with LAOSCC receiving upfront radical surgery at a single institute from January 2007 to February 2017 were enrolled. The primary outcomes in the study were 5-year overall survival (OS) and cancer-specific survival (CSS) rates, and a nomogram based on GNRI and other clinical-pathological factors was established for individualized OS prediction., Results: There were 343 patients enrolled in this study. The optimal cut-off value of GNRI was observed to be 97.8. Patients in the high-GNRI group (GNRI ≥97.8) had statistically significantly better outcomes in 5-year OS (74.7% vs. 57.2%, p = 0.001) and CSS (82.2% vs. 68.9%, p = 0.005) when compared with the low-GNRI group (GNRI <97.8). In Cox models, low GNRI remained an independent negative prognosticator of OS (HR: 1.6; 95% CI: 1.124-2.277; p = 0.009) and CSS (HR: 1.907; 95% CI: 1.219-2.984; p = 0.005). The c-index of the proposed nomogram, incorporating assorted clinicopathological factors and GNRI, had a statistically significant increase compared with the predictive nomogram constructed by the TNM staging system alone (0.692 vs. 0.637, p < 0.001).", Conclusion: Preoperative GNRI is an independent prognostic factor of OS and CSS in patients with LAOSCC. A multivariate nomogram that includes GNRI may better help us to accurately estimate individual survival outcomes., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Purpose: Endotype-driven treatment has been introduced in the management of chronic rhinosinusitis with nasal polyps (CRSwNP), and an understanding of the associations between phenotypes and endotypes of CRSwNP will be beneficial in identifying responders. We aimed to determine the correlations between clinical manifestations and type 2 inflammatory mediators of sinonasal tissues., Methods: Adult patients undergoing endoscopic sinus surgery for bilateral CRSwNP were prospectively enrolled. Tissue eosinophilia and type 2 mediator expression in tissue homogenates were assessed and correlated with clinical features, including symptoms, comorbidities, blood eosinophil counts, specific allergen immunoglobulin (IgE) testing, computed tomography (CT) scan findings, and Sino-Nasal Outcome Test-22 scores., Results: A total of 93 subjects were recruited in our study. Fifty-nine (63.4%) cases were identified as the eosinophilic endotype, demonstrating with higher rates of comorbidity of asthma, blood eosinophilia and a high ethmoid-maxillary ratio on CT images. To correlate of phenotypes with the inflammatory mediator profile, multivariate analyses revealed the associations of IgE expression in nasal polyp tissues with allergen sensitization (p = 0.042), CT ethmoid-maxillary ratio (p = 0.001) and tissue eosinophil counts (p = 0.022); the association of interleukin (IL-5) expression with the blood eosinophil percentage (p = 0.020); and the association of IL-13 expression with white blood cell count (p = 0.002) and central compartment-type inflammation (p < 0.001)., Conclusion: We demonstrated associations of IgE and IL-5 expression with clinical features of eosinophilic-type inflammation and a significantly elevated level of IL-13 in patients with central-compartment-type CRSwNP. These observations may be useful when considering the use of type 2 biologic treatment and require further validation studies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Coronavirus disease-2019 (COVID-19) remains a global public health concern, and remdesivir plus dexamethasone combination therapy is suggested for patients with severe disease. However, the factors associated with poor outcomes in these patients remain unclear. We identified the factors associated with poor outcomes in Taiwanese patients with severe COVID-19 treated with remdesivir plus dexamethasone., Methods: Adults with severe COVID-19 (oxygen saturation <94% on room air or requiring supplemental oxygen) treated with remdesivir and dexamethasone were identified between 1 May and 31 July 2021. The main outcomes were 14-day non-recovery, 28-day mortality, and progression to respiratory failure requiring invasive mechanical ventilation or death in initially non-ventilated patients. The prognostic factors associated with poor outcomes were analyzed by multivariate logistic regression and Cox regression., Results: Of the 110 patients treated with remdesivir and dexamethasone, 57 (51.8%) recovered within 14 days and 6 (5.5%) died within 28 days. Of the 89 initially non-ventilated patients, 12 (13.5%) progressed to respiratory failure or death. Charlson Comorbidity Index, SOFA score, and admission to remdesivir treatment interval were associated with 14-day non-recovery. C-reactive protein level was associated with 28-day mortality. Pneumonia Severity Index and admission to remdesivir treatment interval were associated with progression to respiratory failure requiring invasive mechanical ventilation or death in initially non-ventilated patients., Conclusion: High disease severity on admission and delayed initiation of remdesivir therapy were associated with poor outcomes in COVID-19 patients treated with remdesivir and dexamethasone., (Copyright © 2023. Published by Elsevier B.V.)

Objectives. Current approaches via physiological features detecting aberrant driving behaviour (ADB), including speeding, abrupt steering, hard braking and aggressive acceleration, are developing. This study proposes using machine learning approaches incorporating heart rate variability (HRV) parameters to predict ADB occurrence. Methods . Naturalistic driving data of 10 highway bus drivers in Taiwan from their daily routes were collected for 4 consecutive days. Their driving behaviours and physiological data during a driving task were determined using a navigation mobile application and heart rate watch. Participants' self-reported data on sleep, driving-related experience, open-source data on weather and the traffic congestion level were obtained. Five machine learning models - logistic regression, random forest, naive Bayes, support vector machine and gated recurrent unit (GRU) - were employed to predict ADBs. Results . Most drivers with ADB had low sleep efficiency (≤80%), with significantly higher scores in driver behaviour questionnaire subcategories of lapses and errors and in the Karolinska sleepiness scale than those without ADBs. Moreover, HRV parameters were significantly different between baseline and pre-ADB event measurements. GRU had the highest accuracy (81.16-84.22%). Conclusions . Sleep deficit may be related to the increased fatigue level and ADB occurrence predicted from HRV-based models among bus drivers.

This study investigated combination of the Rapid Sepsityper Kit and a machine learning (ML)-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) approach for rapid prediction of methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Klebsiella pneumoniae (CRKP) from positive blood culture bottles. The study involved 461 patients with monomicrobial bloodstream infections. Species identification was performed using the conventional MALDI-TOF MS Biotyper system and the Rapid Sepsityper protocol. The data underwent preprocessing steps, and ML models were trained using preprocessed MALDI-TOF data and corresponding labels. The interpretability of the model was enhanced using SHapely Additive exPlanations values to identify significant features. In total, 44 S. aureus isolates comprising 406 MALDI-TOF MS files and 126 K. pneumoniae isolates comprising 1249 MALDI-TOF MS files were evaluated. This study demonstrated the feasibility of predicting MRSA among S. aureus and CRKP among K. pneumoniae isolates using MALDI-TOF MS and Sepsityper. Accuracy, area under the receiver operating characteristic curve, and F1 score for MRSA/methicillin-susceptible S. aureus were 0.875, 0.898 and 0.904, respectively; for CRKP/carbapenem-susceptible K. pneumoniae, these values were 0.766, 0.828 and 0.795, respectively. In conclusion, the novel ML-based MALDI-TOF MS approach enables rapid identification of MRSA and CRKP from flagged blood cultures within 1 h. This enables earlier initiation of targeted antimicrobial therapy, reducing deaths due to sepsis. The favourable performance and reduced turnaround time of this method suggest its potential as a rapid detection strategy in clinical microbiology laboratories, ultimately improving patient outcomes., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Exosome therapy is a novel trend in regeneration medicine. However, identifying a suitable biomarker that can associate the therapeutic efficacy of exosomes with SCA3/MJD is essential. In this study, parental cells were preconditioned with butylidenephthalide (Bdph) for exosome preparation to evaluate the therapeutic effect of SCA3/MJD. The therapeutic agent hsa-miRNA-6780-5p was enriched up to 98-fold in exosomes derived from butylidenephthalide (Bdph)-preconditioned human olfactory ensheathing cells (hOECs) compared with that in naïve hOECs exosomes. The particle sizes of exosomes derived from naïve hOECs and those derived from hOECs preconditioned with Bdph were approximately 113.0 ± 3.5 nm and 128.9 ± 0.7 nm, respectively. A liposome system was used to demonstrate the role of hsa-miRNA-6780-5p, wherein hsa-miRNA-6780-5p was found to enhance autophagy and inhibit the expression of spinocerebellar ataxia type 3 (SCA3) disease proteins with the polyglutamine (polyQ) tract. Exosomes with enriched hsa-miRNA-6780-5p were further applied to HEK-293-84Q cells, leading to decreased expression of polyQ and increased autophagy. The results were reversed when 3MA, an autophagy inhibitor, was added to the cells treated with hsa-miRNA-6780-5p-enriched exosomes, indicating that the decreased polyQ expression was modulated via autophagy. SCA3 mice showed improved motor coordination behavior when they intracranially received exosomes enriched with hsa-miRNA-6780-5p. SCA3 mouse cerebellar tissues treated with hsa-miRNA-6780-5p-enriched exosomes showed decreased expression of polyQ and increased expression of LC3II/I, an autophagy marker. In conclusion, our findings can serve as a basis for developing an alternative therapeutic strategy for SCA3 disease treatment using miRNA-enriched exosomes derived from chemically preconditioned cells., (Copyright © 2023. Published by Elsevier B.V.)

The initial contagiousness of a communicable disease within a given population is quantified by the basic reproduction number, R 0 . This number depends on both pathogen and population properties. On the basis of compartmental models that reproduce Coronavirus Disease 2019 (COVID-19) surveillance data, we used Bayesian inference and the next-generation matrix approach to estimate region-specific R 0 values for 280 of 384 metropolitan statistical areas (MSAs) in the United States (US), which account for 95% of the US population living in urban areas and 82% of the total population. We focused on MSA populations after finding that these populations were more uniformly impacted by COVID-19 than state populations. Our maximum a posteriori (MAP) estimates for R 0 range from 1.9 to 7.7 and quantify the relative susceptibilities of regional populations to spread of respiratory diseases. ONE-SENTENCE SUMMARY: Initial contagiousness of Coronavirus Disease 2019 varied over a 4-fold range across urban areas of the United States., Competing Interests: Declaration of Competing Interest Authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

We investigated clinical information underneath the beat-to-beat fluctuation of the arterial blood pressure (ABP) waveform morphology. We proposed the Dynamical Diffusion Map algorithm (DDMap) to quantify the variability of morphology.  The underlying physiology could be the compensatory mechanisms involving complex interactions between various physiological mechanisms to regulate the cardiovascular system. As a liver transplant surgery contains distinct periods, we investigated its clinical behavior in different surgical steps. Our study used DDmap algorithm, based on unsupervised manifold learning, to obtain a quantitative index for the beat-to-beat variability of morphology. We examined the correlation between the variability of ABP morphology and disease acuity as indicated by Model for End-Stage Liver Disease (MELD) scores, the postoperative laboratory data, and 4 early allograft failure (EAF) scores. Among the 85 enrolled patients, the variability of morphology obtained during the presurgical phase was best correlated with MELD-Na scores. The neohepatic phase variability of morphology was associated with EAF scores as well as postoperative bilirubin levels, international normalized ratio, aspartate aminotransferase levels, and platelet count. Furthermore, variability of morphology presents more associations with the above clinical conditions than the common BP measures and their BP variability indices. The variability of morphology obtained during the presurgical phase is indicative of patient acuity, whereas those during the neohepatic phase are indicative of short-term surgical outcomes., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Heart rhythm complexity (HRC), a subtype of heart rate variability (HRV), is an important tool to investigate cardiovascular disease. In this study, we aimed to analyze serial changes in HRV and HRC metrics in patients with inferior ST-elevation myocardial infarction (STEMI) within 1 year postinfarct and explore the association between HRC and postinfarct left ventricular (LV) systolic impairment. We prospectively enrolled 33 inferior STEMI patients and 74 control subjects and analyzed traditional linear HRV and HRC metrics in both groups, including detrended fluctuation analysis (DFA) and multiscale entropy (MSE). We also analyzed follow-up postinfarct echocardiography for 1 year. The STEMI group had significantly lower standard deviation of RR interval (SDNN), and DFAα2 within 7 days postinfarct (acute stage) comparing to control subjects. LF power was consistently higher in STEMI group during follow up. The MSE scale 5 was higher at acute stage comparing to control subjects and had a trend of decrease during 1-year postinfarct. The MSE area under scale 1-5 showed persistently lower than control subjects and progressively decreased during 1-year postinfarct. To predict long-term postinfarct LV systolic impairment, the slope between MSE scale 1 to 5 (slope 1-5) had the best predictive value. MSE slope 1-5 also increased the predictive ability of the linear HRV metrics in both the net reclassification index and integrated discrimination index models. In conclusion, HRC and LV contractility decreased 1 year postinfarct in inferior STEMI patients, and MSE slope 1-5 was a good predictor of postinfarct LV systolic impairment., (© 2023. The Author(s).)

Background: This study evaluated the cost-effectiveness of serplulimab plus chemotherapy versus chemotherapy alone in treating advanced/metastatic esophageal squamous cell carcinoma (ESCC) within the Chinese health care system., Methods: A partitioned survival model based on ASTRUM-007 trial patient characteristics was developed. Efficacy, safety, and medical/economic data were obtained from the trial and real-world clinical practice. Costs, quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICERs) were calculated for both treatment strategies. Sensitivity, subgroup, and scenario analyses were performed to assess the uncertainty impact., Results: Serplulimab combined with chemotherapy yielded an ICER of US$ 53,538.27/QALY. Deterministic sensitivity analysis identified patient survival and serplulimab price as influential parameters. Probabilistic sensitivity analysis showed a 47.33% probability of cost-effectiveness at a willingness-to-pay (WTP) threshold of US$ 53,541/QALY and 0.05% at three times China's GDP per capita. Subgroup analysis revealed that patients with a programmed death-ligand 1 (PD-L1) expression combined positive score (CPS) ⩾10 had a lower hazard ratio (0.59) and ICER (US$ 29,935.23/QALY), with a 95.36% probability of cost-effectiveness. Scenario analysis demonstrated that the drug donation discount policy significantly increased the likelihood of cost-effective serplulimab-chemotherapy combinations in Jiangsu, Fujian, and Guangdong at 99.99%, 99.90%, and 94.16%, respectively., Conclusion: Compared to chemotherapy alone, serplulimab combined with chemotherapy is currently not a cost-effective first-line treatment for advanced/metastatic ESCC in China. However, as serplulimab plus chemotherapy regimens evolve and price competition among programmed death 1 (PD-1) inhibitors intensifies, this combination may become a cost-effective treatment option., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Converging evidence indicates the beneficial effects of aerobic exercise on motor learning performance. Underlying mechanisms might be an impact of aerobic exercise on neuroplasticity and cortical excitability. Evidence suggests that motor learning and cortical excitability alterations correlate with the intensity of aerobic exercise and the activity level of participants. Thus, this study aims to investigate the effects of different aerobic exercise intensities on motor learning and cortical excitability in sedentary individuals. The study was conducted in a crossover and double-blind design. Twenty-six healthy sedentary individuals (13 women and 13 men) performed a motor learning task and received a cortical excitability assessment before and after a single session of low-, moderate-, and high-intensity aerobic exercise or a control intervention. The study revealed that motor learning performance and cortical excitability were significantly enhanced in the moderate-intensity aerobic exercise, compared with the other conditions. These findings suggest aerobic exercise intensity-dependent effects on motor learning in sedentary adults. The underlying mechanism might be an exercised-induced alteration of cortical excitability, specifically a reduction of GABA activity., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Kuo et al.)

We present a scheme to precisely resolve the unperturbed line shape of an optical rubidium clock transition in a high vacuum, by which we avoided the systematic errors of "collision shift" and "modulation shift." The spectral resolution resolved by this scheme is significantly improved such that we can use "Zeeman broadening" to inspect the stray magnetic field, through which we were able to compensate the magnetic field inside the Rb cells to be below 10- 3  Gauss. We thus update the absolute frequency of the clock transition and propose a standard operation procedure (SOP) for the clock self-calibration.

Purpose: To examine the use of multimodal data and multi-omics strategies for optic nerve disease screening., Methods: This was a single-center retrospective study. A deep learning model was created from fundus photography and infrared reflectance (IR) images of patients with diabetic optic neuropathy, glaucomatous optic neuropathy, and optic neuritis. Patients who were seen at the Ophthalmology Department of First Affiliated Hospital of Nanchang University in Jiangxi Province from November 2019 to April 2023 were included in this study. The data were analyzed in single and multimodal modes following the traditional omics, Resnet101, and fusion models. The accuracy and area-under-the-curve (AUC) of each model were compared., Results: A total of 312 images fundus and infrared fundus photographs were collected from 156 patients. When multi-modal data was used, the accuracy of the traditional omics mode, Resnet101, and fusion models with the training set were 0.97, 0.98, and 0.99, respectively. The accuracy of the same models with the test sets were 0.72, 0.87, and 0.88, respectively. We compared single- and multi-mode states by applying the data to the different groups in the learning model. In the traditional omics model, the macro-average AUCs of the features extracted from fundus photography, IR images, and multimodal data were 0.94, 0.90, and 0.96, respectively. When the same data were processed in the Resnet101 model, the scores were 0.97 equally. However, when multimodal data was utilized, the macro-average AUCs in the traditional omics, Resnet101, and fusion modesl were 0.96, 0.97, and 0.99, respectively., Conclusion: The deep learning model based on multimodal data and multi-omics strategies can improve the accuracy of screening and diagnosing diabetic optic neuropathy, glaucomatous optic neuropathy, and optic neuritis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Cellulose microfibrils (CMFs) are a major load-bearing component in plant cell walls. Thus, their structures have been studied extensively with spectroscopic and microscopic characterization methods, but the findings from these two approaches were inconsistent, which hampers the mechanistic understanding of cell wall mechanics. Here, we report the regiospecific assembly of CMFs in the periclinal wall of plant epidermal cells. Using sum frequency generation spectroscopic imaging, we found that CMFs are highly aligned in the cell edge region where two cells form a junction, whereas they are mostly isotropic on average throughout the wall thickness in the flat face region of the epidermal cell. This subcellular-level heterogeneity in the CMF alignment provided a new perspective on tissue-level anisotropy in the tensile modulus of cell wall materials. This finding also has resolved a previous contradiction between the spectroscopic and microscopic imaging studies, which paves a foundation for better understanding of the cell wall architecture, especially structure-geometry relationships.

Cardiovascular disease (CVD) and its risk factors seem to be linked with deteriorated graft function and persists as the major cause of mortality in kidney transplant recipients (KTRs). Diet quality is associated with CVD prevention in the healthy population, however, less study focuses on KTRs. The study aimed to determine the association between diet quality indices and lipid profile abnormalities as risk factors for CVD in KTRs. This prospective study enrolled 106 KTRs who had functioning allografts from September 2016. Lipid profiles included low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglyceride (TG) and were based on the National Cholesterol Education Program Adult Treatment Panel III recommendations. Three-day dietary data were collected by a well-trained registered dietitian. The Alternative Healthy Eating Index-Taiwan (AHEI-Taiwan), Alternative Healthy Eating Index-2010 (AHEI-2010), and Healthy Eating Index-2015 (HEI-2015) scores were calculated and divided into quartiles and compared accordingly. KTRs' mean LDL-C, HDL-C, TC, and TG levels were 119.8 ± 36.6 mg/dL, 52.0 ± 17.9 mg/dL, 205.8 ± 43.9 mg/dL, and 160.2 ± 121.6 mg/dL, respectively. Compared with the lowest quartile, only the highest quartile of AHEI-Taiwan had lower TC and LDL-C levels. After adjustment for age, gender, energy, Charlson comorbidity index, transplant duration, and dialysis duration, logistic regression analysis revealed that the highest quartile of AHEI-Taiwan had 82% (odds ratio [OR], 0.18; 95% confidence interval [CI] 0.04-0.72, p < 0.05) lower odds of high TC and 88% (OR 0.12; 95% CI 0.03-0.58, p < 0.05) lower odds of high LDL-C, and the highest quartile of HEI-2015 had 77% (OR 0.23; 95% CI 0.05-0.95, p < 0.05) lower odds of high LDL-C. Higher adherence to a healthy diet as per AHEI-Taiwan and HEI-2015 guidelines associated with lower risk of lipid profile abnormalities in KTRs., (© 2023. The Author(s).)

Background: Next-generation sequencing (NGS) of plasma cell-free DNA identifies driver mutations in advanced non-small cell lung cancer (NSCLC) and may complement routine molecular evaluation. The utility of liquid NGS at the start of tumour workup is undetermined., Methods: This is a randomised study of patients with suspected advanced NSCLC. All patients received blood liquid NGS testing at their first clinic visit and underwent standard histological diagnosis and tissue genotyping, encompassing polymerase chain reaction based methods for EGFR mutation, immunohistochemical (IHC) staining for ALK fusion and BRAF V600E mutation, and an IHC screening followed by confirmation using fluorescence in situ hybridization confirmation for ROS1 fusion. They were then randomly assigned to receive NGS results either after tissue genotyping (Group A) or as soon as possible after histological diagnosis of advanced NSCLC (Group B). The study measured time to start of systemic treatment as the primary endpoint and secondary endpoints included biomarker discovery rate, objective response rate (ORR), and progression-free survival (PFS)., Results: This study enroled 180 patients with suspected advanced NSCLC, randomised into two groups. 63 patients in Group A and 59 in Group B with advanced NSCLC were confirmed as advanced NSCLC and analysed. Most had adenocarcinoma (Group A: 77.8%, Group B: 79.7%). The prevalence of EGFR mutations in the two groups was similar (Group A: 57.1%; Group B: 56.6%). Other driver alterations were rare. The median time to treatment was shorter in Group B (20 days) than in Group A (28 days). ORR and PFS did not differ between groups significantly. Liquid NGS had high concordance with tissue testing and identified driver mutations in 42.6% (20/47) of tissue-negative cases., Conclusion: Performing liquid NGS at the initial clinic visit for suspected advanced NSCLC identifies more patients suitable for targeted therapies and shortens time to the start of treatment., Competing Interests: Declaration of Competing Interest Jin-Yuan Shih has received speaking honoraria from ACTgenomics, Amgen, Genconn Biotech, AstraZeneca, Roche, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Chugai Pharma, Takeda, CStone Pharmaceuticals, Janssen, TTY Biopharm, Orient EuroPharma, MundiPharma, Ono Pharmaceutical, and Bristol-Myers Squibb. Dr. Yen-Ting Lin has received speaking honoraria from ACT Genomics, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Illumina, Janssen, Manudipharma, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda. Dr. Cho-Chi Ho has received speaking honoraria from Amgen, Boehringer Ingelheim, Roche/Genentech/Chugai Pharmaceutical, Eli Lilly, Pfizer, and Merck Sharp & Dohme. Sujog Jain and Steve Olsen are both employess of Guardant Health and hold the stocks of Guardant Healths. James Chih-Hsin Yang has received advisory board and speaker honoraria from Boehringer Ingelheim, AstraZeneca, Roche/Genentech, Pfizer, Novartis, MSD, Merck Serono, Clovis Oncology, and Bayer. All remaining authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Postoperative free flap monitoring is a critical part of reconstructive microsurgery. Postoperative clinical assessments rely heavily on specialty-trained staff. Therefore, in regions with limited specialist availability, the feasibility of performing microsurgery is restricted. This study aimed to apply artificial intelligence in postoperative free flap monitoring and validate the ability of machine learning in predicting and differentiating types of postoperative free flap circulation., Methods: Postoperative data from 176 patients who received free flap surgery were prospectively collected, including free flap photographs and clinical evaluation measures. Flap circulation outcome variables included normal, arterial insufficiency, and venous insufficiency. The Synthetic Minority Oversampling Technique plus Tomek Links (SMOTE-Tomek) was applied for data balance. Data were divided into 80%:20% for model training and validation. Shapley Additive Explanations were used for prediction interpretations of the model., Results: Of 805 total included flaps, 555 (69%) were normal, 97 (12%) had arterial insufficiency, and 153 (19%) had venous insufficiency. The most effective prediction model was developed based on random forest, with an accuracy of 98.4%. Temperature and color differences between the flap and the surrounding skin were the most significant contributing factors to predict a vascular compromised flap., Conclusions: This study demonstrated the reliability of a machine-learning model in differentiating various types of postoperative flap circulation. This novel technique may reduce the burden of free flap monitoring and encourage the broader use of reconstructive microsurgery in regions with a limited number of staff specialists., (Copyright © 2023 by the American Society of Plastic Surgeons.)

A class of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones were designed and synthesized via Michael addition, cyclization, aldol condensation, and deprotonation to inhibit the human transmembrane protease serine 2 (TMPRSS2) and Furin, which are involved in priming the SARS-CoV-2 Spike for virus entry. The most potent inhibitor 2f (81) was found to efficiently inhibit the replication of various SARS-CoV-2 delta and omicron variants in VeroE6 and Calu-3 cells, with EC 50 range of 0.001-0.026 μM by pre-incubation with the virus to avoid the virus entry. The more potent antiviral activities than the proteases inhibitory activities led to discovery that the synthesized compounds also inhibited Spike's receptor binding domain (RBD):angiotensin converting enzyme 2 (ACE2) interaction as a main target, and their antiviral activities were enhanced by inhibiting TMPRSS2 and/or Furin. To further confirm the blocking effect of 2f (81) on virus entry, SARS-CoV-2 Spike pseudovirus was used in the entry assay and the results showed that the compound inhibited the pseudovirus entry in a ACE2-dependent pathway, via mainly inhibiting RBD:ACE2 interaction and TMPRSS2 activity in Calu-3 cells. Finally, in the in vivo animal model of SARS-CoV-2 infection, the oral administration of 25 mg/kg 2f (81) in hamsters resulted in reduced bodyweight loss and 5-fold lower viral RNA levels in nasal turbinate three days post-infection. Our findings demonstrated the potential of the lead compound for further preclinical investigation as a potential treatment for SARS-CoV-2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Bacterial communication interruption based on quorum quenching (QQ) has been proven its potential in biofilm formation inhibition and biofouling control. However, it would be more satisfying if QQ could be combined with the efficient degradation of contaminants in environmental engineering. In this study, we engineered a biofilm of Pseudomonas putida through introducing a QQ synthetic gene, which achieved both biofilm formation inhibition and efficient degradation of benzene series in wastewater. The aiiO gene introduced into the P. putida by heat shock method was highly expressed to produce QQ enzyme to degrade AHL-based signal molecules. The addition of this engineered P. putida reduced the AHLs concentration, quorum sensing gene expression, and connections of the microbial community network in activated sludge and therefore inhibited the biofilm formation. Meanwhile, the sodium benzoate degradation assay indicated an enhanced benzene series removal ability of the engineering bacteria on activated sludge. Besides, we also demonstrated a controllable environmental risk of this engineered bacteria through monitoring its abundance and horizontal gene transfer test. Overall, the results of this study suggest an alternative strategy to solve multiple environmental problems through genetic engineering means and provide support for the application of engineered bacteria in environmental biotechnology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Patients with remitted psychosis face a dilemma between the wish to discontinue antipsychotics and the risk of relapse. We test if an operationalized guided-dose-reduction algorithm can help reach a lower effective dose without increased risks of relapse., Methods: A 2-year open-label randomized prospective comparative cohort trial from Aug 2017 to Sep 2022. Patients with a history of schizophrenia-related psychotic disorders under stable medications and symptoms were eligible, randomized 2:1 into guided dose reduction group (GDR) v. maintenance treatment group (MT1), together with a group of naturalistic maintenance controls (MT2). We observed if the relapse rates would be different between 3 groups, to what extent the dose could be reduced, and if GDR patients could have improved functioning and quality of life., Results: A total of 96 patients, comprised 51, 24, and 21 patients in GDR, MT1, and MT2 groups, respectively. During follow-up, 14 patients (14.6%) relapsed, including 6, 4, and 4 from GDR, MT1, and MT2, statistically no difference between groups. In total, 74.5% of GDR patients could stay well under a lower dose, including 18 patients (35.3%) conducting 4 consecutive dose-tapering and staying well after reducing 58.5% of their baseline dose. The GDR group exhibited improved clinical outcomes and endorsed better quality of life., Conclusions: GDR is a feasible approach as the majority of patients had a chance to taper antipsychotics to certain extents. Still, 25.5% of GDR patients could not successfully decrease any dose, including 11.8% experienced relapse, a risk comparable to their maintenance counterparts.

Background: We aimed to evaluate the prognostic significance of preoperative neutrophil-to-albumin ratio (NAR) in oral squamous cell carcinoma (OSCC)., Methods: A total of 622 patients with surgically treated OSCC were enrolled. NAR was defined as the absolute neutrophil count divided by the serum albumin level in peripheral blood before the radical surgery. Cox proportional hazards model were used to discover survival outcome-associated factors., Results: The optimal cut-off of NAR to predict overall survival (OS) was determined to be 0.1. In Cox model, high NAR was identified as an independent negative prognosticator of OS, cancer-specific survival, and recurrence-free survival (adjusted hazard ratio: 1.503, 1.958, and 1.727, respectively; all p < 0.05). The NAR-based nomogram accurately predicted OS (concordance index: 0.750)., Conclusion: Our study suggests that preoperative NAR is a convenient and effective prognostic marker for OSCC and NAR-based nomogram can be a promising prognostic tool in clinical setting., (© 2023 Wiley Periodicals LLC.)

Competing Interests: Declaration of completion interest None.

Elevated urinary cystine levels are closely associated with the development of cystine stone. Therefore, the ability to rapidly and efficiently determine urinary cystine levels is crucial for physicians to manage patients with cystinuria or those undergoing cystine medication. In this study, an amperometric method employing a commercial screen-printed silver electrode was successfully established. The resulting calibration curve indicated a detection limit of 0.65 mg/dL. Satisfactory recoveries ranging from 89% to 109% were obtained for urine samples. The method was also effective for the quality control analysis of cystine in pharmaceutical tablets. The recovery of cystine from pharmaceutical tablets ranged from 98% to 101% using the developed method. This method enables the rapid and accurate determination of cystine in both urine samples and pharmaceutical tablets and provides valuable information for clinical diagnosis and pharmaceutical quality control., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hwei-yan Tsai reports financial support was provided by the National Science and Technology Council of Taiwan., (Copyright © 2023 Elsevier B.V. All rights reserved.)

It has become common to perform kinetic analysis using approximate Koopman operators that transform high-dimensional timeseries of observables into ranked dynamical modes. The key to the practical success of the approach is the identification of a set of observables that form a good basis on which to expand the slow relaxation modes. Good observables are, however, difficult to identify a priori and suboptimal choices can lead to significant underestimations of characteristic time scales. Leveraging the representation of slow dynamics in terms of Hidden Markov Models (HMM), we propose a simple and computationally efficient clustering procedure to infer surrogate observables that form a good basis for slow modes. We apply the approach to an analytically solvable model system as well as on three protein systems of different complexities. We consistently demonstrate that the inferred indicator functions can significantly improve the estimation of the leading eigenvalues of Koopman operators and correctly identify key states and transition time scales of stochastic systems, even when good observables are not known a priori .

Background and Aim: Fecal microbiota transplantation (FMT) is used to treat recurrent or refractory Clostridioides difficile infection (CDI). In the past, screening of fecal donors required surveillance of personal behavior, medical history, and diseases that could be transmitted by the blood or fecal-oral route. In addition, the exclusion of multidrug-resistant organisms (MDROs) has been recommended since 2018. This task has become more complicated in the era of the coronavirus disease-2019 (COVID-19) pandemic. To prevent fecal transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is crucial to commence screening for SARS-CoV-2, alongside other traditional tests. Our aim was to investigate whether hidden carriers of SARS-CoV-2 were enrolled for stool donation, and the status of the presence or incidence of MDRO during fecal donation in Taiwan., Methods: Fecal products collected from March 2019 to December 2022 were tested for MDRO and nucleic acid amplification tests for SARS-CoV-2 using the pooling method. The period of fecal product collection crossed the time before and during the COVID pandemic in Taiwan., Results: A total of 151 fecal samples were collected. The fecal products were tested using polymerase chain reaction (PCR) to detect SARS-CoV-2. The results were negative for all stocks. This was similar to the results of MDRO testing. The safety of FMT products has been guaranteed during the pandemic., Conclusion: Our FMT center produced MDRO-free and COVID-19-free products before and during the COVID-19 outbreak in Taiwan. Our protocol was effective for ensuring the safety of FMT products., (© 2023 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Perfluoroalkyl substances (PFAS) have been reported to be harmful to multiple organs in the human body. Based on a previous study suggesting that hemodialysis (HD) may be a means of eliminating PFAS from the human body, we aimed to compare the serum PFAS concentrations of patients undergoing regular HD, patients with chronic kidney disease (CKD) and controls. Additionally, we also investigated the correlation between PFAS and biochemical data, as well as concurrent comorbidities. We recruited 301 participants who had been on maintenance dialysis for >90 days, 20 participants with stage 5 non-dialysis CKD, and 55 control participants who did not have a diagnosis of kidney disease, with a mean creatinine level of 0.77 mg/dl. Eight different PFAS, namely perfluorooctanoic acid (PFOA), total and linear perfluorooctanesulfonic acid (PFOS), perfluoroheptanoic acid (PFHpA), perfluorohexanesulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), were measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Spearman correlation and multivariable linear regression with 5 % false discovery rate were used to evaluate the relationships between PFAS and clinical parameters in HD patients and controls. Circulating concentrations of seven PFAS, including total and linear PFOS (T-PFOS and L-PFOS) PFDA, PFNA, PFHxS, PFOA, and PFUnDA, were significantly lower in the HD group compared to the CKD and control group. For the interplay between biochemical data and PFAS, all of the studied PFAS were positively correlated with aspartate aminotransferase, alanine aminotransferase, glucose, blood urea nitrogen, ferritin, and vitamin D in the controls, while in HD patients, the PFAS were all positively correlated with albumin, uric acid, iron, and vitamin D. These findings may offer valuable insights for future studies seeking to eliminate PFAS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Helicobacter pylori (HP) infection is associated with various diseases. Early detection can prevent the onset of illness. We constructed a nomogram to predict groups at high risk of HP infection., Methods: Patients who underwent regular medical check-ups at hospital in Chaoshan, China from March to September 2022 were randomly allocated to the training and validation cohorts. Risk factors including basic characteristics and lifestyle habits associated with HP infection were analyzed by logistic regression analyses. The independent varieties were calculated and plotted into a nomogram. The nomogram was internally validated by receiver operating characteristic curve, calibration, and decision curve analyses (DCAs)., Results: Of the 945 patients, 680 were included in the training cohort and 265 in the validation cohort. 356 patients in training cohort with positive 13 C-UBT results served as the infected group, and 324 without infection were the control group. The multivariate regression analyses showed that the risk factors for HP infection included alcohol consumption (OR = 1.29, 95%CI = 0.78-2.13, P = 0.03), family history of gastric disease (OR = 4.35, 95%CI = 1.47-12.84, P = 0.01), living with an HP-positive individual (OR = 18.09, 95%CI = 10.29-31.82, P < 0.0001), drinking hot tea (OR = 1.58, 95%CI = 1.05-2.48, P = 0.04), and infection status of co-drinkers unknown (OR = 2.29, 95%CI = 1.04-5.06, P = 0.04). However, drinking tea > 3 times per day (OR = 0.56, 95%CI = 0.33-0.95, P = 0.03), using serving chopsticks (OR = 0.30, 95%CI = 0.12-0.49, P < 0.0001) were protective factors for HP infection. The nomogram had an area under the curve (AUC) of 0.85 in the training cohort. The DCA was above the reference line within a large threshold range, indicating that the model was better. The calibration analyses showed the actual occurrence rate was basically consistent with the predicted occurrence rate. The model was validated in the validation cohort, and had a good AUC (0.80), DCA and calibration curve results., Conclusions: This nomogram, which incorporates basic characteristics and lifestyle habits, is an efficient model for predicting those at high risk of HP infection in the Chaoshan region., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The antiviral DNA cytosine deaminase APOBEC3B has been implicated as a source of mutation in many cancers. However, despite years of work, a causal relationship has yet to be established in vivo. Here, we report a murine model that expresses tumor-like levels of human APOBEC3B. Animals expressing full-body APOBEC3B appear to develop normally. However, adult males manifest infertility, and older animals of both sexes show accelerated rates of carcinogenesis, visual and molecular tumor heterogeneity, and metastasis. Both primary and metastatic tumors exhibit increased frequencies of C-to-T mutations in TC dinucleotide motifs consistent with the established biochemical activity of APOBEC3B. Enrichment for APOBEC3B-attributable single base substitution mutations also associates with elevated levels of insertion-deletion mutations and structural variations. APOBEC3B catalytic activity is required for all of these phenotypes. Together, these studies provide a cause-and-effect demonstration that human APOBEC3B is capable of driving both tumor initiation and evolution in vivo., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Hippocampal oxytocin receptor (OXTR) signaling is crucial for discrimination of social stimuli to guide social recognition, but circuit mechanisms and cell types involved remain incompletely understood. Here, we report a role for OXTR-expressing hilar mossy cells (MCs) of the dentate gyrus in social stimulus discrimination by regulating granule cell (GC) activity. Using a Cre-loxP recombination approach, we found that ablation of Oxtr from MCs impairs discrimination of social, but not object, stimuli in adult male mice. Ablation of MC Oxtr increases spontaneous firing rate of GCs, synaptic excitation to inhibition ratio of MC-to-GC circuit, and GC firing when temporally associated with the lateral perforant path inputs. Using mouse hippocampal slices, we found that bath application of OXTR agonist [Thr 4 ,Gly 7 ]-oxytocin causes membrane depolarization and increases MC firing activity. Optogenetic activation of MC-to-GC circuit ameliorates social discrimination deficit in MC OXTR deficient mice. Together, our results uncover a previously unknown role of MC OXTR signaling for discrimination of social stimuli and delineate a MC-to-GC circuit responsible for social information processing., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Posttraumatic finger osteoarthritis of the proximal interphalangeal joint (PIPJ) is a difficult problem. Over the past decade, we have reported several methods for improving the outcomes of vascularized toe joint transfer (VJT). In this study, we focused on determining poor prognostic factors which lead to a suboptimal outcome., Methods: A consecutive series of patients with posttraumatic osteoarthritis of the PIPJ who received VJT between January 2008 and January 2021 were enrolled in this study. The senior surgeon (Y.-T.L.) performed the surgery in all cases. In this retrospective study, we reexamine the initial trauma-related soft tissue and bony structure injuries of the recipient finger, to assess the baseline tissue quality before VJT. The injuries were classified into five major categories according to their anatomic region. The functional outcome parameters (including range of motion, percentage of use, and extensor lag of the transferred PIPJ) were collected. Univariate and multivariate linear regression analyses were performed using the generalized estimated equation model to identify the correlation between the injury category involved and functional outcome., Results: A total of 59 digits were enrolled. Our results revealed that the fingers with previous vascular injury that received revascularization procedures had relatively suboptimal functional outcomes. These fingers had a significantly lower percentage of use both before (β = -0.222, P  = 0.006) and after (β = -0.177, P  = 0.006) receiving secondary procedures to improve functional outcome., Conclusions: Patients with prior revascularization surgery were associated with a poor functional outcome after VJT., Competing Interests: The authors have no financial interest to declare in relation to the content of this article. This study was supported by Chang Gung Memorial Hospital, Linkou, Taiwan [grant no. CMRPG3K1851]., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: Patients with glycogen storage disease type Ia (GSDIa) are prone to hypoglycemia. Uncooked cornstarch (CS) is the treatment, but maintaining nighttime blood glucose levels is still difficult., Methods: The study enrolled patients with GSDIa to investigate the benefits of bedtime extended release CS (ER-CS, Glycosade®) versus regular CS. The daytime CS schedule was not altered. A 7-day continuous glucose monitoring (CGM) was performed at the baseline and 12 weeks after using ER-CS. Biochemical profile, sleep quality (Pittsburgh Sleep Quality Index, PSQI), and quality of life (SF-36 questionnaire) were measured at the baseline and 24 weeks after using ER-CS., Results: Nine patients (9 to 33 years of age) were enrolled. Compared with the baseline (80.0 ± 6.33 mg/dL), the 12-week evaluations revealed higher mean morning glucose levels (86.5 ± 8.26 mg/dL, p = 0.015). Twenty-four weeks after the use of bedtime ER-CS, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels both decreased (from 69.3 ± 77.8 to 41.1 ± 40.4 U/L and from 78.8 ± 99.6 to 37.8 ± 28.81 U/L, respectively, p = 0.013 for both analyses), and sleep and fasting time both elongated (from 7.8 ± 0.87 to 8.6 ± 1.02 h and from 6.5 ± 1.22 to 7.6 ± 1.02 h, respectively, p = 0.011 for both analyses). The mean PSQI score in the five adult patients decreased significantly (from 5.8 ± 1.29 to 3.0 ± 1.71, p = 0.042)., Conclusion: This study provides evidence of clinically meaningful improvements by shifting only bedtime regular CS to ER-CS in patients with GSDIa. As ER-CS is considerably more expensive than regular CS, this approach presents a cost-effective alternative., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: The issue of carbapenem-resistant Escherichia coli was aggravated yearly. The previous studies reported the varied but critical epidemiology of carbapenem-resistant E. coli among which the carbapenemase-producing strains were regarded as one of the most notorious issues. AS101, an organic tellurium-containing compound undergoing clinical trials, was revealed with antibacterial activities. However, little is known about the antibacterial effect of AS101 against carbapenemase-producing E. coli (CPEC)., Materials and Methods: The minimum inhibitory concentration (MIC) of AS101 against the 15 isolates was examined using a broth microdilution method. The scanning electron microscopy, pharmaceutical manipulations, reactive oxygen species level, and DNA fragmentation assay were carried out to investigate the antibacterial mechanism. The sepsis mouse model was employed to assess the in vivo treatment effect., Results: The bla NDM (33.3%) was revealed as the dominant carbapenemase gene among the 15 CPEC isolates, followed by the bla KPC gene (26.7%). The MICs of AS101 against the 15 isolates ranged from 0.5 to 32 μg/ml, and 99.9% of bacterial eradication was observed at 8 h, 4 h, and 2 h for 1×, 2×, and 4 × MIC, respectively. The mechanistic investigations suggest that AS101 would enter the bacterial cell, and induce ROS generation, leading to DNA fragmentation. The in vivo study exhibited that AS101 possessed a steady treatment effect in a sepsis mouse model, with an up to 83.3% of survival rate., Conclusion: The in vitro activities, mechanisms, and in vivo study of AS101 against CPEC were unveiled. Our finding provided further evidence for the antibiotic development of AS101., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Conjugated polymers (CPs) have recently gained increasing attention as photocatalysts for sunlight-driven hydrogen evolution. However, they suffer from insufficient electron output sites and poor solubility in organic solvents, severely limiting their photocatalytic performance and applicability. Herein, solution-processable all-acceptor (A 1 -A 2 )-type CPs based on sulfide-oxidized ladder-type heteroarene are synthesized. A 1 -A 2 -type CPs showed upsurging efficiency improvements by two to three orders of magnitude, compared to their donor-acceptor -type CP counterparts. Furthermore, by seawater splitting, PBDTTTSOS exhibited an apparent quantum yield of 18.9% to 14.8% at 500 to 550 nm. More importantly, PBDTTTSOS achieved an excellent hydrogen evolution rate of 35.7 mmol h -1  g -1 and 150.7 mmol h -1  m -2 in the thin-film state, which is among the highest efficiencies in thin film polymer photocatalysts to date. This work provides a novel strategy for designing polymer photocatalysts with high efficiency and broad applicability., (© 2023 Wiley-VCH GmbH.)

Competing Interests: The authors have no conflicts of interest relevant to this article.

Background: The tumour microenvironment (TME) is a specialised niche involving intercellular communication among cancer cells and various host cells. Among the host cells, the quantity and quality of immune cells within the TME play essential roles in cancer development and management. The immunologically suppressive, so-called 'cold' TME established by a series of tumour-host interactions, including generating immunosuppressive cytokines and recruiting regulatory host immune cells, is associated with resistance to therapies and worse clinical outcomes., Main Body: Various therapeutic approaches have been used to target the cold TME, including immune checkpoint blockade therapy and adoptive T-cell transfer. A promising, less explored therapeutic strategy involves targeting TME-associated exosomes. Exosomes are nanometer-sized, extracellular vesicles that transfer material from donor to recipient cells. These particles can reprogram the recipient cells and modulate the TME. In particular, exosomes from haematopoietic cells are known to promote or suppress cancer progression under specific conditions. Understanding the effects of haematopoietic cell-secreted exosomes may foster the development of therapeutic exosomes (tExos) for personalised cancer treatment. However, the development of exosome-based therapies has unique challenges, including scalable production, purification, storage and delivery of exosomes and controlling batch variations. Clinical trials are being conducted to verify the safety, feasibility, availability and efficacy of tExos., Conclusion: This review summarises our understanding of how haematopoietic cell-secreted exosomes regulate the TME and antitumour immunity and highlights present challenges and solutions for haematopoietic cell-derived exosome-based therapies., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Cell-surface proteins play a critical role in cell function and are primary targets for therapeutics. CITE-seq is a single-cell technique that enables simultaneous measurement of gene and surface protein expression. It is powerful but costly and technically challenging. Computational methods have been developed to predict surface protein expression using gene expression information such as from single-cell RNA sequencing (scRNA-seq) data. Existing methods however are computationally demanding and lack the interpretability to reveal underlying biological processes. We propose CrossmodalNet, an interpretable machine learning model, to predict surface protein expression from scRNA-seq data. Our model with a customized adaptive loss accurately predicts surface protein abundances. When samples from multiple time points are given, our model encodes temporal information into an easy-to-interpret time embedding to make prediction in a time-point-specific manner, and is able to uncover noise-free causal gene-protein relationships. Using three publicly available time-resolved CITE-seq data sets, we validate the performance of our model by comparing it with benchmarking methods and evaluate its interpretability. Together, we show that our method accurately and interpretably profiles surface protein expression using scRNA-seq data, thereby expanding the capacity of CITE-seq experiments for investigating molecular mechanisms involving surface proteins., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Metastasis is a multistep process involving the migration and invasion of cancer cells and is a hallmark of cancer malignancy. Long non-coding RNAs (lncRNAs) play critical roles in the regulation of metastasis. This study aims to elucidate the role of the lncRNA solute carrier organic anion transporter family member 4A1-antisense 1 (SLCO4A1-AS1) in metastasis and its underlying regulatory mechanisms., Methods: A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify metastasis-associated lncRNAs. Transwell migration and invasion assays, and a tail vein-injection mouse model were used to assess the migration and invasion of cancer cells in vitro and in vivo, respectively. High-throughput screening methods, including MASS Spectrometry and RNA sequencing (RNA-seq), were used to identify the downstream targets of SLCO4A1-AS1. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting, RNA pull-down, RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH), and chromatin immunoprecipitation (ChIp) assays were conducted to identify and validate the underlying regulatory mechanisms of SLCO4A1-AS1., Results: SLCO4A1-AS1 reduced cancer cell migration and invasion by disrupting cytoskeleton filaments, and was associated with longer overall survival in patients with lung adenocarcinoma. SLCO4A1-AS1 directly interacted with the DNA-binding protein, TOX High Mobility Group Box Family Member 4 (TOX4), to inhibit TOX4-induced migration and invasion. Furthermore, RNA-seq revealed that neurotensin receptor 1 (NTSR1) is a novel and convergent downstream target of SLCO4A1-AS1 and TOX4. Mechanistically, SLCO4A1-AS1 functions as a decoy of TOX4 by interrupting its interaction with the NTSR1 promoter and preventing NTSR1 transcription. Functionally, NTSR1 promotes cancer cell migration and invasion through cytoskeletal remodeling, and knockdown of NTSR1 significantly inhibits TOX4-induced migration and invasion., Conclusion: These findings demonstrated that SLCO4A1-AS1 antagonizes TOX4/NTSR1 signaling, underscoring its pivotal role in lung cancer cell migration and invasion. These findings hold promise for the development of novel therapeutic strategies targeting the SLCO4A1-AS1/TOX4/NTSR1 axis as a potential avenue for effective therapeutic intervention in lung cancer., (© 2023. National Science Council of the Republic of China (Taiwan).)