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Yu-Wen Chiu,1 Yu-Hsiang Kao,1 Michael J Simoff,2 David E Ost,3 Oliver Wagner,4 James Lavin,4 Richard A Culbertson,1 Dean G Smith1 1Health Policy & Systems Management, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA; 2Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, Michigan, USA; 3Department of Pulmonology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 4Intuitive Surgical, Sunnyvale, California, USACorrespondence: Dean G SmithLSU Health Sciences Center – New Orleans, School of Public Health, 2020 Gravier St., New Orleans, LA, 70112, USAEmail dgsmith@lsuhsc.eduPurpose: To describe the distribution of diagnostic procedures, rates of complications, and total cost of biopsies for patients with lung cancer.Patients and Methods: Observational study using data from IBM Marketscan® Databases for continuously insured adult patients with a primary lung cancer diagnosis and treatment between July 2013 and June 2017. Costs of lung cancer diagnosis covered 6 months prior to index biopsy through treatment. Costs of chest CT scans, biopsy, and post-procedural complications were estimated from total payments. Costs of biopsies incidental to inpatient admissions were estimated by comparable outpatient biopsies.Results: The database included 22,870 patients who had a total of 37,160 biopsies, of which 16,009 (43.1%) were percutaneous, 14,997 (40.4%) bronchoscopic, 4072 (11.0%) surgical and 2082 (5.6%) mediastinoscopic. Multiple biopsies were performed on 41.9% of patients. The most common complications among patients receiving only one type of biopsy were pneumothorax (1304 patients, 8.4%), bleeding (744 patients, 4.8%) and intubation (400 patients, 2.6%). However, most complications did not require interventions that would add to costs. Median total costs were highest for inpatient surgical biopsies ($29,988) and lowest for outpatient percutaneous biopsies ($1028). Repeat biopsies of the same type increased costs by 40– 80%. Complications account for 13% of total costs.Conclusion: Costs of biopsies to confirm lung cancer diagnosis vary substantially by type of biopsy and setting. Multiple biopsies, inpatient procedures and complications result in higher costs.Keywords: cancer, diagnosis, economics, frequency

Background: Previous studies have shown that smoking tobacco significantly increases both incidence and mortality rates for many diseases. Social media has become one of the most influential platforms for various smoking cessation interventions. However, results from smoking cessation interventions have differed from study to study. Limited studies have summarised cessation outcomes from social media–based interventions. Therefore, the objective of this review is to explore the effectiveness of using social media for smoking cessation. Methods: We searched PubMed, MEDLINE, PsycINFO, and CINAHL for articles between June 2008 and June 2018, and also assessed the references of selected articles. We included studies that used social media as intervention platforms, provided a baseline assessment before the intervention, and provided smoking cessation outcomes after the intervention. Results: We identified 13 original studies that enrolled between 16 and 1698 participants; 7-day Point Prevalence Abstinence (PPA) rate was the most frequently used measure of abstinence, with a range of 7%–75%, regardless of the measurement time, study design, and analysis methods. Social media–based smoking cessation interventions were effective, because (1) smokers reported higher 7-day PPA rates after intervention compared to baseline and (2) smokers reported higher 7-day PPA rates in intervention groups than in control groups. Moreover, at each time point, approximately half of all smokers in studies reporting abstinence were found to be biochemically abstinent. There were no significant differences in the effectiveness of smoking cessation outcomes between those that used existing popular social networking platforms (e.g. Pechmann et al 's studies) and those that used individually designed interactive platforms (e.g. MyLastDip, iQuit system, Quitxt system). Conclusions: This review highlights the effectiveness of social media–based smoking cessation intervention studies. Due to the widespread use of social media, as well as its low cost, we suggest embedding smoking cessation interventions within existing popular social media platforms. [ABSTRACT FROM AUTHOR]

Radioembolization is an effective locoregional therapy for patients with intermediate or advanced stage hepatocellular carcinoma (HCC). It has been shown that radioembolization is safe in patients with portal vein thrombosis. This case report describes safe radioembolization after portal vein embolization in a patient with multifocal HCC. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Sarcoplasmic reticulum Ca-ATPases (SERCA2a) plays an essential role in the Ca homeostasis and cardiac functions. Tumor necrosis factor-alpha (TNF-alpha) decreases the SERCA2a, which may underlie cardiac dysfunction during sepsis and heart failure. Because the promoter region of SERCA2a contains CpG islands, gene methylation should be critical in regulating SERCA2a. The present study was to evaluate whether TNF-alpha can modulate SERCA2a via enhancing methylation and to investigate the underlying mechanisms. DESIGN: Controlled laboratory experiment. SETTING: University research laboratory. SUBJECTS: HL-1 cardiomyocytes. INTERVENTIONS: TNF-alpha (1-50 ng/mL) was administered in HL-1 cardiomyocytes with and without co-administration of an NF-kappaB inhibitor (SN-50, 50 microg/mL), antioxidant agents (ascorbic acid, 100 microM, or coenzyme Q10, 10 microM), or methylation inhibitor (5-aza-2'-deoxycytidine, 0.1, 1 microM). MEASUREMENTS AND MAIN RESULTS: TNF-alpha (50 ng/mL) decreased the SERCA2a RNA and protein by quantitative polymerase chain reaction and immunoblot. Furthermore, TNF-alpha (50 ng/mL) increased the methylation in the SERCA2a promoter region, which was not influenced by the co-administration of SN-50, ascorbic acid, or coenzyme Q10, but was attenuated by 5-aza-2'-deoxycytidine (0.1 microM). Additionally, TNF-alpha (50 ng/mL) increased the expression of DNA methyltransferase 1. CONCLUSIONS: TNF-alpha increased DNA methyltransferase levels, thus enhancing the methylation in the SERCA2a promoter region with a result of reducing SERCA2a. These findings suggest that inhibition of hypermethylation may be a novel treatment strategy for cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Introduction: Outstanding results have been achieved using vertebroplasty for the treatment of osteoporotic spinal compression fractures. However, few reports are available in the management of multiple-level compression fractures due to severe osteoporosis. This study prospectively evaluated the clinical and surgical outcomes of patients receiving vertebroplasty due to multiple-level osteoporotic spinal compression fractures. Patients and Methods: Eighteen patients underwent more than four levels of vertebroplasty due to multiple-level osteoporotic spinal compression fracture. All patients received a preoperative magnetic resonance imaging (MRI) check-up to determine which level needed vertebroplasty. Detailed evaluations were made in accordance with the patients' clinical tracking, pre- and postoperative daily activities, Denis pain scale, and Roland-Morris score. Results: After an average follow-up period of 36 months, the group receiving multiple-level vertebroplasty showed significant improvement, as registered on the Denis pain scale, Roland-Morris score, and in the activity of daily living. No major complications occurred during operation or postoperation, except one patient who expired due to suffocation at the rehabilitation center 3 weeks after vertebroplasty. Conclusions: The use of vertebroplasty with cement to treat multiple-level osteoporotic spinal compression fractures in the elderly does have value, and brings good results to patients which were previously unimaginable. Preoperative MRI to evaluate the non-union levels and determine which levels needed vertebroplasty is very important. [ABSTRACT FROM AUTHOR]

Objective: Most reports in the literature focus on the efficacy of a single procedure for obstructive sleep apnea (OSA). We review the overall efficacy of a surgical methodology based on localizing the level of anatomic obstruction for each patient and surgical correction of the nasal, oropharyngeal, or hypopharyngeal obstruction. Study design and setting Retrospective review of cases performed by a single practitioner using a systematic approach to surgery for OSA with preoperative and postoperative sleep studies.Results: Forty-two patients with a respiratory disturbance index (RDI) greater than 15 were included in the study. Surgery involved at least 2 levels of obstruction usually performed in 2 stages. All patients reported symptomatic improvement. Overall, 83.3% (35 of 42) of patients were cured according to the accepted RDI criteria of more than 50% reduction and final RDI of less than 20. All 21 patients with mild OSA (RDI, <29), 73% of patients with moderate OSA (RDI, 30 to 49), and 50% of patients with severe OSA (RDI, >50) were cured.Conclusion: The use of an anatomically based methodology in approaching patients with OSA seems to offer a higher efficacy than a single procedure as reported in the literature. [ABSTRACT FROM AUTHOR]

Background: The therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) on brain infarction area (BIA) and neurological status in a rat model of acute ischemic stroke (IS) was investigated.Methods: Adult male Sprague-Dawley (SD) rats (n = 30) were divided into IS plus intra-venous 1 mL saline (at 0, 12 and 24 h after IS induction) (control group) and IS plus intra-venous ADMSCs (2.0 x 106) (treated interval as controls) (treatment group) after occlusion of distal left internal carotid artery. The rats were sacrificed and brain tissues were harvested on day 21 after the procedure.Results: The results showed that BIA was larger in control group than in treatment group (p < 0.001). The sensorimotor functional test (Corner test) identified a higher frequency of turning movement to left in control group than in treatment group (p < 0.05). mRNA expressions of Bax, caspase 3, interleukin (IL)-18, toll-like receptor-4 and plasminogen activator inhibitor-1 were higher, whereas Bcl-2 and IL-8/Gro were lower in control group than in treatment group (all p < 0.05). Western blot demonstrated a lower CXCR4 and stromal-cell derived factor-1 (SDF-1) in control group than in treatment group (all p < 0.01). Immunohistofluorescent staining showed lower expressions of CXCR4, SDF-1, von Willebran factor and doublecortin, whereas the number of apoptotic nuclei on TUNEL assay was higher in control group than in treatment group (all p < 0.001). Immunohistochemical staining showed that cellular proliferation and number of small vessels were lower but glial fibrillary acid protein was higher in control group than in treatment group (all p < 0.01).Conclusions: ADMSC therapy significantly limited BIA and improved sensorimotor dysfunction after acute IS. [ABSTRACT FROM AUTHOR]

We devised and clinically validated a schema of rapid personalized predictive dosimetry for 177 Lu-PSMA-I&T in metastatic castration-resistant prostate cancer. It supersedes traditional empiric prescription by providing clinically meaningful predicted absorbed doses for first-strike optimization. Methods: Prostate-specific membrane antigen PET was conceptualized as a simulation study that captures the complex dosimetric interplay between tumor, marrow, and kidneys at a single time point. Radiation principles of fractionation, heterogeneity, normal-organ constraints (marrow, kidney), absorbed dose, and dose rate were introduced. We created a predictive calculator in the form of a free, open-source, and user-friendly spreadsheet that can be completed within minutes. Our schema achieves speed and accuracy by sampling tissue radioconcentrations (kBq/cm 3 ) to be analyzed in conjunction with clinical input from the user that reflect dosimetric preconditions. The marrow-absorbed dose constraint was 0.217 Gy (dose rate, ≤0.0147 Gy/h) per fraction with an interfraction interval of at least 6 wk. Results: Our first 10 patients were analyzed. The first-strike mean tumor-absorbed dose threshold for any prostate-specific antigen (PSA) response was more than 10 Gy (dose rate, >0.1 Gy/h). The metastasis with the lowest first-strike tumor-absorbed dose correlated the best with the percentage decrease of PSA; its threshold to achieve hypothetical zero PSA was 20 Gy or more. Each patient's PSA doubling time can be used to personalize their unique absorbed dose-response threshold. The predicted mean first-strike prescription constrained by marrow-absorbed dose rate per fraction was 11.0 ± 4.0 GBq. Highly favorable conditions (tumor sink effect) were dosimetrically expressed as the combination of tumor-to-normal-organ ratios of more than 150 for marrow and more than 4 for kidney. Our schema obviates the traditional role of the SUV as a predictive parameter. Conclusion: Our rapid schema is feasible to implement in any busy real-world theranostics unit and exceeds today's best practice standards. Our dosimetric thresholds and predictive parameters can radiobiologically rationalize each patient's first-strike prescription down to a single becquerel. Favorable tumor-to-normal-organ ratios can be prospectively exploited by predictive dosimetry to optimize the first-strike prescription. The scientific framework of our schema may be applied to other systemic radionuclide therapies., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: In clinical trials, frontline pembrolizumab for advanced NSCLC has demonstrated durable, clinically meaningful, long-term survival benefits over chemotherapy. Our objective was to evaluate 5-year survival rates outside the idealized setting of clinical trials for advanced/metastatic NSCLC treated with frontline pembrolizumab monotherapy., Methods: Using a nationwide, electronic health record-derived, deidentified database in the United States, we studied adult patients with advanced/metastatic NSCLC (unresectable stage IIIB/IIIC, or stage IV), with PD-L1 expression ≥ 50%, no documented EGFR, ALK, or ROS1 genomic alteration, and ECOG performance status of 0-1 initiating frontline pembrolizumab monotherapy from November 1, 2016, through March 31, 2020, excluding those in clinical trials. Kaplan-Meier was used to determine overall survival (OS). Data cutoff was May 31, 2023., Results: A total of 804 patients were eligible for the study, including 404 women (50%); median age was 72 years (range, 38-85 years), with 310 patients (39%) ≥ 75 years old. Median follow-up time from pembrolizumab initiation to data cutoff was 60.5 months (range, 38.0-78.7). At data cutoff, 549 patients (68%) had died. Median OS was 19.2 months (95% CI, 16.6-21.4), and survival rate at 5 years was 25.1% (95% CI, 21.7-28.7). Overall, 266 patients (33%) received 1 or more subsequent regimens, most commonly an anti-PD-(L)1 agent (as monotherapy or combination therapy) or platinum-based chemotherapy., Conclusions: With 5-year follow-up in a real-world population, frontline pembrolizumab monotherapy continues to demonstrate long-term effectiveness, with survival outcomes consistent with those of pivotal clinical trials, for treating patients with advanced NSCLC with PD-L1 expression of ≥ 50% and no EGFR, ALK, or ROS1 genomic alteration., (Copyright © 2024 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. All rights reserved.)

CD19-targeted chimeric antigen receptor (CAR) T cell therapies have driven a paradigm shift in the treatment of relapsed/refractory B-cell malignancies. However, >50% of CD19-CAR-T-treated patients experience progressive disease mainly due to antigen escape and low persistence. Clinical prognosis is heavily influenced by CAR-T cell function and systemic cytokine toxicities. Furthermore, it remains a challenge to efficiently, cost-effectively, and consistently manufacture clinically relevant numbers of virally engineered CAR-T cells. Using a highly efficient piggyBac transposon-based vector, Quantum pBac™ (qPB), we developed a virus-free cell-engineering system for development and production of multiplex CAR-T therapies. Here, we demonstrate in vitro and in vivo that consistent, robust and functional CD20/CD19 dual-targeted CAR-T stem cell memory (CAR-TSCM) cells can be efficiently produced for clinical application using qPB™. In particular, we showed that qPB™-manufactured CAR-T cells from cancer patients expanded efficiently, rapidly eradicated tumors, and can be safely controlled via an iCasp9 suicide gene-inducing drug. Therefore, the simplicity of manufacturing multiplex CAR-T cells using the qPB™ system has the potential to improve efficacy and broaden the accessibility of CAR-T therapies., Competing Interests: GenomeFrontier Therapeutics TW Co., Ltd. funded the study and played a crucial role in the study design, data collection and analysis, decision to publish, and preparation of the manuscripts. The coauthors – Peter S. Chang, Yi-Chun Chen, Wei-Kai Hua, Jeff C. Hsu, Jui-Cheng Tsai, Yi-Wun Huang, Yi-Hsin Kao, Pei-Hua Wu, Kuo-Lan Karen Wen, and Sareina Chiung-Yuan Wu – are affiliated with GenomeFrontier Therapeutics TW Co., Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Chang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: This study aimed to evaluate trends in polypharmacy prevalence among adults with asthma in the United States., Methods: Data from the 2001-2020 National Health and Nutrition Examination Survey were used to estimate the weighted prevalence of polypharmacy. Joinpoint regression analysis was conducted to evaluate trends in polypharmacy. Trends were first evaluated overall and then stratified by asthma severity and asthma control. A multivariable logistic regression model was used to identify factors associated with polypharmacy., Results: From 2001 to 2020, a stable trend in polypharmacy among U.S. adults with asthma was observed (average annual percent change [AAPC]=1.02, p =0.71). Trends across different asthma severity were stable (mild asthma: AAPC=2.93, p =0.20; moderate asthma: AAPC=-2.22, p =0.35; severe asthma: AAPC=0.45, p =0.82). Trends in adults with good asthma control and those with poor control stayed constant (good control: AAPC=0.82, p =0.68; poor control: AAPC=-1.22, p =0.82). Several factors, including older age, females, Non-Hispanic Black, health insurance coverage, family income, number of healthcare visits, former smokers, multi-morbidities, asthma severity, and asthma control, were associated with polypharmacy., Conclusions: Polypharmacy prevalence has remained constant among U.S. adults with asthma over the past two decades. Despite a stable overall trend, disparities in polypharmacy prevalence persist across different asthma severity and control status, underscoring the need for tailored medication management to improve asthma care.

Background: Sodium‒glucose cotransporter-2 (SGLT2) inhibitors offer glycaemic and cardiorenal benefits in the early stage of chronic kidney disease (CKD). However, the use of SGLT2 inhibitors may increase the risk of genitourinary tract infection (GUTI). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may also cause deterioration of kidney function. The long-term follow-up of cardiorenal outcomes and GUTI incidence in patients with advanced CKD receiving SGLT2 inhibitors combined with ACEIs/ARBs should be further investigated. Methods: We analysed data from 5,503 patients in Taiwan's Taipei Medical University Research Database (2016-2020) who were part of a pre-end-stage renal disease (ESRD) program (CKD stages 3-5) and received ACEIs/ARBs. SGLT2 inhibitor users were matched 1:4 with nonusers on the basis of sex, CKD, and program entry duration. Results: The final cohort included 205 SGLT2 inhibitor users and 820 nonusers. SGLT2 inhibitor users experienced a significant reduction in ESRD/dialysis risk (aHR = 0.35, 95% CI = 0.190.67), and SGLT2 inhibitor use was not significantly associated with acute kidney injury or acute kidney disease risk. Among SGLT2 inhibitor users, those with a history of cardiovascular disease (CVD) had greater CVD rates. Conversely, those without a CVD history had lower rates of congestive heart failure, arrhythmia, acute pulmonary oedema, and acute myocardial infarction, although the differences were not statistically significant. Notably, SGLT2 inhibitor usage was associated with a greater GUTI incidence (aHR = 1.78, 95% CI = 1.122.84) shortly after initiation, irrespective of prior GUTI history status. Conclusion: Among patients with CKD stages 3-5, SGLT2 inhibitor use was linked to increased GUTI incidence, but it also significantly reduced the ESRD/dialysis risk without an episodic AKI or AKD risk. Clinical physicians should consider a personalized medicine approach by balancing GUTI episodes and cardiorenal outcomes for advanced CKD patients receiving SGLT2 inhibitors., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to viral entry and can cause cardiac injuries. Toll-like receptor 4 (TLR4) and NOD-, LPR-, and pyrin-domain-containing 3 (NLRP3) inflammasome are critical immune system components implicated in cardiac fibrosis. The spike protein activates NLRP3 inflammasome through TLR4 or angiotensin-converting enzyme 2 (ACE2) receptors, damaging various organs. However, the role of spike protein in cardiac fibrosis in humans, as well as its interactions with NLRP3 inflammasomes and TLR4, remain poorly understood., Methods: We utilized scratch assays, Western blotting, and immunofluorescence to evaluate the migration, fibrosis signaling, mitochondrial calcium levels, reactive oxygen species (ROS) production, and cell morphology of cultured human cardiac fibroblasts (CFs) treated with spike (S1) protein for 24 h with or without an anti-ACE2 neutralizing antibody, a TLR4 blocker, or an NLRP3 inhibitor., Results: S1 protein enhanced CFs migration and the expressions of collagen 1, α-smooth muscle actin, transforming growth factor β1 (TGF-β1), phosphorylated SMAD2/3, interleukin 1β (IL-1β), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). S1 protein increased ROS production but did not affect mitochondrial calcium content and cell morphology. Treatment with an anti-ACE2 neutralizing antibody attenuated the effects of S1 protein on collagen 1 and TGF-β1 expressions. Moreover, NLRP3 (MCC950) and NF-kB inhibitors, but not the TLR4 inhibitor TAK-242, prevented the S1 protein-enhanced CFs migration and overexpression of collagen 1, TGF-β1, and IL-1β., Conclusion: S1 protein activates human CFs by priming NLRP3 inflammasomes through NF-κB signaling in an ACE2-dependent manner.

Introduction: The accumulation of microbiota-derived trimethylamine N-oxide (TMAO) in the atrium is linked to the development and progression of atrial arrhythmia. Butyrate, a major short-chain fatty acid, plays a crucial role in sustaining intestinal homeostasis and alleviating systemic inflammation, which may reduce atrial arrhythmogenesis., Objectives: This study explored the roles of butyrate in regulating TMAO-mediated atrial remodeling and arrhythmia., Methods: Whole-cell patch clamp experiments, Western blotting, and immunocytochemistry were used to analyze electrical activity and signaling, respectively, in TMAO-treated HL-1 atrial myocytes with or without sodium butyrate (SB) administration. Telemetry electrocardiographic recording and echocardiography and Masson's trichrome staining and immunohistochemistry were employed to examine atrial function and histopathology, respectively, in mice treated with TMAO with and without SB administration., Results: Compared with control cells, TMAO-treated HL-1 myocytes exhibited reduced action potential duration (APD), elevated sarcoplasmic reticulum (SR) calcium content, larger L-type calcium current (I Ca-L ), increased Na + /Ca 2+ exchanger (NCX) current, and increased potassium current. However, the combination of SB and TMAO resulted in similar APD, SR calcium content, I Ca-L , transient outward potassium current (I to ), and ultrarapid delayed rectifier potassium current (I Kur ) compared with controls. Additionally, TMAO-treated HL-1 myocytes exhibited increased activation of endoplasmic reticulum (ER) stress signaling, along with increased PKR-like ER stress kinase (PERK)/IRE1α axis activation and expression of phospho-IP3R, NCX, and Kv1.5, compared with controls or HL-1 cells treated with the combination of TMAO and SB. TMAO-treated mice exhibited atrial ectopic beats, impaired atrial function, increased atrial fibrosis, and greater activation of ER stress signaling with PERK/IRE1α axis activation compared with controls and mice treated with TMAO combined with SB., Conclusion: TMAO administration led to PERK/IRE1α axis activation, which may increase atrial remodeling and arrhythmogenesis. SB treatment mitigated TMAO-elicited ER stress. This finding suggests that SB administration is a valuable strategy for treating TMAO-induced atrial arrhythmia., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Background and Objectives : Exercise enhances cardiovascular health through various mechanisms, including the modulation of autonomic nervous system activity. This study aimed to systematically examine the impact of exercise on heart rate variability (HRV) in adults during and within one hour after exercise (WHAE). Materials and Methods : A comprehensive literature review was conducted using the MEDLINE, Embase, Cochrane Library, Scopus, and PubMed databases to identify published studies that reported the impact of exercise on autonomic nervous system activity in adults. The studies measured the absolute power of the low-frequency band (0.04-0.15 Hz) to the absolute power of the high-frequency band (0.015-0.4 Hz) (LF/HF ratio) to assess sympathetic activity and the root mean square of successive differences between normal heartbeats (RMSSD) to assess parasympathetic activity. Results : A total of 3329 studies were screened for relevance, and finally, 10 articles that utilized methods for measuring autonomic nervous system activity, such as the LF/HF ratio and RMSSD, covering 292 adult patients, were included for meta-analysis. In the current meta-analysis, we observed a significant decrease in parasympathetic activity during and after exercise, as indicated by RMSSD, compared to pre-exercise levels (mean difference [MD] = -4.96, 95% confidence interval [CI]: -8.00 to -1.91, p = 0.003). However, sympathetic activity after exercise, represented by the LF/HF ratio, showed a borderline significant increase compared to pre-exercise levels (MD = 1.06, 95% CI: -0.01 to 2.12, p = 0.052). The meta-regression model found that factors associated with RMSSD included mean age, male gender, and duration post-exercise. Additionally, the factor associated with the LF/HF ratio was the healthy condition of participants. The trial sequential analysis provided robust evidence of a decrease in RMSSD and an increase in the LF/HF ratio during and WHAE. Conclusions : Given the limitations of the current study, the findings suggest that a significant decrease in parasympathetic activity and a borderline significant increase in sympathetic activity in adults during and WHAE, as confirmed by trial sequential analysis. Meta-regression analysis indicated that parasympathetic activity was negatively associated with participant age and male gender, but positively associated with duration post-exercise. Additionally, increased sympathetic activity was linked to the healthy conditions of participants. This study suggests that exercise might differentially affect autonomic balance in individuals with chronic conditions compared to healthy individuals. This highlights the potential need for tailored exercise interventions to improve autonomic function across different populations.

Sleep deprivation (SD) is a recognized risk factor for atrial fibrillation (AF), yet the precise molecular and electrophysiological mechanisms behind SD-induced AF are unclear. This study explores the electrical and structural changes that contribute to AF in chronic partial SD. We induced chronic partial SD in Wistar rats using a modified multiple-platform method. Echocardiography demonstrated impaired systolic and diastolic function in the left ventricle (LV) of the SD rats. The SD rats exhibited an elevated heart rate and a higher low-frequency to high-frequency ratio in a heart-rate variability analysis. Rapid transesophageal atrial pacing led to a higher incidence of AF and longer mean AF durations in the SD rats. Conventional microelectrode recordings showed accelerated pulmonary vein (PV) spontaneous activity in SD rats, along with a heightened occurrence of delayed after-depolarizations in the PV and left atrium (LA) induced by tachypacing and isoproterenol. A Western blot analysis showed reduced expression of G protein-coupled receptor kinase 2 (GRK2) in the LA of the SD rats. Chronic partial SD impairs LV function, promotes AF genesis, and increases PV and LA arrhythmogenesis, potentially attributed to sympathetic overactivity and reduced GRK2 expression. Targeting GRK2 signaling may offer promising therapeutic avenues for managing chronic partial SD-induced AF. Future investigations are mandatory to investigate the dose-response relationship between SD and AF genesis.

Abstract: A patient with widespread intensely prostate-specific membrane antigen-expressing, BRCA gene mutation-positive bone metastases at the time of prostate cancer diagnosis had progressed on multiple lines of standard therapy. He received 177 Lu-prostate-specific membrane antigen 8.5 GBq augmented by a short course of olaparib radiosensitization and achieved 90% decrease in serum PSA level after a single treatment. His tumor response was much better than expected by predictive dosimetry. However, his marrow radiotoxicity was worse than anticipated and required hospitalization. This suggests radiosensitizing agents to be a double-edged sword that must be carefully considered and balanced during activity prescription., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Diabetic autonomic neuropathy is a common complication of type 2 diabetes mellitus (T2DM), especially in patients with long-term, poorly controlled diabetes. This study investigates the effects of exercise on autonomic nervous system activity in T2DM patients over time., Methods: A literature review using MEDLINE, Embase, Cochrane Library, Scopus, and PubMed identified studies assessed via heart rate variability. Papers were categorized into three groups: immediate effects (within 60 min), short-term effects (2-3 months), and long-term effects (over 4 months)., Results: Nine articles with 161 T2DM patients were included in the meta-analysis. RMSSD changes after exercise were -4.3 ( p = 0.227), 8.14 ( p < 0.001), and 4.17 ( p = 0.002) for the immediate, short-term, and long-term groups, respectively. LF/HF ratio changes were 0.21 ( p = 0.264), -3.04 ( p = 0.102), and -0.05 ( p = 0.006) for the respective groups. Meta-regression indicated age, male gender, and exercise duration were associated with increased RMSSD, with coefficients of 2.36 ( p = 0.001), 13.76 ( p = 0.008), and 1.50 ( p = 0.007), respectively. Age positively correlated with the LF/HF ratio, with a coefficient of 0.049 ( p = 0.048)., Conclusions: Regular exercise (≥3 times per week) for over 2 months increases parasympathetic activity in T2DM patients, while sympathetic activity decreases significantly after 4 months. Further study is needed to validate these findings.

Interleukin (IL)-33, a cytokine involved in immune responses, can activate its receptor, suppression of tumorigenicity 2 (ST2), is elevated during atrial fibrillation (AF). However, the role of IL-33/ST2 signaling in atrial arrhythmia is unclear. This study explored the pathological effects of the IL-33/ST2 axis on atrial remodeling and arrhythmogenesis. Patch clamping, confocal microscopy, and Western blotting were used to analyze the electrical characteristics of and protein activity in atrial myocytes (HL-1) treated with recombinant IL-33 protein and/or ST2-neutralizing antibodies for 48 hrs. Telemetric electrocardiographic recordings, Masson's trichrome staining, and immunohistochemistry staining of the atrium were performed in mice receiving tail vein injections with nonspecific immunoglobulin (control), IL-33, and IL-33 combined with anti-ST2 antibody for 2 weeks. IL-33-treated HL-1 cells had a reduced action potential duration, lower L-type Ca 2+ current, greater sarcoplasmic reticulum (SR) Ca 2+ content, increased Na + /Ca 2+ exchanger (NCX) current, elevation of K + currents, and increased intracellular calcium transient. IL-33-treated HL-1 myocytes had greater activation of the calcium-calmodulin-dependent protein kinase II (CaMKII)/ryanodine receptor 2 (RyR2) axis and nuclear factor kappa B (NF-κB) / NLR family pyrin domain containing 3 (NLRP3) signaling than did control cells. IL-33 treated cells also had greater expression of Nav1.5, Kv1.5, NCX, and NLRP3 than did control cells. Pretreatment with neutralizing anti-ST2 antibody attenuated IL-33-mediated activation of CaMKII/RyR2 and NF-κB/NLRP3 signaling. IL-33-injected mice had more atrial ectopic beats and increased AF episodes, greater atrial fibrosis, and elevation of NF-κB/NLRP3 signaling than did controls or mice treated with IL-33 combined with anti-ST2 antibody. Thus, IL-33 recombinant protein treatment promotes atrial remodeling through ST2 signaling. Blocking the IL-33/ST2 axis might be an innovative therapeutic approach for patients with atrial arrhythmia and elevated serum IL-33., (Copyright © 2024. Published by Elsevier Inc.)

The mutated SCN5A gene encoding defective Nav1.5 protein causes arrhythmic ailments and is associated with enhanced cardiac fibrosis. This study investigated whether SCN5A mutation directly affects cardiac fibroblasts and explored how defective SCN5A relates to cardiac fibrosis. SCN5A knockdown (SCN5AKD) human cardiac fibroblasts (HCF) had higher collagen, α-SMA, and fibronectin expressions. Micro-RNA deep sequencing and qPCR analysis revealed the downregulation of miR-452-5p and bioinformatic analysis divulged maladaptive upregulation of transforming growth factor β (TGF-β) signaling in SCN5AKD HCF. Luciferase reporter assays validated miR-452-5p targets SMAD4 in SCN5AKD HCF. Moreover, miR-452-5p mimic transfection in SCN5AKD HCF or AAV9-mediated miR-452-5p delivery in isoproterenol-induced heart failure (HF) rats, resulted in the attenuation of TGF-β signaling and fibrogenesis. The exogenous miR-452-5p significantly improved the poor cardiac function in HF rats. In conclusion, miR-452-5p regulates cardiac fibrosis progression by targeting the TGF-β/SMAD4 axis under the loss of the SCN5A gene., Competing Interests: Authors declare no conflict of interest., (© 2024 The Author(s).)

Background: Metabolic stress predisposes to ventricular arrhythmias and sudden cardiac death. Right ventricular outflow tract (RVOT) is the common origin of ventricular arrhythmias. Adenosine monophosphate-regulated protein kinase (AMPK) activation is an important compensatory mechanism for cardiac remodeling during metabolic stress., Objectives: The purpose of this study was to access whether AMPK inhibition would modulate RVOT electrophysiology, calcium (Ca 2+ ) regulation, and RVOT arrhythmogenesis or not., Methods: Conventional microelectrodes were used to record electrical activity before and after compound C (10 µM, an AMPK inhibitor) in isoproterenol (1 µM)-treated rabbit RVOT tissue preparations under electrical pacing. Whole-cell patch-clamp and confocal microscopic examinations were performed in baseline and compound C-treated rabbit RVOT cardiomyocytes to investigate ionic currents and intracellular Ca 2+ transients in isolated rabbit RVOT cardiomyocytes., Results: Compound C decreased RVOT contractility, and reversed isoproterenol increased RVOT contractility. Compound C decreased the incidence, rate, and duration of isoproterenol-induced RVOT burst firing under rapid pacing. Compared to baseline, compound C-treated RVOT cardiomyocytes had a longer action potential duration, smaller intracellular Ca 2+ transients, late sodium (Na + ), peak L-type Ca 2+ current density, Na + -Ca 2+ exchanger, transient outward potassium (K + ) current, and rapid and slow delayed rectifier K + currents., Conclusion: AMPK inhibition modulates RVOT electrophysiological characteristics and Ca 2+ homeostasis, contributing to lower RVOT arrhythmogenic activity. Accordingly, AMPK inhibition might potentially reduce ventricular tachyarrhythmias., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Objective: The management of postoperative deep infection after anterior cervical discectomy and fusion (ACDF) remains challenging for spine surgeons. Our institution uses handmade antibiotic-loaded cement spacers to treat these complex cases. This study aimed to determine the efficacy and feasibility of this treatment., Methods: This study included 4 patients with deep cervical spine infections after ACDF who underwent our treatment between March 2012 and January 2022. Patients' laboratory data, visual analog scale scores, comorbidities, complications, and neurological status were recorded. Their clinical conditions were also evaluated based on the Neck Disability Index, Japanese Orthopaedic Association score, and Odom criteria., Results: Infection eradication was achieved in all patients after treatment. The average preoperative visual analog scale score was 7.5 (range: 7-8); this decreased to 1.25 (range: 1-2) at 1 year postoperatively. None of the patients experienced severe complications, such as neurological deterioration or bone graft dislodgement. The Neck Disability Index improved from a preoperative value of 54% (range: 48-60%) to 6% (range: 4-8%) at 1 year postoperatively. The Japanese Orthopaedic Association score improved from a preoperative score of 10.25 (range: 10-11)-14.75 (range: 14-16) at 1 year postoperatively. All patients achieved excellent outcomes based on Odom criteria at 1 year postoperatively., Conclusions: Good clinical outcomes were achieved in this study. Although 2-stage surgery is required, this technique could be an alternative for patients with postoperative deep infection after ACDF., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objectives : The mechanisms connecting obstructive sleep apnea (OSA) and cardiovascular disease are multifactorial, involving intermittent hypoxia, hypercapnia, and sympathetic activation. The aim of this study was to explore the oscillations of sympathetic activity during the sleep apnea episodes throughout the entire night in patients with OSA. Materials and Methods : The participants received whole-night polysomnography (PSG), and electrocardiogram (EKG) data from the PSG were collected for heart rate variability (HRV) analysis. HRV measurements were conducted in the time and frequency domains. The root mean square of successive differences between normal heartbeats (RMSSD), which reflects parasympathetic activity, and the ratio of the absolute power of the low-frequency band (0.04-0.15 Hz) to the absolute power of the high-frequency band (0.015-0.4 Hz) (LF/HF ratio), which indicates sympathetic activity, were computed. Results : A total of 43 participants (35 men and 8 women) were included in the analysis. The mean age of the participants was 44.1 ± 11.3 years old, and the mean BMI was 28.6 ± 5.4 kg/m 2 . The sleep apnea episodes throughout the entire night in patients with OSA were selected randomly and occurred most frequently during the non-REM stages (39, 90.7%). The selected sleep apnea episodes typically exhibited multiple apneas, often interrupted by snoring respiration and followed by hyperventilation at the end of the episode (HE). Our findings indicate that the centers of the 5 min HRV window for the lowest and highest LF/HF ratios, at 111.8 ± 88.2 and 117.4 ± 88.6 min after sleep onset, respectively, showed a statistically significant difference ( p < 0.001). Similarly, the ratios of the lowest and highest LF/HF, at 0.82 ± 0.56 and 3.53 ± 2.94, respectively, exhibited a statistically significant difference ( p < 0.001). Conclusions : In the current study, the selected sleep apnea episodes throughout the entire night in patients with OSA occurred primarily during the non-REM stages. Additionally, we observed that sympathetic activity reached its peak in the window that includes hyperventilation at the end stage of apnea, potentially posing a cardiovascular risk. However, additional studies are needed to validate these results.

Carcinogens, such as arecoline, play a crucial role in cancer progression and continuous gene mutations by generating reactive oxygen species (ROS). Antioxidants can reduce ROS levels and potentially prevent cancer progression but may paradoxically enhance the survival of cancer cells. This study investigated whether epigallocatechin-3-gallate (EGCG), an antioxidant from green tea, could resolve this paradox. Prostate cancer cells (PC-3 cell line) were cultured and treated with arecoline combined with NAC (N-acetylcysteine) or EGCG; the combined effects on intracellular ROS levels and cell viability were examined using the MTT and DCFDA assays, respectively. In addition, apoptosis, cell cycle, and protein expression were investigated using flow cytometry and western blot analysis. Our results showed that EGCG, similar to NAC (N-acetylcysteine), reduced the intracellular ROS levels, which were elevated by arecoline. Moreover, EGCG not only caused cell cycle arrest but also facilitated cell apoptosis in arecoline-treated cells in a synergistic manner. These were evidenced by elevated levels of cyclin B1 and p27, and increased fragmentation of procaspase-3, PARP, and DNA. Our findings highlight the potential use of EGCG for cancer prevention and therapy.

(1) Background: Pneumonia stands as a prevalent infectious disease globally, contributing significantly to mortality and morbidity rates. In Taiwan, pneumonia ranks as the third leading cause of death, particularly affecting the elderly population (92%). This study aims to investigate factors associated with community-acquired pneumonia (CAP) among elderly individuals receiving home-based care. (2) Methods: Conducted between January 2018 and December 2019, this retrospective study involved a medical chart review of elderly patients under home-based care. A multiple logistic regression model was employed to identify factors associated with CAP in this demographic. (3) Results: Analysis encompassed 220 elderly patients with an average age of 82.0 ± 1.1 years. Eighty-five patients (38.6%) were hospitalized for CAP. Predominant diagnoses included cancer (32.3%), stroke (24.5%), and dementia (23.6%). Significant predictors of CAP for elderly patients under home-based care included male gender (odds ratio [OR] = 4.10, 95% confidence interval [CI]: 1.95-8.60, p < 0.001), presence of a nasogastric (NG) tube (OR = 8.85, 95% CI: 3.64-21.56, p < 0.001), and a borderline negative association with the use of proton pump inhibitors (PPIs) (OR = 0.37, 95% CI: 0.13-1.02, p = 0.0546). End-of-life care indicators for these patients with CAP included an increased number of hospital admission days in the last month of life (OR = 1.13, 95% CI: 1.08-1.18, p < 0.001) and a higher likelihood of hospital death (OR = 3.59, 95% CI: 1.51-8.55, p = 0.004). (4) Conclusions: In the current study, significant predictors of CAP among elderly patients receiving home-based care included the presence of an NG tube and male gender, while the use of PPIs was borderline inversely associated with the risk of CAP. Notably, more admission days in the last month of life and death in the hospital were found to be associated with end-of-life care for this group.

Acetyl-CoA carboxylase 2 plays a crucial role in regulating mitochondrial fatty acid oxidation in cardiomyocytes. Lithium, a monovalent cation known for its cardioprotective potential, has been investigated for its influence on mitochondrial bioenergetics. The present study explored whether lithium modulated acetyl-CoA carboxylase 2 and mitochondrial fatty acid metabolism in cardiomyocytes and the potential therapeutic applications of lithium in alleviating metabolic stress. Mitochondrial bioenergetic function, fatty acid oxidation, reactive oxygen species production, membrane potential and the expression of proteins involved in fatty acid metabolism in H9c2 cardiomyocytes treated with LiCl for 48 h was measured by using a Seahorse extracellular flux analyzer, fluorescence microscopy and western blotting. Small interfering RNA against glucose transporter type 4 was transfected into H9c2 cardiomyocytes for 48 h to induce metabolic stress mimicking insulin resistance. The results revealed that LiCl at a concentration of 0.3 mM (but not at a concentration of 0.1 or 1.0 mM) upregulated the expression of phosphorylated (p-)glycogen synthase kinase-3 beta and downregulated the expression of p-acetyl-CoA carboxylase 2 but did not affect the expression of adenosine monophosphate-activated protein kinase or calcineurin. Cotreatment with TWS119 (8 µM) and LiCl (0.3 mM) downregulated p-acetyl-CoA carboxylase 2 expression to a similar extent as did treatment with TWS119 (8 µM) alone. Moreover, LiCl (0.3 mM) inhibited mitochondrial fatty acid oxidation, improved coupling efficiency and the cellular respiratory control ratio, hindered reactive oxygen species production and proton leakage and restored mitochondrial membrane potential in glucose transporter type 4 knockdown-H9c2 cardiomyocytes. These findings suggested that low therapeutic levels of lithium can downregulate p-acetyl-CoA carboxylase 2, thus reducing mitochondrial fatty acid oxidation and oxidative stress in cardiomyocytes., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Chen et al.)

Objectives: In systemic radionuclide therapy such as radioiodine (I-131) for differentiated thyroid cancer, post-therapy dosimetry is essential to verify pre-therapy predictions, which in turn informs the next treatment. However, post-therapy multi-time point dosimetry is resource intensive and unfeasible in many institutions. We devised a schema of rapid predictive dosimetry by circumventing post-First Strike multi-time point dosimetry with carefully assigned gestalt values of predicted kinetics to personalise the Second Strike prescription., Methods: Verification is performed after the First Strike. Patient-specific time-activity curve is plotted from serial measurements of whole body exposure rates to obtain its decay constant; its inverse is the whole body Time Integrated Activity Coefficient (TIAC). The percentage of whole body TIAC attributed to blood is carefully assigned by gestalt based on population kinetics tabulated in Part 1, adjusted by any metastasis on I-131 whole body scintigraphy. Marrow absorbed dose is calculated by EANM formularism. Lung safety threshold at 48h post-therapy is linearly scaled by height, where the patient's risk of lung radiotoxicity is revealed from the whole body time-activity curve value at 48h. Predictive prescription for the second I-131 fraction (Second Strike) is by careful gestalt assessment based on predicted kinetics, remaining marrow and lung tolerance, marrow dose rate constraint per fraction (0.265 Gy/h), local regulatory and facility requirements in relation to radiation protection. Tumour dosimetry is obviated under the assumption of severe tumour absorbed dose heterogeneity. The final prescription for the Second Strike is usually the lowest I-131 activity amongst all clinical, dosimetric and regulatory constraints., Results: This schema is incorporated into a Predictive Calculator spreadsheet for rapid predictive dosimetry, and is freely available. Calculations may be completed within minutes to generate personalised predictive prescriptions, making it feasible for routine clinical implementation., Conclusion: Our innovative schema of rapid verification and predictive dosimetry bridges the technological gap between empiric vs theranostic prescription to help institutions modernise. Its expeditious design makes this schema feasible to be integrated into the routine clinical workflow. Its predictive estimates provide invaluable dosimetric insight to inform the next I-131 fraction, allowing every prescription to be scientifically rationalised and personalised according to individual circumstances., Competing Interests: Y.H. Kao previously received research funding from Genzyme Corporation and Sirtex Medical Limited, and is a consultant for Sirtex Medical Limited. This work is unfunded. Y.H. Kao previously received research funding from Genzyme Corporation and Sirtex Medical Limited, and is a proctor for Sirtex Medical Limited.

Economics of today's busy clinical practice demand both time and cost-efficient methods of predictive dosimetry for liver radioembolisation. A rapid predictive schema adapted from the Medical Internal Radiation Dose (MIRD) method i.e., Partition Model, has been devised that can be completed within minutes. This rapid schema may guide institutions that do not have access to software capable of comprehensive auto-segmentation of lung, tumour and non-tumorous liver, or where rigorous artery-specific tomographic predictive dosimetry is unfeasible for the routine clinical workflow. This rapid schema is applicable to any beta-emitting radiomicrosphere, although absorbed dose-response thresholds will differ according to device. Sampling errors in lung, tumour and non-tumorous liver will compound and propagate throughout this schema. This rapid schema achieves efficiency in lieu of accuracy. The user must be mindful of potentially large sampling errors and assumes all responsibility. Any suspicion of significant error requires the user to revert back to standard-of-care methods., (© 2024 mums.ac.ir All rights reserved.)

Low back pain (LBP) is a leading cause of long-term disability globally. Intervertebral disk degeneration (IVDD) is mainly responsible for discogenic pain in LBP-affected young patients. There is no effective therapy to reverse disease severity and IVDD progression. This study investigates the effect of human peripheral blood-derived mononuclear cells (PBMCs) on pain relief and life quality improvement in IVDD patients. The enriched monocytes of the PBMCs could differentiate into CD14 and CD206 double-positive M2 macrophages in vitro . Preclinical evidence in rats showed that the transplanted PBMCs exhibited anti-inflammatory and moderate tissue-repair effects on controlling IVDD progress in the rat model. The PBMCs significantly steered the aggrecan and type II collagen expressions and attenuated the pro-inflammatory cytokines in the affected disk. Based on the animal results, 36 patients with chronic low back pain (CLBP) were included in clinical trials. The control group was conservative care only, and the experimental group was platelet-rich plasma (PRP) and PBMCs intradiscal injections. We first confirmed the single lumbar disk causing the discogenic pain by provocative discography or magnetic resonance imaging (MRI). Discogenic LBP participants received one intradiscal injection of autologous PBMCs and followed for 6 months. Our clinical trial showed that patients' LBP and disability were significantly ameliorated after the PBMCs transplantation rather than PRP. These preclinical and pilot clinical studies indicate that intradiscal injection of the enriched PBMCs might be a feasible and potential cell therapy to control pain and disability in IVDD patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors have the following competing interests. The technology transfer office of National Chung Hsing University has received consultancy, speaker fees, and research grants on behalf of H-LS from Duogenic StemCells Corporation and Hualien Tzu Chi Medical Center. F-HW, C-YH, and C-IS are employees of Duogenic StemCells Corporation. F-HW, C-YH, C-IS, H-LS, and C-LL are shareholders of Duogenic StemCells Corporation. Y-HC, M-HH, S-CK, Y-HK, C-HC, and D-WCC have no conflict of interest with respect to the research, authorship, and publication of this article. Patents, products in development, and marketing products are associated with this research.

Background: Rheumatoid arthritis (RA) is a systemic inflammatory disease in which TNF-α plays an important role. Fibroblast growth factor receptor 3 (FGFR3) is reportedly involved in RA by regulating the expression of inflammatory cytokines., Objective: This study examined the expression profile of FGFR3 in human synovial biopsy tissues and evaluated its gene-silencing effects on behaviors of synovial cells., Methods: Immunohistochemical staining was used to measure FGFR3 expression in human RA joint tissues. Cell proliferation, migration, and apoptosis assays were used to monitor behavioral changes in cultured synovial SW-982 cells with siRNA-mediated FGFR3 gene silencing. Immunofluorescent staining and western blotting were used to detect molecular changes in the FGFR3 gene-silenced cells., Results: FGFR3 up-regulation was noted in both cytoplasms and nuclei of synovial cells in human RA joints. FGFR3 siRNA delivery experiments corroborated that FGFR3 knockdown decreased proliferation and migration, and triggered apoptosis of synovial cells. The FGFR3 gene knockdown enhanced constitutive expression of epithelial marker E-cadherin and conversely suppressed expression of epithelial-mesenchymal transition (EMT) markers, including Snail, fibronectin, and vimentin. In addition, FGFR3 silencing significantly reduced the constitutive expressions of TNF-α, transcription factor NF-κΒ, and downstream COX-2 protein and collagenolytic enzyme MMP-9. MAPK inhibition markedly suppressed constitutive levels of NF-κΒ, COX-2, and MMP-9., Conclusion: Genetic interference of FGFR3 could modulate the expression of inflammatory mediators and EMT markers in the synovial cells. Targeting the FGFR3/MAPK signal axis may be considered a useful therapeutic strategy to ameliorate the development of RA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

While the worldwide distribution of geogenic arsenic (As)-affected groundwater is highly overlapped with the areas with abundant groundwater, utilization of As-contained groundwater is an inevitable compromise in those areas where surface water is not enough for irrigation. Since the occurrence of As in groundwater is often accompanied by high iron (Fe) contents, the facilitation of As and Fe precipitation without adding additional oxidizers and adsorbents is considered an environmental-friendly approach to removing As in groundwater. In the present study, the oxidation/filtration dual-process with sprinkling height of 25 cm and 120 kg filter media efficiently increased the dissolved oxygen (DO) concentration (0.36-1.52 mg/L) and oxidation-reduction potential (ORP) (24-63 mV), which facilitated the formation of Fe oxides and As co-precipitation. The correlation of As removal efficiencies with their respective flow rates indicated that a decrease in groundwater Fe and an increase of Fe in sands and gravels filters as the flow rate increased evidenced the rapid oxidation of Fe to form the Fe hydroxides. In a 40-hour continuous aeration/filtration operation, As and Fe concentrations in groundwater were reduced by 79.5% and 64.88% within 40 hrs, respectively. The ease of filter replacement and cost-effectiveness in operation can be the major attractions and innovations for future field practices.

Background: Mesenchymal stem cells (MSCs)-derived exosomes have been previously demonstrated to promote tissue regeneration in various animal disease models. This study investigated the protective effect of exosome treatment in carbon tetrachloride (CCl4)-induced acute liver injury and delineated possible underlying mechanism., Methods: Exosomes collected from conditioned media of previously characterized human umbilical cord-derived MSCs were intravenously administered into male CD-1 mice with CCl 4 -induced acute liver injury. Biochemical, histological and molecular parameters were used to evaluate the severity of liver injury. A rat hepatocyte cell line, Clone-9, was used to validate the molecular changes by exosome treatment., Results: Exosome treatment significantly suppressed plasma levels of AST, ALT, and pro-inflammatory cytokines, including IL-6 and TNF-α, in the mice with CCl 4 -induced acute liver injury. Histological morphometry revealed a significant reduction in the necropoptic area in the injured livers following exosome therapy. Consistently, western blot analysis indicated marked elevations in hepatic expression of PCNA, c-Met, Ets-1, and HO-1 proteins after exosome treatment. Besides, the phosphorylation level of signaling mediator JNK was significantly increased, and that of p38 was restored by exosome therapy. Immunohistochemistry double staining confirmed nuclear Ets-1 expression and cytoplasmic localization of c-Met and HO-1 proteins. In vitro studies demonstrated that exosome treatment increased the proliferation of Clone-9 hepatocytes and protected them from CCl4-induced cytotoxicity. Kinase inhibition experiment indicated that the exosome-driven hepatoprotection might be mediated through the JNK pathway., Conclusion: Exosome therapy activates the JNK signaling activation pathway as well as up-regulates Ets-1 and HO-1 expression, thereby protecting hepatocytes against hepatotoxin-induced cell death., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The red marrow is often the dose-limiting organ in systemic radionuclide therapy. However, multi-time-point personalised predictive dosimetry is resource intensive and impractical for routine clinical implementation. Single-time-point methods are a reasonable alternative for streamlining dosimetric workflows. However, there is a lack of single time-point methodology specific for the marrow. A simplified schema for rapid marrow predictive dosimetry is proposed based on direct image quantification of marrow radioconcentration, which may be generalised to most forms of systemic radionuclide therapy., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

A ketogenic diet (KD) might alleviate patients with diabetic cardiomyopathy. However, the underlying mechanism remains unclear. Myocardial function and arrhythmogenesis are closely linked to calcium (Ca 2+ ) homeostasis. We investigated the effects of a KD on Ca 2+ homeostasis and electrophysiology in diabetic cardiomyopathy. Male Wistar rats were created to have diabetes mellitus (DM) using streptozotocin (65 mg/kg, intraperitoneally), and subsequently treated for 6 weeks with either a normal diet (ND) or a KD. Our electrophysiological and Western blot analyses assessed myocardial Ca 2+ homeostasis in ventricular preparations in vivo. Unlike those on the KD, DM rats treated with an ND exhibited a prolonged QTc interval and action potential duration. Compared to the control and DM rats on the KD, DM rats treated with an ND also showed lower intracellular Ca 2+ transients, sarcoplasmic reticular Ca 2+ content, sodium (Na + )-Ca 2+ exchanger currents (reverse mode), L-type Ca 2+ contents, sarcoplasmic reticulum ATPase contents, Cav1.2 contents. Furthermore, these rats exhibited elevated ratios of phosphorylated to total proteins across multiple Ca 2+ handling proteins, including ryanodine receptor 2 (RyR2) at serine 2808, phospholamban (PLB)-Ser16, and calmodulin-dependent protein kinase II (CaMKII). Additionally, DM rats treated with an ND demonstrated a higher frequency and incidence of Ca 2+ leak, cytosolic reactive oxygen species, Na + /hydrogen-exchanger currents, and late Na + currents than the control and DM rats on the KD. KD treatment may attenuate the effects of DM-dysregulated Na + and Ca 2+ homeostasis, contributing to its cardioprotection in DM.

(1) Background: Snoring is a cardinal symptom of obstructive sleep apnea (OSA) and has been suggested to potentially increase sympathetic activity. On the other hand, sleep itself usually leads to a decrease in sympathetic activity. Heart rate variability (HRV) analysis is a non-invasive technique used to assess autonomic nervous system function. However, there is limited research on the combined impact of sleep and snoring on sympathetic activity in individuals with OSA, particularly during the first hour of sleep (non-rapid eye movement sleep). The current study aims to investigate the net effect of sleep and snoring on sympathetic activity and explore factors that might contribute to increased sympathetic activity in individuals with OSA during the first hour of sleep. (2) Methods: The participants were referred from the outpatient department for OSA diagnosis and underwent whole-night polysomnography (PSG). Electrocardiogram (EKG) data from the PSG were downloaded for HRV analysis. HRV measurements were conducted in both the time and frequency domain, including the root mean square of successive differences between normal heartbeats (RMSSD) and the ratio of the absolute power of the low-frequency (LF) band (0.04-0.15 Hz) to the absolute power of the high-frequency (HF) band (0.15-0.4 Hz) (LF/HF ratio), respectively. (3) Results: A total of 45 participants (38 men and 7 women) were included in the analysis. The RMSSD gradually increased from 0-5 min to 50-60 min ( p = 0.024), while the LF/HF ratio decreased ( p < 0.001) during the first hour of sleep (non-rapid eye movement sleep). The LF/HF ratios of the "S" (snoring) episodes were compared with those of the pre-S episodes. An elevated LF/HF ratio during the S episode was associated with the first snoring episode occurring more than 20 min after lying down to sleep (Odds ratio, OR = 10.9, p = 0.004) and with patients diagnosed with severe OSA (OR = 5.01, p = 0.045), as determined by logistic regression. (4) Conclusions: The study observed an increase in the value of RMSSD and a decrease in the value of the LF/HF ratio during the first hour of sleep for patients with OSA. Higher LF/HF ratios were associated with the first occurrence of snoring while lying down for more than 20 min and with patients with severe OSA.

Resistin and suppressors of cytokine signaling (SOCSs) have been reported to regulate prostate cancer (PCa) cell proliferation and survival, respectively. Whether any of the SOCS molecules mediate the mitogenic effect of resistin on PCa cells is unknown. Using PC-3 human PCa cells, we found that resistin upregulates the expression of SOCS3 and SOCS5 mRNA, but not SOCS7 mRNA, in a dose- and time-dependent manner. The resistin-induced increases in SOCS3 and SOCS5 expression and cell proliferation were prevented by pretreatment with specific inhibitors of the TLR4, ERK, p38 MAPK, JNK, PI3K, and JAK2 proteins. However, pretreatment with a TLR2 inhibitor had no effect on resistin-mediated SOCS3 and SOCS5 expression. In addition, the effects of resistin on SOCS3 , SOCS5 , and SOCS7 mRNA levels were cell type-specific. Overexpression of either SOCS3 or SOCS5 enhanced further resistin-stimulated growth of PC-3 cells, whereas silencing SOCS3 or SOCS5 antagonized resistin-increased cell growth. Further PCa tissue analysis demonstrated higher levels of RETN , TLR4 , SOCS3 , and SOCS5 mRNAs in cancer tissues than benign prostate hyperplasia and indicated positive correlations among RETN , TLR4 , and SOCS5 . These data suggest that SOCS5, TLR4, and, to a lesser extent, SOCS3 can mediate the mitogenic effect of resistin on PC-3 PCa cells., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Data on utilization and clinical outcomes of programmed cell death protein or programmed death-ligand 1 (PD-[L]1) inhibitors in NSCLC with uncommon oncogenic alterations is limited., Methods: This retrospective study used a deidentified U.S. nationwide clinicogenomic database to select patients with advanced nonsquamous NSCLC without EGFR , ALK , or ROS1 alterations, diagnosed from January 1, 2016 to September 30, 2020, who initiated first-line therapy. Our objectives were to summarize characteristics and treatment patterns for patients with four little-studied genomic alterations or driver-negative NSCLC. We estimated Kaplan-Meier real-world time on treatment (rwTOT) and time to next treatment for patients receiving PD-(L)1 inhibitors. The data cutoff was September 30, 2021., Results: Of the 3971 eligible patients, 84 (2%) had NSCLC with BRAF V600E mutation, 117 (3%) had MET exon 14 skipping mutation, 130 (3%) had MET amplification, 91 (2%) had ERBB2 activation mutation, and 691 patients (17%) had driver-negative NSCLC. Patient characteristics differed among cohorts as expected. The most common first-line regimen in each cohort was a PD-(L)1 inhibitor as monotherapy or in combination with chemotherapy. The median rwTOT with anti-PD-(L)1 monotherapy was 4.6 months in the driver-negative cohort and ranged from 2.9 months ( ERBB2 mutation) to 7.6 months ( BRAF V600E mutation). The median rwTOT with anti-PD-(L)1-chemotherapy combination was 5.2 months in the driver-negative cohort and 6 months in all but the BRAF V600E cohort (17.5 mo). The patterns of real-world time to next treatment results were similar., Conclusions: Substantial use of anti-PD-(L)1 therapy and associated clinical outcomes are consistent with previous real-world findings and suggest no detriment from PD-(L)1 inhibitors for advanced nonsquamous NSCLC harboring one of these four genomic alterations relative to driver-negative NSCLC., (© 2023 by the International Association for the Study of Lung Cancer.)

Objectives: To define pregnancy episodes and estimate gestational age within electronic health record (EHR) data from the National COVID Cohort Collaborative (N3C)., Materials and Methods: We developed a comprehensive approach, named Hierarchy and rule-based pregnancy episode Inference integrated with Pregnancy Progression Signatures (HIPPS), and applied it to EHR data in the N3C (January 1, 2018-April 7, 2022). HIPPS combines: (1) an extension of a previously published pregnancy episode algorithm, (2) a novel algorithm to detect gestational age-specific signatures of a progressing pregnancy for further episode support, and (3) pregnancy start date inference. Clinicians performed validation of HIPPS on a subset of episodes. We then generated pregnancy cohorts based on gestational age precision and pregnancy outcomes for assessment of accuracy and comparison of COVID-19 and other characteristics., Results: We identified 628 165 pregnant persons with 816 471 pregnancy episodes, of which 52.3% were live births, 24.4% were other outcomes (stillbirth, ectopic pregnancy, abortions), and 23.3% had unknown outcomes. Clinician validation agreed 98.8% with HIPPS-identified episodes. We were able to estimate start dates within 1 week of precision for 475 433 (58.2%) episodes. 62 540 (7.7%) episodes had incident COVID-19 during pregnancy., Discussion: HIPPS provides measures of support for pregnancy-related variables such as gestational age and pregnancy outcomes based on N3C data. Gestational age precision allows researchers to find time to events with reasonable confidence., Conclusion: We have developed a novel and robust approach for inferring pregnancy episodes and gestational age that addresses data inconsistency and missingness in EHR data., Competing Interests: K.R.B. and S.L. are employees of Palantir Technologies. Y.K. and L.L. are employees of Sema4. M.N.L. is Managing Director of IPQ Analytics, LLC., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Body mass index (BMI) as well as sugar-sweetened beverages (SSB) has been suggested to independently decrease 25-hydroxyvitamin D (25(OH)D). However, the relationship between SSB, BMI, and 25(OH)D is uncertain. This study aimed to investigate the potential mediating role of BMI in the association between SSB intake and 25(OH)D. A total of 4505 representative U.S. adults aged above 20 years and without liver conditions were selected from the 2013-2014 NHANES. All analyses were performed under survey modules with appropriate sampling weights. The prevalence of 25(OH)D insufficiency and deficiency was 37.8% and 24.1% in U.S. adults, respectively. Compared with non-SSB consumers, an increased risk of vitamin D deficiency was found in either heavy SSB consumers or soda consumers, respectively (aOR = 2.10, 95% CI = 1.25-3.54 in heavy SSB consumers; aOR = 1.61, 95% CI = 1.06-2.44 in soda consumers). Around 21.3% of the total effect of sugar intake from SSB on decreased 25(OH)D was explained by BMI. In conclusion, high total sugar intake from SSB and BMI independently contribute to lower 25(OH)D, and BMI mediates the inverse association between total sugar intake from SSB intake and 25(OH)D. Furthermore, an increased risk of having vitamin D deficiency was found in the population who consumed higher levels of sugar from SSB or soda drinks.

Background: Anaphylaxis is a potentially fatal condition; in severe cases of anaphylaxis, the cardiovascular system is often heavily involved. Adrenaline (epinephrine) is a cornerstone of the initial treatment of anaphylaxis. The use of epinephrine remains below expectations in clinical practice. Whether the underuse of epinephrine affects the prognosis of patients with anaphylaxis is still unclear., Materials and Methods: This retrospective study included patients with anaphylaxis between 2011 and 2020 who were admitted to an emergency department (ED) in Taiwan. All patients were divided into two groups based on the use of epinephrine (or not), and we compared the demographic characteristics, allergens, clinical manifestations, management, and patient outcomes., Results: We reviewed the records of 314 subjects (216 males, 98 females; mean age: 52.78 ± 16.02 years) who visited our ED due to anaphylaxis; 107 (34.1%) and 207 (65.9%) patients were categorized into the epinephrine use group and the non-epinephrine use group, respectively. Arrival via ambulance ( p = 0.019), hypotension ( p  = 0.002), airway compromise ( p  < 0.001) and altered consciousness ( p  < 0.001) were the deciding factors for epinephrine use among anaphylactic patients in the ED. The epinephrine use group had higher rates of other inotropic agent usage and fluid challenge. More than 90% of patients received bed rest, steroids, antihistamines, and monitoring. The epinephrine use group had a longer ED length of stay (387.64 ± 374.71 vs. 313.06 ± 238.99 min, p  = 0.03) and a greater need of hospitalization. Among all severe symptoms, hypotension was the most tolerated decision factor for not using epinephrine. In this retrospective analysis, some patients with serious anaphylaxis did not experience adverse outcomes or death even without the use of epinephrine at ED admission. Emergent care focuses first on the airway, breathing, and circulation (ABC) and may compensate for the underusage of epinephrine. This could be the reason why epinephrine was underused among patients with anaphylaxis in the ED., Conclusion: In summary, early ABC management continues to play an important role in treating patients with severe anaphylaxis, even when epinephrine is not immediately available in clinical scenarios., 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 Lin, Chang, Kao, Chuu, Chiang, Chang, Li, Chu, Chan and Hsiao.)

Renal fibrosis is a hallmark of chronic and progressive renal diseases characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and a loss of renal function, eventually leading to end-stage renal diseases. MicroRNA-26a-5p (miR-26a-5p) downregulation has been previously noted in the sera of unilateral ureteral occlusion (UUO)-injured mice, and exosome-mediated miR-26a-5p reportedly attenuated experimental pulmonary and cardiac fibrosis. This study evaluated the expression patterns of miR-26a in a human tissue microarray with kidney fibrosis and in tissues from a mouse model of UUO-induced renal fibrosis. Histologic analyses showed that miR-26a-5p was downregulated in human and mouse tissues with renal interstitial nephritis and fibrosis. Moreover, miR-26a-5p restoration by intravenous injection of a mimic agent prominently suppressed the expression of transforming growth factor β1 (TGF-β1) and its cognate receptors, the inflammatory transcription factor NF-κB, epithelial-mesenchymal transition, and inflammatory markers in UUO-injured kidney tissues. In vitro, miR-26a-5p mimic delivery significantly inhibited TGF-β1-induced activation of cultured normal rat kidney NRK-49F cells, in terms of downregulation of TGF-β1 receptors, restoration of the epithelial marker E-cadherin, and suppression of mesenchymal markers, including vimentin, fibronectin, and α-smooth muscle actin, as well as TGF-β1/SMAD3 signaling activity. Our findings identified miR-26a-5p downregulation in kidney tissues with human interstitial nephritis and UUO-induced mouse kidney fibrosis. MiR-26a-5p restoration may exhibit an antifibrotic effect through the blockade of both TGF-β and NF-κB signaling axes and is considered a novel therapeutic target for treating obstruction-induced renal fibrosis., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)