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Obstructive sleep apnea (OSA) with a low arousal threshold (low-ArTH) phenotype can cause minor respiratory events that exacerbate sleep fragmentation. Although anthropometric features may affect the risk of low-ArTH OSA, the associations and underlying mechanisms require further investigation. This study investigated the relationships of body fat and water distribution with polysomnography parameters by using data from a sleep center database. The derived data were classified as those for low-ArTH in accordance with criteria that considered oximetry and the frequency and type fraction of respiratory events and analyzed using mean comparison and regression approaches. The low-ArTH group members ( n = 1850) were significantly older and had a higher visceral fat level, body fat percentage, trunk-to-limb fat ratio, and extracellular-to-intracellular (E-I) water ratio compared with the non-OSA group members ( n = 368). Significant associations of body fat percentage (odds ratio [OR]: 1.58, 95% confident interval [CI]: 1.08 to 2.3, p < 0.05), trunk-to-limb fat ratio (OR: 1.22, 95% CI: 1.04 to 1.43, p < 0.05), and E-I water ratio (OR: 1.32, 95% CI: 1.08 to 1.62, p < 0.01) with the risk of low-ArTH OSA were noted after adjustments for sex, age, and body mass index. These observations suggest that increased truncal adiposity and extracellular water are associated with a higher risk of low-ArTH OSA.

This study aimed to compare the outcomes of arthroscopic rotator cuff repair (ARCR) surgery between younger and older patients. We performed this systematic review and meta-analysis of cohort studies comparing outcomes between patients older than 65 to 70 years and a younger group following arthroscopic rotator cuff repair surgery. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and other sources for relevant studies up to 13 September 2022, and then assessed the quality of included studies using the Newcastle-Ottawa Scale (NOS). We used random-effects meta-analysis for data synthesis. The primary outcomes were pain and shoulder functions, while secondary outcomes included re-tear rate, shoulder range of motion (ROM), abduction muscle power, quality of life, and complications. Five non-randomized controlled trials, with 671 participants (197 older and 474 younger patients), were included. The quality of the studies was all fairly good, with NOS scores ≥ 7. The results showed no significant differences between the older and younger groups in terms of Constant score improvement, re-tear rate, or other outcomes such as pain level improvement, muscle power, and shoulder ROM. These findings suggest that ARCR surgery in older patients can achieve a non-inferior healing rate and shoulder function compared to younger patients.

We previously found that the RING-type E3 ligase DEFECTIVE IN ANTHER DEHISCENCE1- (DAD1-) Activating Factor (DAF) controls anther dehiscence by activating the jasmonate biosynthetic pathway in Arabidopsis. Here, we show that in Arabidopsis, the DAF ancestor was duplicated into three genes (DAF, Ovule Activating Factor (OAF), DAFL2), which evolved divergent partial functions from their ancestor through subfunctionalization. In this case, DAF-DAD1-JA signaling regulates anther dehiscence, whereas OAF controls ovule development by negatively regulating cinnamyl alcohol dehydrogenase 9 (CAD9) activity and being negatively regulated by miR847 itself in Arabidopsis. Downregulation of OAF or upregulation of CAD9 and miR847 caused similar abortion of ovule formation due to precocious ovule lignification in transgenic Arabidopsis. Interestingly, only one DAF-like gene, PaOAF, exists in the monocot orchids, which has likely evolved through nonfunctionalization and maintains a conserved function as Arabidopsis OAF in regulating ovule development since defective ovules were observed in the virus-induced gene silencing (VIGS) PaOAF Phalaenopsis orchids. The absence of the DAF ortholog and its function in orchids is likely due to the evolution of stamens to a unique pollinium structure that lacks the feature of anther dehiscence. These findings expand the current knowledge underlying the multifunctional evolution and diverse functionalization of duplicate gene pairs within/among plants., (© 2023. The Author(s).)

Helicobacter pylori infection is an important issue worldwide, and several guidelines have been published for clinicians to achieve successful eradication. However, there are still some patients who remain infected with H. pylori after treatment. Clinicians should identify the reasons that caused treatment failure and find strategies to manage them. We have searched and organized the literature and developed methods to overcome factors that contribute to prior treatment failure, such as poor compliance, inadequate intragastric acid suppression, and antibiotic resistance. To improve compliance, telemedicine or smartphone applications might play a role in the modern world by increasing doctor-patient relationships, while concomitant probiotics could be administered to reduce adverse effects and enhance adherence. For better acid suppression, high-potency and high-dose proton-pump inhibitors or potassium-competitive acid blockers have preferable efficacy. To overcome antibiotic resistance, susceptibility tests either by culture or by genotyping are the most commonly used methods and have been suggested for antibiotic selection before rescue therapy, but empirical therapy according to detailed medical history could be an alternative. Eradication with a longer treatment period (14 days) has a better outcome than shorter period (7 or 10 days). Ultimately, clinicians should select antibiotics based on the patient's history of drug allergy, previous antibiotic exposure, local antibiotic resistance, available medications, and cost. In addition, identifying patients with a high risk of cancer and shared decision-making are also essential for those who have experienced eradication failure., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

This study assessed the clinical efficacy of nirmatrelvir plus ritonavir (NMV-r) in treating patients with coronavirus disease-2019 (COVID-19) and substance use disorders (SUDs). This study included two cohorts: the first examined patients with SUDs, with and without a prescription for NMV-r, while the second compared patients prescribed with NMV-r, with and without a diagnosis of SUDs. SUDs were defined using ICD-10 codes, related to SUDs, including alcohol, cannabis, cocaine, opioid, and tobacco use disorders (TUD). Patients with underlying SUDs and COVID-19 were identified using the TriNetX network. We used 1:1 propensity score matching to create balanced groups. The primary outcome of interest was the composite outcome of all-cause hospitalization or death within 30 days. Propensity score matching yielded two matched groups of 10 601 patients each. The results showed that the use of NMV-r was associated with a lower risk of hospitalization or death, 30 days after COVID-19 diagnosis (hazard ratio (HR), 0.640; 95% confidence interval (CI): 0.543-0.754), as well as a lower risk of all-cause hospitalization (HR, 0.699; 95% CI: 0.592-0.826) and all-cause death (HR, 0.084; 95% CI: 0.026-0.273). However, patients with SUDs had a higher risk of hospitalized or death within 30 days of COVID-19 diagnosis than those without SUDs, even with the use of NMV-r (HR, 1.783; 95% CI: 1.399-2.271). The study also found that patients with SUDs had a higher prevalence of comorbidities and adverse socioeconomic determinants of health than those without SUDs. Subgroup analysis showed that the benefits of NMV-r were consistent across most subgroups with different characteristics, including age (patients aged ≥60 years [HR, 0.507; 95% CI: 0.402-0.640]), sex (women [HR, 0.636; 95% CI: 0.517-0.783] and men [HR, 0.480; 95% CI: 0.373-0.618]), vaccine status (vaccinated <2 doses [HR, 0.514; 95% CI: 0.435-0.608]), SUD subtypes (alcohol use disorder [HR, 0.711; 95% CI: 0.511- 0.988], TUD [HR, 0.666; 95% CI: 0.555-0.800]) and Omicron wave (HR, 0.624; 95% CI: 0.536-0.726). Our findings indicate that NMV-r could reduce all-cause hospitalization and death in the treatment of COVID-19 among patients with SUDs and support the use of NMV-r for treating patients with SUDs and COVID-19., (© 2023 Wiley Periodicals LLC.)

Objective: To treat intractable hematuria with intravesical instillation of epinephrine., Methods: Sixty patients were treated with intravesical instillation of epinephrine at Mackay Memorial Hospital. The control group was composed of 60 patients who were treated with standard-of-care cystoscopic electrocautery fulguration. Under general anesthesia, epinephrine-treated group were injected with 150 mL of diluted epinephrine (1:10,000) through cystoscopy, followed by bladder irrigation with 1:100,000-diluted epinephrine at the ward. Successful hemostasis was defined as hematuria resolution within 1 month post-treatment without additional invasive procedures., Results: In the 60 patients who underwent intravesical instillation of epinephrine, radiation cystitis was the most common etiology (65.0%). Fifty-two patients (86.7%) required no additional therapy within 1 month after one course of intravesical epinephrine instillation treatment compared with 28 patients (46.7%) in the electrocautery fulguration-control group (P <.001). We observed a significant decrease in both the median length of hospitalization (P = .049) and the need for additional invasive procedures (P <.001) in the epinephrine group. In addition, cardiopulmonary monitoring of mean blood pressure, mean heart rate, and mean respiratory rate demonstrated no significant differences after epinephrine treatment., Conclusion: In this study, intravesical instillation of epinephrine was an innovative method of hemostasis for intractable lower urinary tract hematuria with a success rate of 86.7%, compared to 46.7% in the control group, and significantly reduced the number of additional procedures required and the length of hospitalization. It was well-tolerated by all patients, and was a safe and effective treatment modality for intractable hematuria or bladder hemorrhage., Competing Interests: Conflicts of Interest The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the effect of suprascapular nerve release in arthroscopic rotator cuff repair surgery., Methods: This systematic review was performed to include randomized controlled trials (RCTs) and non-RCTs that compared the outcomes of patients who did and did not receive suprascapular nerve release (SSNR) during arthroscopic rotator cuff repair surgery. MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant studies. Methodological Index for Non-randomized Studies (MINORS) was used for cohort study assessment. The Cochrane risk of bias assessment tool (version 1.0) was used to assess the risk of bias in randomized trials. The primary outcomes were pain and shoulder function. The secondary outcome was the re-tear rate., Results: Two RCTs and three non-RCTs with a total of 187 patients (90 patients received SSNR and 97 patients did not receive SSNR) were included in this systematic review. The meta-analysis revealed that the SSNR group did not had a more pain reduction, assessed by visual analogue scale, compared to the non-SSNR group. Also, the SSNR group did not have a significantly more improvement in the UCLA score, compared to the non-SSNR group. In addition, there was no significant difference between the two groups in terms of Constant score and re-tear rate., Conclusions: The result of this study showed that additional suprascapular nerve release did not provide additional benefit in arthroscopic rotator cuff repair surgery. Routine arthroscopic SSNR is not recommended when treating patients with rotator cuff tear., Level of Evidence: Level III., (© 2022. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Purpose: Sarcopenia is prevalent in ovarian cancer and contributes to poor survival. This study is aimed at investigating the association of prognostic nutritional index (PNI) with muscle loss and survival outcomes in patients with ovarian cancer., Methods: This retrospective study analyzed 650 patients with ovarian cancer treated with primary debulking surgery and adjuvant platinum-based chemotherapy at a tertiary center from 2010 to 2019. PNI-low was defined as a pretreatment PNI of < 47.2. Skeletal muscle index (SMI) was measured on pre- and posttreatment computed tomography (CT) at L3. The cut-off for the SMI loss associated with all-cause mortality was calculated using maximally selected rank statistics., Results: The median follow-up was 4.2 years, and 226 deaths (34.8%) were observed. With a median duration of 176 days (interquartile range: 166-187) between CT scans, patients experienced an average decrease in SMI of 1.7% (P < 0.001). The cut-off for SMI loss as a predictor of mortality was - 4.2%. PNI-low was independently associated with SMI loss (odds ratio: 1.97, P = 0.001). On multivariable analysis of all-cause mortality, PNI-low and SMI loss were independently associated with all-cause mortality (hazard ratio: 1.43, P = 0.017; hazard ratio: 2.27, P < 0.001, respectively). Patients with both SMI loss and PNI-low (vs. neither) had triple the risk of all-cause mortality (hazard ratio: 3.10, P < 0.001)., Conclusions: PNI is a predictor of muscle loss during treatment for ovarian cancer. PNI and muscle loss are additively associated with poor survival. PNI can help clinicians guide multimodal interventions to preserve muscle and optimize survival outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Macrolide antibiotics are important drugs to combat infections. The pharmacokinetics (PK) of these drugs are essential for the determination of their optimal dose regimens, which affect antimicrobial pharmacodynamics and treatment success. For most drugs, the measurement of their concentrations in plasma/serum is the surrogate for drug concentrations in target tissues for therapy. However, for macrolides, simple reliance on total or free drug concentrations in serum/plasma might be misleading. The macrolide antibiotic concentrations of serum/plasma, interstitial fluid (ISF), and target tissue itself usually yield very different PK results. In fact, the PK of a macrolide antibiotic based on serum/plasma concentrations alone is not an ideal predictor for the in vivo efficacy against respiratory pathogens. Instead, the PK based on drug concentrations at the site of infection or ISF provide much more clinically relevant information than serum/plasma concentrations. This review aims to summarize and compare/discuss the use of drug concentrations of serum/plasma, airway ISF, and tissues for computing the PK of macrolides. A better understanding of the PK of macrolide antibiotics based on airway ISF concentrations will help optimize the antibacterial dose regimen as well as minimizing toxicity and the emergence of drug resistance in clinical practice.

Background: Picture My Participation (PmP) is a picture-supported child-report instrument of participation of children with disabilities., Aims: This study described the development of a mobile application of the PmP Traditional Chinese version (PmP-C) and evaluated its usability., Methods: The PmP-C App includes features that allow the input of a child's demographics, identification of frequency and involvement of 22 culturally appropriate activities, selection of the three most important activities and the specification of the environmental facilitators and barriers. The usability test was conducted with 10 healthcare workers, who interviewed 10 children with disabilities aged 6-12 years. The healthcare workers completed a usability questionnaire and were asked to provide feedback on the ease of use, learning, satisfaction and perceived usefulness., Results: The mean score for the usability questionnaire ranged from 2.7 to 4.6 out of 5.0. The feedback indicated that the interface was simple to operate by the healthcare workers and was attractive and motivating to children. Improvements of layout design, operation instructions and technical problems were recommended, which contributed to the app program optimization., Conclusions: The PmP-C App provides a practical tool with initial support for usability to enable active engagement and communication of children with disabilities with healthcare providers.

The effect of nirmatrelvir plus ritonavir (NMV-r) on post-acute COVID-19 sequelae beyond 3 months of SARS-CoV-2 infection remains unknown. This retrospective cohort study utilized data from the TriNetX Research Network. We identified nonhospitalized adult patients with COVID-19 receiving a diagnosis between January 1 and July 31, 2022. Propensity score matching (PSM) was used to create two matched cohorts: NMV-r and non-NMV-r groups, respectively. We measured the primary outcomes using a composite of all-cause emergency room (ER) visits or hospitalization and a composite of post-COVID-19 symptoms according to the WHO Delphi consensus, which also stated that post COVID-19 condition occurs usually 3 months from the onset of COVID-19, during the follow-up period between 90 days after the index diagnosis of COVID-19 and the end of follow-up (180 days). Initially, we identified 12 247 patients that received NMV-r within 5 days of diagnosis and 465 135 that did not. After PSM, 12 245 patients remained in each group. During the follow-up period, patients treated with NMV-r had a lower risk of all-cause hospitalization and ER visits compared with untreated patients (659 vs. 955; odds ratio [OR], 0.672; 95% confidence interval [CI], 0.607-0.745; p < 0.0001). However, the overall risk of post-acute COVID-19 symptoms did not significantly differ between the two groups (2265 vs. 2187; OR, 1.043; 95% CI, 0.978-1.114; p = 0.2021). The reduced risk of all-cause ER visits or hospitalization in the NMV-r group and the similarities in the risk of post-acute COVID-19 symptoms between the two groups were consistent in the subgroups stratified by sex, age, and vaccination status. Early NMV-r treatment of nonhospitalized patients with COVID-19 was associated with reduced risk of hospitalization and ER visits during the period of 90-180 days after diagnosis compared with no NMV-r treatment; however, post-acute COVID-19 symptoms and mortality risk did not differ significantly between the groups., (© 2023 Wiley Periodicals LLC.)

Background: The optimal type of esophagectomy and extent of lymphadenectomy for patients after neoadjuvant chemoradiotherapy (nCRT) for esophageal squamous cell carcinoma remain controversial. We hypothesized that a more radical resection is associated with better survival., Methods: Data of patients who received nCRT followed by resection for esophageal squamous cell carcinoma between 2012 and 2021 were analyzed. Modified en bloc esophagectomy (mEBE) involves total mediastinal lymphadenectomy and resection of all periesophageal node-bearing tissues. Perioperative outcomes and survival rates of mEBE were compared with those of conventional esophagectomy (CE)., Results: A total of 238 patients were included. Compared with CE, mEBE was associated with a longer operative time, higher total number of resected lymph nodes, fewer complications, and less anastomotic leakage; length of stay was similar between the 2 groups. There was no difference in overall survival rates between patients with ypT0 N0 stage in the mEBE and CE groups; however, in patients with non-ypT0 N0 stage in the mEBE and CE groups, the 3-year overall survival rates were 58.5% and 28.5%, respectively (P < .001). On disease-free survival analysis, no difference was observed in patients with ypT0 N0 stage, whereas patients with non-ypT0 N0 stage after nCRT had significantly better disease-free survival after mEBE compared with CE (49.7% vs 27.2%; P = .017)., Conclusions: Survival after mEBE was significantly better than that after CE. The mEBE did not increase postoperative hospital stay and complication rates., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Obstructive sleep apnea (OSA) is typically diagnosed by polysomnography (PSG). However, PSG is time-consuming and has some clinical limitations. This study thus aimed to establish machine learning models to screen for the risk of having moderate-to-severe and severe OSA based on easily acquired features., Methods: We collected PSG data on 3529 patients from Taiwan and further derived the number of snoring events. Their baseline characteristics and anthropometric measures were obtained, and correlations among the collected variables were investigated. Next, six common supervised machine learning techniques were utilized, including random forest (RF), extreme gradient boosting (XGBoost), k-nearest neighbor (kNN), support vector machine (SVM), logistic regression (LR), and naïve Bayes (NB). First, data were independently separated into a training and validation dataset (80%) and a test dataset (20%). The approach with the highest accuracy in the training and validation phase was employed to classify the test dataset. Next, feature importance was investigated by calculating the Shapley value of every factor, which represented the impact on OSA risk screening., Results: The RF produced the highest accuracy (of >70%) in the training and validation phase in screening for both OSA severities. Hence, we employed the RF to classify the test dataset, and results showed a 79.32% accuracy for moderate-to-severe OSA and 74.37% accuracy for severe OSA. Snoring events and the visceral fat level were the most and second most essential features of screening for OSA risk., Conclusions: The established model can be considered for screening for the risk of having moderate-to-severe or severe OSA., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Stereotactic ablative radiotherapy (SABR) is now the standard of care for patients with inoperable early-stage lung cancer. Many of these patients are elderly. EGFR (epidermal growth factor receptor) mutation is also common in the Asian population., Methods: To evaluate the effects of old age and EGFR mutation on treatment outcomes and toxicity, we reviewed the medical records of 71 consecutive patients with inoperable early-stage non-small cell lung cancer (NSCLC) who received SABR at Taipei Veterans General Hospital between 2015 and 2021., Results: The study revealed that median age, follow-up, Charlson comorbidity index, and ECOG score were 80 years, 2.48 years, 3, and 1, respectively. Of these patients, 37 (52.1%) were 80 years or older, and 50 (70.4%) and 21 (29.6%) had T1 and T2 diseases, respectively. EGFR mutation status was available for 33 (46.5%) patients, of whom 16 (51.5%) had a mutation. The overall survival rates at 1, 3, and 5 years were 97.2, 74.9, and 58.3%, respectively. The local control rate at 1, 3, and 5 years was 97.1, 92.5, and 92.5%, respectively. Using Cox proportional hazards regression we found that male sex was a risk factor for overall survival (p = 0.036, 95% CI: 1.118-26.188). Two patients had grade 2 pneumonitis, but no other grade 2 or higher toxicity was observed. We did not find any significant differences in treatment outcomes or toxicity between patients aged 80 or older and those with EGFR mutations in this cohort., Conclusion: These findings indicate that age and EGFR mutation status do not significantly affect the effectiveness or toxicity of SABR for patients with inoperable early-stage NSCLC., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Aims: To investigate the safety profile, dose-limiting toxicity and antitumor activity of PEP503 (NBTXR3) nanoparticles with radiotherapy and concurrent chemotherapy in patients with locally advanced or unresectable rectal cancer. Methods: Patients will receive a single intratumoral injection of the nanoparticles, followed by radiotherapy and intravenous infusion of fluorouracil or oral capecitabine concurrently. In phase Ib (escalation phase, 3 + 3 design), volume escalation is based on the tumor volume of 5, 10, 15 and 22% of total baseline tumor volume. In phase II (expansion phase), 18 additional patients will be enrolled. Discussion: This study will be the first prospective, open-label, single-arm, nonrandomized study to investigate the efficacy and safety profile of PEP503 (NBTXR3) nanoparticles with radiotherapy and chemotherapy in these patients. Trial registration number: NCT02465593 (ClinicalTrials.gov).

Glioblastoma (GBM) is one of the most aggressive tumors in the adult central nervous system. We previously revealed that circadian regulation of glioma stem cells (GSCs) affects GBM hallmarks of immunosuppression and GSC maintenance in a paracrine and autocrine manner. Here, we expand the mechanism involved in angiogenesis, another critical GBM hallmark, as a potential basis underlying CLOCK's pro-tumor effect in GBM. Mechanistically, CLOCK-directed olfactomedin like 3 (OLFML3) expression results in hypoxia-inducible factor 1-alpha (HIF1α)-mediated transcriptional upregulation of periostin (POSTN). As a result, secreted POSTN promotes tumor angiogenesis via activation of the TANK-binding kinase 1 (TBK1) signaling in endothelial cells. In GBM mouse and patient-derived xenograft models, blockade of the CLOCK-directed POSTN-TBK1 axis inhibits tumor progression and angiogenesis. Thus, the CLOCK-POSTN-TBK1 circuit coordinates a key tumor-endothelial cell interaction and represents an actionable therapeutic target for GBM., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Obstructive sleep apnea (OSA) is a risk factor for neurodegenerative diseases. This study determined whether continuous positive airway pressure (CPAP), which can alleviate OSA symptoms, can reduce neurochemical biomarker levels. Thirty patients with OSA and normal cognitive function were recruited and divided into the control ( n = 10) and CPAP ( n = 20) groups. Next, we examined their in-lab sleep data (polysomnography and CPAP titration), sleep-related questionnaire outcomes, and neurochemical biomarker levels at baseline and the 3-month follow-up. The paired t-test and Wilcoxon signed-rank test were used to examine changes. Analysis of covariance (ANCOVA) was performed to increase the robustness of outcomes. The Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index scores were significantly decreased in the CPAP group. The mean levels of total tau (T-Tau), amyloid-beta-42 (Aβ 42 ), and the product of the two (Aβ 42 × T-Tau) increased considerably in the control group (ΔT-Tau: 2.31 pg/mL; ΔAβ 42 : 0.58 pg/mL; ΔAβ 42 × T-Tau: 48.73 pg 2 /mL 2 ), whereas the mean levels of T-Tau and the product of T-Tau and Aβ 42 decreased considerably in the CPAP group (ΔT-Tau: -2.22 pg/mL; ΔAβ 42 × T-Tau: -44.35 pg 2 /mL 2 ). The results of ANCOVA with adjustment for age, sex, body mass index, baseline measurements, and apnea-hypopnea index demonstrated significant differences in neurochemical biomarker levels between the CPAP and control groups. The findings indicate that CPAP may reduce neurochemical biomarker levels by alleviating OSA symptoms.

Patients with hematologic malignancies (HMs) have a significantly elevated risk of mortality compared to other cancer patients treated in the intensive care unit (ICU). The prognostic impact of numerous poor outcome indicators has changed, and research has yielded conflicting results. This study aims to determine the ICU and hospital outcomes and risk factors that predict the prognosis of critically ill patients with HMs. In this retrospective study, conducted at a referral hospital in Taiwan, 213 adult patients with HMs who were admitted to the medical ICU were evaluated. We collected clinical data upon hospital and ICU admission. Using a multivariate regression analysis, the predictors of ICU and hospital mortality were assessed. Then, a scoring system (Hospital outcome of critically ill patients with Hematological Malignancies (HHM)) was built to predict hospital outcomes. Most HMs (76.1%) were classified as high grade, and more than one-third of patients experienced a relapsed or refractory disease. The ICU and hospital mortality rates were 55.9% and 71.8%, respectively. Moreover, the disease severity was high (median Sequential Organ Failure Assessment (SOFA) score: 11 and Acute Physiology and Chronic Health Evaluation (APACHE II) score: 28). The multivariate analysis revealed that high-grade HMs, invasive mechanical ventilation requirement, renal replacement therapy initiation in the ICU, and a high SOFA score correlated with ICU mortality. Furthermore, a higher HHM score predicted hospital mortality. This study demonstrates that ICU mortality primarily correlates with the severity of organ dysfunction, whereas the disease status markedly influences hospital outcomes. Furthermore, the HHM score significantly predicts hospital mortality.

Poor supervision, impaired exercise adherence, and low compliance with exercise regimens result in inconsistent effects regarding exercise interventions. A supervised-walk training regimen (9 km/week) may have a positive effect on functional recovery in female total knee arthroplasty (TKA). This study aimed to evaluate the effect of a supervised walking regimen on lower limb muscle strength, functional fitness, and patient-reported outcomes in female TKA. Twenty-eight female TKA were allocated into a control (CON) ( n = 14) or walk training (WT) ( n = 14) group. WT on treadmills was initiated 12 weeks after TKA. All patients were examined for lower muscle strength (including extension and flexion of hip and knee), physical function (including a 6-min walk test, 8-foot up-and-go test, and 30-s chair stand test), and Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. Knee flexor (WT: CON; 64.4 ± 4.1 nm/kg: 43.7±3.3 nm/kg; p = 0.001; effect size: 5.62) and extensor strengths (WT: CON; 73.1 ± 7.5 nm/kg: 48.2 ± 2.4 nm/kg; p = 0.001; effect size: 4.47) statistically increased in the WT group compared to the CON group. The 6-min walk test (from 341.3 ± 20.5 m to 405.5 ± 30.7 m; p = 0.001; effect size: 2.46) and 8-foot up-and-go test (from 9.5 ± 0.7 s to 8.3 ± 0.7 s; p = 0.002; effect size: 1.71) tests also showed significant improvements in the WT group in the follow-up compared to the baseline. An increase in quality of life score according to the KOOS questionnaire (WT: CON; 91.0 ± 2.8: 68.1 ± 5.8; p = 0.001; effect size: 5.02) was noted in the WT group compared to the CON group in the follow-up. WT facilitated improvements in knee muscle strength and functional outcomes in TKA patients.

Background: Pneumoconiosis has considerable comorbidities, most notably pulmonary and cardiovascular diseases. However, the relationship between pneumoconiosis and chronic kidney disease (CKD) is largely unknown. The present study aimed to use a retrospective cohort study design to further clarify the association between pneumoconiosis and subsequent CKD risk. Methods: This is a nationwide, population-based, retrospective cohort study that used data from Taiwan’s National Health Insurance Database. Between 2008 and 2018, 17,952 newly diagnosed patients were included in the pneumoconiosis cohort, while 71,808 individuals without pneumoconiosis were included in the comparison cohort, with a propensity score matching for age, gender, and date of pneumoconiosis diagnosis. The development of CKD was monitored until the end of 2019. The risk was assessed using Cox proportional hazard regression models. Results: After controlling for age, gender, and comorbidity, the overall incidence of CKD was 1.69-fold higher in the pneumoconiosis cohort than in the comparison cohort (19.71 vs. 11.76 per 1000 person-years, respectively, p < 0.001), with an adjusted hazard ratio of 1.83 (95% confidence interval: 1.73−1.93). Stratified analyses by age group, gender, and presence of comorbidity revealed that the adjusted hazard ratios of CKD associated with pneumoconiosis remained significant (8/9). Furthermore, pneumoconiosis and tri-high (hypertension, hyperglycemia, and hyperlipidemia) interact positively with CKD development (p < 0.001). Conclusion: Patients with pneumoconiosis had a significantly higher risk of developing CKD than those without. Pneumoconiosis combined with hypertension, hyperglycemia, or hyperlipidemia would increase the risk even further. More studies are required to understand the possible pathophysiological mechanisms., Competing Interests: The authors declare no conflict of interest.

Introduction: High-intensity exercise causes oxidative stress, muscle soreness, and muscle fatigue, leading to reduced exercise performance. Curcumin possesses antioxidative and anti-inflammatory properties and thus alleviates postexercise damage. Therefore, this study evaluated the effect of curcumin on athletes' postexercise recovery., Methods: A non-randomized prospective cohort investigation was done. We recruited middle and high school athletes engaged in wrestling, soccer, and soft tennis. During the 12-week daily exercise training, the participants were assigned to receive curcumin supplementation (curcumin group) or not (control group). Body composition, exercise performance, inflammatory factors, muscle fatigue, and muscle soreness were recorded at the baseline and end of the study. We used the Mann-Whitney U test to compare the participants' demographics, such as age, height, weight, and training years. The Wilcoxon test was used to compare the differences between the groups before and after curcumin supplementation., Results: Of 28 participants (21 men and 7 women, with a mean age of 17 years), 13 were in the curcumin group and 15 in the control group. A significant decrease in muscle fatigue and muscle soreness scores was observed in the curcumin group after 12 weeks. Moreover, a significant decrease in the 8-hydroxy-2 deoxyguanosine level and a significant increase in basic metabolic rate and fat-free mass were observed in the curcumin group., Conclusion: Curcumin can reduce muscle fatigue and soreness after exercise, indicating its potential to alleviate postexercise damage. It could be considered to cooperate with nutritional supplements in regular training in adolescent athletes., 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 Bai, Liu, Fan, Kuo, Hsu, Yu and Chen.)

Background: Aeromonas necrotizing fasciitis (NF) causes high rates of amputation and mortality, even after aggressive surgical debridement and antibacterial therapy. This study investigated the effects of rational use of antibiotics and education by infectious disease (ID) physicians on Aeromonas NF treatment outcomes., Methods: Retrospective review for conducted for four years (period I, without an ID physician, December 2001 to December 2005) and 15 years (period II, with an ID physician, January 2006 to March 2021). In period II, the hospital-wide computerized antimicrobial approval system (HCAAS) was also implemented. A pretest-posttest time series analysis compared the two periods. Differences in clinical outcomes, demographics, comorbidities, signs and symptoms, laboratory findings, Aeromonas antibiotic susceptibility, and antibiotic regimens were compared between the two periods., Results: There were 19 patients in period I and 53 patients in period II. Patients had a lower rate of amputation or mortality in period II (35.8%) compared with period I (63.2%). Forty-four patients (61.1%) had polymicrobial infections. In the emergency room, the rate of misdiagnosis decreased from 47.4% in period I to 28.3% in period II, while effective empiric antibiotic usage increased from 21.1% in period I to 66.0% in period II. After the ID physician's adjustment, 69.4% received monotherapy in period II compared to 33.3% in period I., Conclusions: Because Aeromonas NF had a high mortality rate and was often polymicrobial, choosing an antibiotic regimen was difficult. Using the HCAAS by an experienced ID physician can improve rational antibiotic usage and clinical outcomes in Aeromonas NF.

Objectives: Obstructive sleep apnea (OSA) may increase the risk of Alzheimer's disease (AD). However, potential associations among sleep-disordered breathing, hypoxia, and OSA-induced arousal responses should be investigated. This study determined differences in sleep parameters and investigated the relationship between such parameters and the risk of AD., Methods: Patients with suspected OSA were recruited and underwent in-lab polysomnography (PSG). Subsequently, blood samples were collected from participants. Patients' plasma levels of total tau (T-Tau) and amyloid beta-peptide 42 (Aβ 42 ) were measured using an ultrasensitive immunomagnetic reduction assay. Next, the participants were categorized into low- and high-risk groups on the basis of the computed product (Aβ 42 × T-Tau, the cutoff for AD risk). PSG parameters were analyzed and compared., Results: We included 36 patients in this study, of whom 18 and 18 were assigned to the low- and high-risk groups, respectively. The average apnea-hypopnea index (AHI), apnea, hypopnea index [during rapid eye movement (REM) and non-REM (NREM) sleep], and oxygen desaturation index (≥3%, ODI-3%) values of the high-risk group were significantly higher than those of the low-risk group. Similarly, the mean arousal index and respiratory arousal index (R-ArI) of the high-risk group were significantly higher than those of the low-risk group. Sleep-disordered breathing indices, oxygen desaturation, and arousal responses were significantly associated with an increased risk of AD. Positive associations were observed among the AHI, ODI-3%, R-ArI, and computed product., Conclusions: Recurrent sleep-disordered breathing, intermittent hypoxia, and arousal responses, including those occurring during the NREM stage, were associated with AD risk. However, a longitudinal study should be conducted to investigate the causal relationships among these factors., 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 © 2022 Tsai, Wu, Kuan, Lin, Hsu, Hsu, Liu, Majumdar, Stettler, Yang, Lee, Wu, Lee, Wu, Kang and Liu.)

We demonstrate that several visible-light-mediated carbon-heteroatom cross-coupling reactions can be carried out using a photoactive Ni II precatalyst that forms in situ from a nickel salt and a bipyridine ligand decorated with two carbazole groups (Ni(Czbpy)Cl 2 ). The activation of this precatalyst towards cross-coupling reactions follows a hitherto undisclosed mechanism that is different from previously reported light-responsive nickel complexes that undergo metal-to-ligand charge transfer. Theoretical and spectroscopic investigations revealed that irradiation of Ni(Czbpy)Cl 2 with visible light causes an initial intraligand charge transfer event that triggers productive catalysis. Ligand polymerization affords a porous, recyclable organic polymer for heterogeneous nickel catalysis of cross-coupling reactions. The heterogeneous catalyst shows stable performance in a packed-bed flow reactor during a week of continuous operation., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Obstructive sleep apnea (OSA) is a global health concern and is typically diagnosed using in-laboratory polysomnography (PSG). However, PSG is highly time-consuming and labor-intensive. We, therefore, developed machine learning models based on easily accessed anthropometric features to screen for the risk of moderate to severe and severe OSA. We enrolled 3503 patients from Taiwan and determined their PSG parameters and anthropometric features. Subsequently, we compared the mean values among patients with different OSA severity and considered correlations among all participants. We developed models based on the following machine learning approaches: logistic regression, k-nearest neighbors, naïve Bayes, random forest (RF), support vector machine, and XGBoost. Collected data were first independently split into two data sets (training and validation: 80%; testing: 20%). Thereafter, we adopted the model with the highest accuracy in the training and validation stage to predict the testing set. We explored the importance of each feature in the OSA risk screening by calculating the Shapley values of each input variable. The RF model achieved the highest accuracy for moderate to severe (84.74%) and severe (72.61%) OSA. The level of visceral fat was found to be a predominant feature in the risk screening models of OSA with the aforementioned levels of severity. Our machine learning models can be employed to screen for OSA risk in the populations in Taiwan and in those with similar craniofacial structures.

Cadmium (Cd) is an ecological pollutant which causes hazardous effects in animals and humans. The aim of this study was to investigate the role of α-bisabolol (BISA) in antagonizing the Cd-induced hepatotoxicity in ducks. Two-week old ducks were allocated into 8 groups (10 ducks/group): Group I received basal diet and was gavaged with sunflower oil (BISA vehicle, 1.1 mL/kg/day); group II was administered BISA orally (50 mg/kg/day; diluted with sunflower oil); groups III, IV, and V were fed the basal diet mixed with CdCl 2 at 37.5, 75, and 150 mg/kg diet, respectively, and were gavaged with sunflower oil; group VI, VII, and VIII were given basal diet containing CdCl 2 at the aforementioned consecutive doses plus BISA. All treatments were provided daily for 4 weeks. Exposure to CdCl 2 induced mortality in ducks, increased hepatic Cd content and serum levels of hepatopathic biomarkers, and caused oxidative stress and morphological alterations in ducks' liver. Furthermore, exposure to Cd caused upregulation of the mRNA of proinflammatory cytokine tumor necrosis factor-α and apoptotic gene Bax, and that of cyclooxygenase-2 protein in the liver. All effects of Cd were dose-dependent. BISA antagonized all of the aforementioned CdCl 2 -induced changes. These findings suggested that BISA exert the hepatoprotective effect against Cd toxicity through reducing the hepatic content of Cd as well as antagonizing oxidative insults, inflammation, and apoptosis. Thus, BISA has a great potential to be used as an antidote in the control of Cd poisoning., 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 © 2022 Elazab and Hsu.)

Introduction: Medical-related long-term care (LTC) service use among community-dwelling older adults in Taiwan is resource-intensive, and planning is essential to promote aging-in-place., Methods: Administrative data from 4/1/2017 to 11/26/2019 among more than 14,000 residents were analyzed with generalized estimating equations (GEEs) to identify determinants of medical-related LTC service use., Results: Older adults using medical-related LTC services tended to be younger (79.9 vs. 80.7; p<.0001), male (42.7% vs. 38.5%; p<.0001), multi-morbid (3.1 vs. 2.5; p<.0001), and higher mean activities of daily living (ADL) disability (8.2 vs. 4.2; p<.0001), instrumental ADL (IADL) disability (11.0 vs. 9.1; p<.0001), and hospitalizations (1.1 vs. 0.4; p<.0001). Significant determinants of medical-related LTC services include age, education, stroke, coronary heart disease, diabetes, vision impairment, ADL disability, and prior hospitalization., Discussion: The success of LTC 2.0 will depend on ADL support and care coordination to manage chronic conditions such as diabetes, vision impairment, coronary heart disease, and stroke., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM), which is a malignant primary brain tumor, is the cancer that spreads most aggressively into the adjacent brain tissue. Patients with metastatic GBM have a poor chance of survival. In this study, we examined the anti-GBM mobility effect of small protein, called GMI, which is cloned and purified from Ganoderma microsporum. Proteomic profiles showed that GMI-mediated proteins were involved in cell motility and cell growth functions. Specifically, we demonstrated that GMI significantly suppressed cell migration and invasion of GBM cells. GMI combined with temozolomide (TMZ), which is a traditional chemotherapeutic agent for GBM treatment, synergistically inhibited motility in GBM cells. Mechanistically, we demonstrated that GMI induced proteasome-dependent degradation of Slug, which is a critical transcription factor, is frequently linked to metastasis and drug resistance in GBM. Knockdown of Slug reduced cell viability and colony formation of GBM cells but enhanced TMZ-suppressed cell migration and viability. The results of this study show that targeting Slug degradation is involved in GMI-suppressed mobility of GBM cells. Moreover, GMI may be a potential supplementary agent for the suppression of GBM., 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 © 2022 Elsevier B.V. All rights reserved.)

Background: Advances in surgical techniques and treatment modalities have improved the outcomes of esophageal cancer, yet difficult decision making for physicians while encountering multiple primary cancers (MPCs) continues to exist. The aim of this study was to evaluate long-term survival for esophageal squamous cell carcinoma (SCC) associated with MPCs. Methods: Data from 544 patients with esophageal SCC who underwent surgery between 2005 and 2017 were reviewed to identify the presence of simultaneous or metachronous primary cancers. The prognostic factors for overall survival (OS) were analyzed. Results: Three hundred and ninety-seven patients after curative esophagectomy were included, with a median observation time of 44.2 months (range 2.6−178.6 months). Out of 52 patients (13.1%) with antecedent/synchronous cancers and 296 patients without MPCs (control group), 49 patients (12.3%) developed subsequent cancers after surgery. The most common site of other primary cancers was the head and neck (69/101; 68.3%), which showed no inferiority in OS. Sex and advanced clinical stage (III/IV) were independent risk factors (p = 0.031 and p < 0.001, respectively). Conclusion: Once curative esophagectomy can be achieved, surgery should be selected as a potential therapeutic approach if indicated, even with antecedent/synchronous MPCs. Subsequent primary cancers were often observed in esophageal SCC, and optimal surveillance planning was recommended.

Breast cancer is a heterogeneous disease, and the survival rate of patients with breast cancer strongly depends on their stage and clinicopathological features. Chemoradiation therapy is commonly employed to improve the survivability of patients with advanced breast cancer. However, the treatment process is often accompanied by the development of drug resistance, which eventually leads to treatment failure. Metabolism reprogramming has been recognized as a mechanism of breast cancer resistance. In this study, we established a doxorubicin-resistant MCF-7 (MCF-7-D500) cell line through a series of long-term doxorubicin in vitro treatments. Our data revealed that MCF-7-D500 cells exhibited increased multiple-drug resistance, cancer stemness, and invasiveness compared with parental cells. We analyzed the metabolic profiles of MCF-7 and MCF-7-D500 cells through liquid chromatography−mass spectrometry. We observed significant changes in 25 metabolites, of which, 21 exhibited increased levels (>1.5-fold change and p < 0.05) and 4 exhibited decreased levels (<0.75-fold change and p < 0.05) in MCF-7 cells with doxorubicin resistance. These results suggest the involvement of metabolism reprogramming in the development of drug resistance in breast cancer, especially the activation of glycolysis, the tricarboxylic acid (TCA) cycle, and the hexamine biosynthesis pathway (HBP). Furthermore, most of the enzymes involved in glycolysis, the HBP, and the TCA cycle were upregulated in MCF-7-D500 cells and contributed to the poor prognosis of patients with breast cancer. Our findings provide new insights into the regulation of drug resistance in breast cancer, and these drug resistance-related metabolic pathways can serve as targets for the treatment of chemoresistance in breast cancer.

Backgrounds and Aims: Given problematic Internet usage's (PIU) negative impact on individual health, this study evaluates how adverse childhood experiences (ACEs) affect young adults' PIU and the possible underlying mechanism of the "feeling of loneliness" (FOL) trajectory., Methods: Analyzing a retrospective cohort sample from the Taiwan Youth Project, 2,393 adolescents were interviewed from the average ages of 14-28. We constructed ACE in 2000 using six categories (e.g., abuse and low family socioeconomic status) and 5-item PIU in 2017 from Chen's Internet Addiction Scale. FOL trajectories measured eight times, at average ages 14, 16, 17, 18, 20, 22, 25, 28 years-old., Results: Overall, 12.65% of the participants did not have ACEs, and 12.78% exhibited PIU. FOL trajectory analyses yielded three groups: "constant low" (reference group: 53.25%); "moderate decline" (36.81%); and "increasing" (9.94%). Regression models showed a dose-response association between ACE and young adults' PIU (adjusted odds ratio = 1.12; 95% confidence interval [CI] = 1.02-1.23) and the two risky loneliness groups (moderate decline: relative risk ratio [RRR] = 1.42, 95% CI = 1.32-1.54; increasing: RRR = 1.52, 95% CI = 1.37-1.71). Structural equation modeling further found that ACEs increase young adults' risk of being in the increasing group, and consequently, the risk of PIU., Discussion and Conclusions: We demonstrated that ACE may be associated with 1) adults' PIU, 2) FOL from adolescence to emerging adulthood, and 3) young adults' PIU through its association with FOL trajectories.

(a) Objective: Obstructive sleep apnea syndrome (OSAS) is typically diagnosed through polysomnography (PSG). However, PSG incurs high medical costs. This study developed new models for screening the risk of moderate-to-severe OSAS (apnea-hypopnea index, AHI ≥15) and severe OSAS (AHI ≥30) in various age groups and sexes by using anthropometric features in the Taiwan population.(b) Participants: Data were derived from 10,391 northern Taiwan patients who underwent PSG.(c) Methods: Patients' characteristics - namely age, sex, body mass index (BMI), neck circumference, and waist circumference - was obtained. To develop an age- and sex-independent model, various approaches - namely logistic regression, k-nearest neighbor, naive Bayes, random forest (RF), and support vector machine - were trained for four groups based on sex and age (men or women; aged <50 or ≥50 years). Dataset was separated independently (training:70%; validation: 10%; testing: 20%) and Cross-validated grid search was applied for model optimization. Models demonstrating the highest overall accuracy in validation outcomes for the four groups were used to predict the testing dataset.(d) Results: The RF models showed the highest overall accuracy. BMI was the most influential parameter in both types of OSAS severity screening models.(e) Conclusion: The established models can be applied to screen OSAS risk in the Taiwan population and those with similar craniofacial features.

Background: Patients with oral cancer are at higher risk of developing second primary esophageal cancer (SPEC) and the consensus for screening strategies remains unclear. This study aimed to examine comparative effectiveness and the stage-shift effect of endoscopic exam among patients with oral cancer., Method: A population-based longitudinal retrospective observational matched case and control cohort study with at least 5 years follow-up was conducted. We identified 45 457 newly diagnosed patients with oral cancer, 2004-2013, and the eligible patient with oral cancer was 39 401. Propensity score matching was used to match comparable groups, and the two groups (screening vs. nonscreening) was 5941, individually. The study primary endpoints were to compare detection of incident SPEC and the stage-shift effect of endoscopic screening between screened and nonscreened incident oral cancer patients. Cox proportional hazard and competing risk models were analyzed. Statistical analyses were conducted in 2020-2021., Result: Detection of incident SPEC in the screened group was significantly higher than in the nonscreened group (hazard ratio: 2.92, 95% confidence interval [CI]: 2.29-3.72). The stage-shift effect from endoscopic screening was found overall in patients with oral cancer (odds ratio [OR]: 0.39, 95%CI: 0.21-0.70), in particular in advanced-stage patients (OR: 0.25, 95%CI: 0.11-0.61), but not in early-stage patients (OR: 0.60, 95%CI: 0.26-1.40)., Conclusion: This study confirmed that endoscopic screening achieved early detection of SPEC among patients with oral cancer. To improve the screening stage-shift effect, patients with oral cancer are encouraged to undergo routine endoscopic screening., (© 2022 Wiley Periodicals LLC.)

Background: Despite patients with severe coronavirus disease (COVID-19) receiving standard triple therapy, including steroids, antiviral agents, and anticytokine therapy, health condition of certain patients continue to deteriorate. In Taiwan, the COVID-19 mortality has been high since the emergence of previous variants of this disease (such as alpha, beta, or delta). We aimed to evaluate whether adjunctive infusion of human umbilical cord mesenchymal stem cells (MSCs) (hUC-MSCs) on top of dexamethasone, remdesivir, and tocilizumab improves pulmonary oxygenation and suppresses inflammatory cytokines in patients with severe COVID-19., Methods: Hospitalized patients with severe or critical COVID-19 pneumonia under standard triple therapy were separated into adjuvant hUC-MSC and non-hUC-MSC groups to compare the changes in the arterial partial pressure of oxygen (PaO 2 )/fraction of inspired oxygen (FiO 2 ) ratio and biological variables., Results: Four out of eight patients with severe or critical COVID-19 received either one ( n = 2) or two ( n = 2) doses of intravenous infusions of hUC-MSCs using a uniform cell dose of 1.0 × 10 8 . Both high-sensitivity C-reactive protein (hs-CRP) level and monocyte distribution width (MDW) were significantly reduced, with a reduction in the levels of interleukin (IL)-6, IL-13, IL-12p70 and vascular endothelial growth factor following hUC-MSC transplantation. The PaO 2 /FiO 2 ratio increased from 83.68 (64.34-126.75) to 227.50 (185.25-237.50) and then 349.56 (293.03-367.92) within 7 days after hUC-MSC infusion ( P < 0.001), while the change of PaO 2 /FiO 2 ratio was insignificant in non-hUC-MSC patients (admission day: 165.00 [102.50-237.61]; day 3: 100.00 [72.00-232.68]; day 7: 250.00 [71.00-251.43], P = 0.923)., Conclusion: Transplantation of hUC-MSCs as adjunctive therapy improves pulmonary oxygenation in patients with severe or critical COVID-19. The beneficial effects of hUC-MSCs were presumably mediated by the mitigation of inflammatory cytokines, characterized by the reduction in both hs-CRP and MDW., 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 © 2022 Chen, Chang, Lin, Ho, Cheng, Shih, Chou, Lin, Chi, Lu, Tien, Wu, Chang, Hsu, Shyu, Cho and Jeng.)

Studies have shown aspirin decreases the risk of some cancers. However, the evidence reported the association between aspirin and cancer risk in the diabetic population. In this study, we investigate whether aspirin and dipyridamole decrease the risk of cancer in patients with type 2 diabetes. A total of 5308 patients with type 2 diabetes were identified by the National Health Insurance from 1998 to 2000 and followed up until 2013. The demographic characteristics among nondipyridamole nor aspirin, aspirin, and dipyridamole users were analyzed by using the χ(2) test. Cox proportional hazard regression models were used to determine the independent effects of no aspirin nor dipyridamole, aspirin, and dipyridamole users on the risk of different cancer. After adjustment with multiple covariates, both low and high doses of aspirin and dipyridamole decrease liver cancer with risk ratios of 0.56 (95% CI, 0.37-0.83), 0.14 (95% CI, 0.05-0.39), 0.61 (95% CI, 0.38-0.99), and 0.28 (95% CI, 0.12-0.66), respectively. Both low and high doses of aspirin decrease any types of cancer with risk ratios of 0.79 (95% CI, 0.64-0.98) and 0.49 (95% CI, 0.34-0.70), respectively. Therefore, we conclude aspirin may decrease any types of cancer and liver cancer, and dipyridamole may decrease the risk of liver cancer in patients with type 2 diabetes., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Metallaphotoredox catalysis is a powerful and versatile synthetic platform that enables cross-couplings under mild conditions without the need for noble metals. Its growing adoption in drug discovery has translated into an increased interest in sustainable and scalable reaction conditions. Here, we report a continuous-flow approach to metallaphotoredox catalysis using a heterogeneous catalyst that combines the function of a photo- and a nickel catalyst in a single material. The catalyst is embedded in a packed-bed reactor to combine reaction and (catalyst) separation in one step. The use of a packed bed simplifies the translation of optimized batch reaction conditions to continuous flow, as the only components present in the reaction mixture are the substrate and a base. The metallaphotoredox cross-coupling of sulfinates with aryl halides was used as a model system. The catalyst was shown to be stable, with a very low decrease of the yield (≈1% per day) during a continuous experiment over seven days, and to be effective for C-O arylations when carboxylic acids are used as nucleophile instead of sulfinates., (Copyright © 2022, Hsu et al.)

Background: Although lung protective strategy and adjunctive intervention are associated with improved survival in patients with acute respiratory distress syndrome (ARDS), the implementation of effective therapies remains low. This study aimed to evaluate whether the use of business intelligence (BI) for real-time data visualization is associated with an improvement in lung protective strategy and adjunctive therapy., Methods: A retrospective observational cohort study was conducted on patients with ARDS admitted between September 2020 and June 2021 at two intensive care units (ICUs) of a tertiary referral hospital in Taiwan. BI was imported for data visualization and integration to assist in clinical decision in one of the ICUs. The primary outcomes were the implementation of low tidal volume ventilation (defined as tidal volume/predicted body weight ≤ 8 mL/kg) within 24 h from ARDS onset. The secondary outcomes included ICU and hospital mortality rates., Results: Among the 1201 patients admitted to the ICUs during the study period, 148 (12.3%) fulfilled the ARDS criteria, with 86 patients in the BI-assisted group and 62 patients in the standard-of-care (SOC) group. Disease severity was similar between the two groups. The application of low tidal volume ventilation strategy was significantly improved in the BI-assisted group compared with that in the SOC group (79.1% vs. 61.3%, p = 0.018). Despite their ARDS and disease severity, the BI-assisted group tended to achieve low tidal volume ventilation. The ICU and hospital mortality were lower in the BI-assisted group., Conclusions: The use of real-time visualization system for data-driven decision support was associated with significantly improved compliance to low tidal volume ventilation strategy, which enhanced the outcomes of patients with ARDS in the ICU., (© 2022. The Author(s).)

Tumor necrosis factor (TNF)-α is involved in the pathogenesis of cardiac injury, inflammation, and apoptosis. It is a crucial pro-inflammatory cytokine in many heart disorders, including chronic heart failure and ischemic heart disease, contributing to cardiac remodeling and dysfunction. The implication of TNF-α in inflammatory responses in the heart has been indicated to be mediated through the induction of C-C Motif Chemokine Ligand 20 (CCL20). However, the detailed mechanisms of TNF-α-induced CCL20 upregulation in human cardiac fibroblasts (HCFs) are not completely defined. We demonstrated that in HCFs, TNF-α induced CCL20 mRNA expression and promoter activity leading to an increase in the secretion of CCL20. TNF-α-mediated responses were attenuated by pretreatment with TNFR1 antibody, the inhibitor of epidermal growth factor receptor (EGFR) (AG1478), p38 mitogen-activated protein kinase (MAPK) (p38 inhibitor VIII, p38i VIII), c-Jun amino N-terminal kinase (JNK)1/2 (SP600125), nuclear factor kappaB (NF-κB) (helenalin), or forkhead box O (FoxO)1 (AS1841856) and transfection with siRNA of TNFR1, EGFR, p38α, JNK2, p65, or FoxO1. Moreover, TNF-α markedly induced EGFR, p38 MAPK, JNK1/2, FoxO1, and NF-κB p65 phosphorylation which was inhibited by their respective inhibitors in these cells. In addition, TNF-α-enhanced binding of FoxO1 or p65 to the CCL20 promoter was inhibited by p38i VIII, SP600125, and AS1841856, or helenalin, respectively. Accordingly, in HCFs, our findings are the first to clarify that TNF-α-induced CCL20 secretion is mediated through a TNFR1-dependent EGFR/p38 MAPK and JNK1/2/FoxO1 or NF-κB cascade. We demonstrated that TNFR1-derived EGFR transactivation is involved in the TNF-α-induced responses in these cells. Understanding the regulation of CCL20 expression by TNF-α on HCFs may provide a potential therapeutic strategy in cardiac inflammatory disorders.

Background: There is a lack of consensus regarding the optimal technique for revision posterior cruciate ligament (PCL) reconstruction., Purpose: To evaluate midterm outcomes after revision PCL reconstruction using a single-bundle transtibial autograft., Study Design: Case series; Level of evidence, 4., Methods: We reviewed 17 patients who underwent revision PCL reconstruction performed in our medical center by a single surgeon from 2003 to 2016. The cohort included 12 male and 5 female patients with a mean age of 31.3 years (range, 17-48 years). All of the patients underwent single-bundle transtibial reconstruction using the same surgical technique and were reviewed at a minimum of 4 years postoperatively. Preoperative and postoperative posterior stress radiography was performed. The preoperative tibial slope and tibiofemoral angle were also measured. Preoperative and postoperative functional outcomes were evaluated using the International Knee Documentation Committee (IKDC) subjective and objective scores as well as the Lysholm score., Results: The most common factor that contributed to the failure of primary surgery was misplaced tunnels, especially on the femoral side. There were 2 patients who had grade 2 laxity preoperatively, and 15 patients had grade 3 laxity preoperatively. At the latest follow-up, all 17 patients had grade 1 laxity. On posterior stress radiography, posterior displacement improved from 10.8 ± 2.1 mm preoperatively to 2.9 ± 1.1 mm at the latest follow-up ( P < .001). The IKDC subjective score improved from 34.9 ± 6.8 preoperatively to 75.3 ± 15.7 postoperatively ( P < .001), and the Lysholm score improved from 38.1 ± 10.0 preoperatively to 88.5 ± 7.6 postoperatively ( P < .001). All patients reached the minimal clinically important difference (MCID) for the Lysholm score, and 94% reached the MCID for the IKDC subjective score, with 65% reaching the Patient Acceptable Symptom State., Conclusion: According to the findings of this study, arthroscopic revision PCL reconstruction with a single-bundle transtibial autograft offered satisfactory outcomes at midterm follow-up., Competing Interests: The authors declared that there are no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2022.)

Aim: Patients with type 2 diabetes mellitus exhibited autonomic nervous system (ANS) dysfunction and comorbidities with depressive or anxiety symptoms were related to poor glycemic control. Heart rate variability (HRV) converted from electrocardiogram (ECG) has been used as the ANS index. The study aimed to explore the associations between depression, anxiety, HRV, and glycemic control in patients with type 2 diabetes mellitus., Methods: The Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) questionnaires were used to assess depressive and anxiety symptoms in 647 patients with type 2 diabetes mellitus (mean age was 63 ± 10 years, 56 % males). The ECG raw signals were collected from a 5-min sitting and resting baseline and then transformed to HRV indices referring ANS activation. Blood glucose and lipid profiles including glycated hemoglobin (HbA1c), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglyceride were obtained from the electronic medical records., Results: Ninety-nine (15 %) participants had depressive symptoms and 59 (9 %) had anxiety symptoms. Depression and HbA1c were negatively correlated with parasympathetic activation. Depression and anxiety were positively correlated with sympathetic activation. After controlling for demographic data and lipid profiles, depression was a significant positive predictor for HbA1c levels; and HRV indices (lnLF and lnHF) were the significant negative predictors for HbA1c levels. Mediation effect analysis showed that depression was a mediator between parasympathetic activation and glycemic control., Conclusions: Lower parasympathetic activation and higher depressive symptoms may affect glycemic control in patients with type 2 diabetes mellitus. Intervention programs targeting to increase parasympathetic activities and reducing depression could be further tested for their effects on glycemic outcomes for potential clinical use., (Copyright © 2022. Published by Elsevier Inc.)

Inactivation of adenomatous polyposis coli (APC) is common across many cancer types and serves as a critical initiating event in most sporadic colorectal cancers. APC deficiency activates WNT signaling, which remains an elusive target for cancer therapy, prompting us to apply the synthetic essentiality framework to identify druggable vulnerabilities for APC-deficient cancers. Tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient colorectal cancer. Mechanistically, APC deficiency results in the TCF4/β-catenin-mediated upregulation of TDO2 gene transcription. TDO2 in turn activates the Kyn-AhR pathway, which increases glycolysis to drive anabolic cancer cell growth and CXCL5 secretion to recruit macrophages into the tumor microenvironment. Therapeutically, APC-deficient colorectal cancer models were susceptible to TDO2 depletion or pharmacologic inhibition, which impaired cancer cell proliferation and enhanced antitumor immune profiles. Thus, APC deficiency activates a TCF4-TDO2-AhR-CXCL5 circuit that affects multiple cancer hallmarks via autonomous and nonautonomous mechanisms and illuminates a genotype-specific vulnerability in colorectal cancer., Significance: This study identifies critical effectors in the maintenance of APC-deficient colorectal cancer and demonstrates the relationship between APC/WNT pathway and kynurenine pathway signaling. It further determines the tumor-associated macrophage biology in APC-deficient colorectal cancer, informing genotype-specific therapeutic targets and the use of TDO2 inhibitors. This article is highlighted in the In This Issue feature, p. 1599., (©2022 American Association for Cancer Research.)

Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non-small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached., Significance: We report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599., (©2022 The Authors; Published by the American Association for Cancer Research.)

FOREVER YOUNG FLOWER (FYF) has been reported to play an important role in regulating flower senescence/abscission. Here, we functionally analyzed five Arabidopsis FYF-like genes, two in the FYF subgroup (FYL1/AGL71 and FYL2/AGL72) and three in the SOC1 subgroup (SOC1/AGL20, AGL19, and AGL14/XAL2), and showed their involvement in the regulation of flower senescence and/or abscission. We demonstrated that in FYF subgroup, FYF has both functions in suppressing flower senescence and abscission, FYL1 only suppresses flower abscission and FYL2 has been converted as an activator to promote flower senescence. In SOC1 subgroup, AGL19/AGL14/SOC1 have only one function in suppressing flower senescence. We also found that FYF-like proteins can form heterotetrameric complexes with different combinations of A/E functional proteins (such as AGL6 and SEP1) and AGL15/18-like proteins to perform their functions. These findings greatly expand the current knowledge behind the multifunctional evolution of FYF-like genes and uncover their regulatory network in plants., (© 2022. The Author(s).)

Background: Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of trinucleotide CAG repeat in the Huntingtin ( Htt ) gene. The major pathogenic pathways underlying HD involve the impairment of cellular energy homeostasis and DNA damage in the brain. The protein kinase ataxia-telangiectasia mutated (ATM) is an important regulator of the DNA damage response. ATM is involved in the phosphorylation of AMP-activated protein kinase (AMPK), suggesting that AMPK plays a critical role in response to DNA damage. Herein, we demonstrated that expression of polyQ-expanded mutant Htt (mHtt) enhanced the phosphorylation of ATM. Ginsenoside is the main and most effective component of Panax ginseng . However, the protective effect of a ginsenoside (compound K, CK) in HD remains unclear and warrants further investigation., Methods: This study used the R6/2 transgenic mouse model of HD and performed behavioral tests, survival rate, histological analyses, and immunoblot assays., Results: The systematic administration of CK into R6/2 mice suppressed the activation of ATM/AMPK and reduced neuronal toxicity and mHTT aggregation. Most importantly, CK increased neuronal density and lifespan and improved motor dysfunction in R6/2 mice. Conversely, CK enhanced the expression of Bcl2 protected striatal cells from the toxicity induced by the overactivation of mHtt and AMPK., Conclusions: Thus, the oral administration of CK reduced the disease progression and markedly enhanced lifespan in the transgenic mouse model (R6/2) of HD., Competing Interests: All the authors declare that they have no conflicts of interest., (© 2021 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Abstract: This study evaluated the incidence rate and risk factors for developing myopia in elementary school students in Chiayi, Taiwan. This prospective cohort study comprised 1816 students without myopia (grades 1 to 5 in Chiayi County). The students underwent a noncycloplegic ocular alignment examinations using an autorefractometer and completed a questionnaires at baseline and at a 1-year follow-up. A univariate logistic regression was used to assess the effects of the categorical variables on new cases of myopia. A multinomial logistic regression was then conducted. A chi-squared test was used to compare new cases of myopia in terms of ocular alignment. A Cox hazard ratio model was then used to validate factors associated with changes in ocular alignment. A P value of <.05 was considered significant. In 370 participants with new cases of myopia out of 1816 participants, a spherical error of -1.51 ± 0.6 diopters was noted at follow-up. The baseline ocular alignment was not a significant risk factor for developing myopia (exophoria vs orthophoria: OR 1.26, 95% CI 0.97-1.62; other vs. orthophoria: OR 1.15, 95% CI 0.73-1.82). However, new cases of myopia (HR 1.36, 95% CI 1.14-1.61), and baseline ocular alignment (exophoria vs orthophoria: HR 3.76, 95% CI 3.20-4.42; other vs orthophoria: HR 3.02, 95% CI 2.05-4.45) were associated with exophoria at follow-up. This study provided epidemiological data on the incidence of myopia in elementary school students in Chiayi, Taiwan. It also demonstrated that physiological exophoria does not predispose patients to developing myopia., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti-PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti-PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti-PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.

Background: Recurrent esophageal cancer is associated with dismal prognosis. There is no consensus about the role of surgical treatments in patients with limited recurrences. This study aimed to evaluate the role of surgical resection in patients with resectable recurrences after curative esophagectomy and to identify their prognostic factors., Methods: We retrospectively reviewed patients with recurrent esophageal cancer after curative esophagectomy between 2004 and 2017 and included those with oligo-recurrence that was amenable for surgical intent. The prognostic factors of overall survival (OS) and post-recurrence survival (PRS), as well as the survival impact of surgical resection, were analyzed., Results: Among 654 patients after curative esophagectomies reviewed, 284 (43.4%) had disease recurrences. The recurrences were found resectable in 63 (9.6%) patients, and 30 (4.6%) patients received surgery. The significant prognostic factors of PRS with poor outcome included mediastinum lymph node (LN) recurrence and pathologic T3 stage. In patients with and without surgical resection for recurrence cancer, the 3-year OS rates were 65.6 and 47.6% (p = 0.108), while the 3-year PRS rates were 42.9 and 23.5% (p = 0.100). In the subgroup analysis, surgery for resectable recurrence, compared with non-surgery, could achieve better PRS for patients without any comorbidities (hazard ratio 0.36, 95% CI: 0.14 to 0.94, p = 0.038)., Conclusions: Mediastinum LN recurrence or pathologic T3 was associated with worse OS and PRS in patients with oligo-recurrences after curative esophagectomies. No definite survival benefit was noted in patients undergoing surgery for resectable recurrence, except in those without comorbidities., (© 2022. The Author(s).)