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Shao-Huan Lan,1 Chih-Cheng Lai,2 Li-Chin Lu,3 Shen-Peng Chang,4 Hui-Ting Huang41School of Pharmaceutical Sciences and Medical Technology, Putian University, Putian, People’s Republic of China; 2Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Taiwan; 3School of Management, Putian University, Putian, People’s Republic of China; 4Department of Pharmacy, Chi Mei Medical Center, Liouying, TaiwanPurpose: To assess the clinical efficacy and safety of delafloxacin for treating acute bacterial skin and skin structure infections (ABSSSIs) in adult patients.Patients and methods: The Cochrane Library, EBSCO, EMBASE, Ovid Medline, PubMed, and Web of Science databases were searched up to November 2018. Only randomized controlled trials (RCTs) that evaluated delafloxacin and other comparators for the treatment of ABSSSIs were included. The primary outcome was the clinical cure rate and the secondary outcomes were microbiological response and the risk of adverse events.Results: Four RCTs were included. Overall, delafloxacin exhibited a clinical cure rate similar to the rates of the comparator drugs in the treatment of ABSSSI (OR, 1.05; 95% CI, 0.87–1.27, I2,=16%) and methicillin-resistant Staphylococcus aureus (MRSA)-associated ABSSSI (OR, 1.12; 95% CI, 0.71–1.77, I2,=0%). Delafloxacin had a microbiological eradication (documented and presumed) rate similar to the rates of the comparators in the treatment of ABSSSI (OR, 1.21; 95% CI, 0.58–2.50, I2,=0%) and MRSA-associated ABSSSIs (OR, 1.16; 95% CI, 0.37–3.60, I2,=0%). Delafloxacin and the comparators did not differ significantly in the risk of serious adverse events (AEs), treatment-emergent adverse events (TEAEs), and TEAEs related to the study drug. However, the risk of discontinuation of the study drug due to an AE was lower for delafloxacin than for the comparators (OR, 0.33; 95% CI, 0.15–0.74, I2,=0%).Conclusion: The clinical efficacy of delafloxacin is as high as that of the comparator drugs in the treatment of ABSSSI, including MRSA-associated infections; furthermore, this antibiotic is as well-tolerated as the comparators.Keywords: delafloxacin, acute bacterial skin and skin structure infections, MRSA, efficacy, safety

Chih-Wei Chen,1,2 Shen-Peng Chang,3 Hui-Ting Huang,4 Hung-Jen Tang,5 Chih-Cheng Lai61Division of Neurosurgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan; 2Department of Occupational Safety and Health/Institute of Industrial Safety and Disaster Prevention, College of Sustainable Environment, Chia Nan University of Pharmacy and Science, Tainan, Taiwan; 3Department of Pharmacy, Chi Mei Medical Center, Liouying, Taiwan; 4School of Pharmacy, China Medical University, Taichung, Taiwan; 5Department of Medicine, Chi Mei Medical Center, Tainan, Taiwan; 6Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, TaiwanObjectives: This meta-analysis aims to assess the clinical efficacy and safety of ceftaroline in treating acute bacterial infections – community-acquired pneumonia (CAP) and skin and skin structure infection (SSSI) in pediatric patients.Methods: The Pubmed, Embase, ClinicalTrials.gov. and the Cochrane databases were searched up to December 31, 2018. Only randomized controlled trials (RCTs) evaluating ceftaroline and other comparators in the treatment of acute bacterial infection in pediatric patients were included. The primary outcome was the clinical cure rate and the secondary outcome was the risk of adverse event.Results: Three RCTs were included. Overall, ceftaroline had a clinical cure rate at end of therapy (EOT) and test of cure (TOC) similar to comparators in the treatment of acute bacterial infection (at EOT, OR, 1.93; 95% CI, 0.88–4.25, I2=0%, and at TOC, OR, 1.36; 95% CI, 0.64–2.91, I2=14%). In addition, ceftaroline had a clinical failure rate at EOT and TOC similar to comparators in the treatment of acute bacterial infection (at EOT, OR, 0.62; 95% CI, 0.22–1.76, I2=0%, and at TOC, OR, 0.68; 95% CI, 0.24–1.91, I2=0%). No significant differences were found for the risk of treatment-emergent adverse events (TEAE) in all and different degrees between ceftaroline and comparators (OR, 0.81; 95% CI, 0.37–1.78, I2=56%). The risks of TEAE and severe adverse events related to study drug were similar between ceftaroline and comparators (TEAE related to study drug, OR, 0.98; 95% CI, 0.52–1.82, I2=0%, severe adverse event related to study drug, OR, 1.09; 95% CI, 0.22–5.44, I2=22%).Conclusions: The clinical efficacy of ceftaroline is as good as comparator therapy in the treatment of acute bacterial infections – CAP and SSSI, and this antibiotic is well tolerated as the comparators.Keywords: ceftaroline, acute bacterial infection, pediatric, community-acquired pneumonia, skin and skin structure infection

Hsiang Tso Huang,1 Hsin-Ming Wang,1 Shih-Cheng Yang,1 Wei-Chen Tai,1 Chih-Ming Liang,1 Keng-Liang Wu,1 Chen-Hsiang Lee,2 Seng-Kee Chuah1 1Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niao-Song District, Kaohsiung 833, Taiwan; 2Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niao-Song District, Kaohsiung 833, Taiwan Purpose: To assess the efficacy of amoxicillin, tetracycline, high-dose metronidazole, and a proton-pump inhibitor for third-line Helicobacter pylori eradication. Methods: We enrolled 70 consecutive patients who had registered, failed to respond to two rounds of H. pylori eradication, and undergone endoscopy for H. pylori culture. Seven patients were lost to follow-up. Patients were treated according to the results of antibiotic-susceptibility testing reports (cultured group, n=39). Those who failed the H. pylori culture were prescribed 14-day quadruple therapy containing esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, tetracycline 500 mg four times daily, and metronidazole 500 mg three times daily (empirical group, n=24). A follow-up urea breath test was performed 8 weeks later. Results: Antibiotic-resistance rates were 79.5% (clarithromycin), 94.9% (levofloxacin), 66.7% (metronidazole), 2.6% (amoxicillin), and 0 (tetracycline). Eradication rates attained by the cultured and empirical group were 89.7% (95% CI 72.7%–97.1%) and 58.3% (95% CI 36.6%–77.9%) in per-protocol analysis (P=0.004) and 81.4% (95% CI 66.6%–91.6%) and 51.8% (95% CI 31.9%–71.3%) in intention-to-treat analysis (P=0.014), respectively. Culture-guided therapy was the only clinical factor influencing the efficacy of H. pylori eradication (OR 0.16, 95% CI 0.04–0.60; P=0.006). Despite the high metronidazole-resistance rate (66.7%) after two treatment failures, the eradication rate in patients with this condition was 84%. Conclusion: Empirical 14-day modified quadruple therapy is not acceptable as an alternative third-line rescue H. pylori treatment. The success rate of third-line susceptibility-guided treatment was near 90%. This report is valuable as a reminder to medical practitioners that rather than a try-and-see approach, susceptibility-guided therapy should always be considered whenever possible for patients who have undergone several treatment failures. Keywords: amoxicillin-resistance, metronidazole-resistance, empirical quadruple therapy, culture-guided therapy

Khai-Jing Ng,1,2,* Chih-Wei Tseng,1–4,* Ting-Tsung Chang,5,6 Shinn-Jia Tzeng,7 Yu-Hsi Hsieh,1,2 Tsung-Hsing Hung,1,2 Hsiang-Ting Huang,8 Shu-Fen Wu,9 Kuo-Chih Tseng1,2 1Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, 2School of Medicine, Tzu Chi University, Hualien, 3Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, 4School of Medicine, National Yang-Ming University, Taipei, 5Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, Tainan, 6Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, 7Department of Agronomy, National Chiayi University, Chia-Yi, 8Department of Nursing, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, 9Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan *These authors contributed equally to this work Background: The aim of this study was to evaluate the clinically significant predictors of hepatocellular carcinoma (HCC) development among hepatitis C virus (HCV) cirrhotic patients receiving combination therapy.Patients and methods: One hundred and five compensated cirrhosis patients who received pegylated interferon plus ribavirin between January 2005 and December 2011 were enrolled. All the patients were examined with abdominal sonography and liver biochemistry at baseline, end of treatment, and every 3–6 months posttreatment. The occurrence of HCC was evaluated every 3–6 months posttreatment.Results: A total of 105 patients were enrolled (mean age 58.3±10.4 years). The average follow-up time for each patient was 4.38 years (standard deviation 1.73 years; range 1.13–9.27 years). Fifteen (14.3%) patients developed HCC during follow-up period. Thirteen of them had high baseline aspartate aminotransferase to platelet ratio index (APRI) (ie, an APRI >2.0). Multivariate analysis showed that those without sustained virologic response (SVR) (hazard ratio [HR] 5.795; 95% confidence interval [CI] 1.370–24.5; P=0.017) and high APRI (HR 5.548; 95% CI 1.191–25.86; P=0.029) had a significantly higher risk of HCC occurrence. The cumulative incidence of HCC was significantly higher (P=0.009) in patients without SVR (3-year cumulative incidence 21.4%; 95% CI 7.4%–35.5%; 5-year cumulative incidence 31.1%; 95% CI 11.2%–51.1%) compared to those with SVR (3- and 5-year cumulative incidence 6.2%; 95% CI 0%–1.3%). Further, the cumulative incidence of HCC was significantly higher (P=0.006) in patients with high APRI (3-year cumulative incidence 21.8%; 95% CI 8.2%–35.3%; 5-year cumulative incidence 30.5%, 95% CI 11.8%–49.3%) compared to those with low APRI (3- and 5-year cumulative incidence 4.2%, 95% CI 0%–1.0%).Conclusion: In HCV-infected cirrhotic patients who received combination therapy, APRI and SVR are the two major predictors of HCC development. Keywords: aspartate aminotransferase to platelet ratio index, chronic hepatitis C, hepatitis C virus, hepatocellular carcinoma, liver cirrhosis, sustained virologic response

Shih-Feng Liu,1–3 Ho-Chang Kuo,1,2,4 Guan-Heng Liu,5 Shu-Chen Ho,4 Huang-Chih Chang,1,3 Hung-Tu Huang,6 Yu-Mu Chen,1 Kuo-Tung Huang,1,3 Kuan-Yi Chen,2 Wen-Feng Fang,1–3 Meng-Chih Lin1–3 1Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, 2Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, 3Chang Gung University College of Medicine, 4Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, 5Li-Chih Valuable School, 6Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China Background: Whether the use of inhaled corticosteroids (ICSs) in patients with COPD can protect from osteoporosis remains undetermined. The aim of this study is to assess the incidence of osteoporosis in patients with COPD with ICS use and without.Patients and methods: This is a retrospective cohort and population-based study in which we extracted newly diagnosed female patients with COPD between 1997 and 2009 from Taiwan’s National Health Insurance (TNHI) database between 1996 and 2011 (International Classification of Diseases, Ninth Revision – Clinical Modification [ICD-9-CM] 491, 492, 496). The patients with COPD were defined by the presence of two or more diagnostic codes for COPD within 12 months on either inpatient or outpatient service claims submitted to TNHI. Patients were excluded if they were younger than 40 years or if osteoporosis had been diagnosed prior to the diagnosis of COPD and cases of asthma (ICD-9 CM code 493.X) before the index date. These enrolled patients were followed up till 2011, and the incidence of osteoporosis was determined. The Cox proportional hazards regression model was also used to estimate hazard ratios (HRs) for incidences of lung cancer.Results: Totally, 10,723 patients with COPD, including ICS users (n=812) and nonusers (n=9,911), were enrolled. The incidence rate of osteoporosis per 100,000 person years is 4,395 in nonusers and 2,709 in ICS users (HR: 0.73, 95% confidence interval [CI]: 0.63–084). The higher ICS dose is associated with lower risk of osteoporosis (0 mg to ≤20 mg, HR: 0.84, 95% CI: 0.69–1.04; >20 mg to ≤60 mg, HR: 0.78, 95% CI: 0.59–1.04; and >60 mg, HR: 0.72, 95% CI: 0.55–0.96; P for trend =0.0023) after adjusting for age, income, and medications. The cumulative osteoporosis probability significantly decreased among the ICS users when compared with the nonusers (P

Chih-Wei Tseng,1,2 Ting-Tsung Chang,3,4 Shinn-Jia Tzeng,5 Yu-Hsi Hsieh,1,2 Tsung-Hsing Hung,1,2 Hsiang-Ting Huang,6 Shu-Fen Wu,7 Kuo-Chih Tseng1,2 1Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, 2School of Medicine, Tzuchi University, Hualien, 3Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, 4Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, 5Department of Agronomy, National Chiayi University, 6Department of Nursing, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 7Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan Objective: We studied the effect of sustained virologic response (SVR) after treatment with pegylated-interferon (PEG-IFN) plus ribavirin on the development of liver cirrhosis in elderly patients with chronic hepatitis C (CHC). Patients and methods: This retrospective study enrolled 145 elderly CHC patients (aged ≥65 years) who were treatment-naïve and were treated with PEG-IFN plus ribavirin for 6 months between January 2005 and December 2011. Abdominal sonography was performed and liver biochemistry was studied at baseline, at the end of treatment, and every 3–6 months thereafter. The development of liver cirrhosis and related complications was evaluated at the follow-ups. The aspartate aminotransferase-to-platelet ratio index was used as a noninvasive maker for fibrosis. Results: The mean patient age was 69.1±3.3 years, and the average follow-up time was 5.5 years (standard deviation: 2.5 years, range: 1.1–12.3 years). Ninety-five patients (65.5%) achieved SVR, and 26 (17.9%) discontinued treatment. Twenty-seven patients (18.6%) developed liver cirrhosis after treatment. Patients without SVR had significantly greater risk of liver cirrhosis than those with SVR (hazard ratio [HR]: 3.39, 95% confidence interval [CI]: 1.312–8.761, P=0.012). The difference in 3-year cumulative incidence of liver cirrhosis was 24.8% greater for patients without SVR (35.2%, 95% CI: 13.0–57.5, P=0.012) compared with those with SVR (10.4%, 95% CI: 3.1–17.7). There was a trend of a higher baseline aspartate aminotransferase-to-platelet ratio index score in patients who progressed to liver cirrhosis compared with those who did not progress (2.1±1.2 vs 1.6±1.3, P=0.055), but the difference failed to reach significance by Cox regression (adjusted HR: 1.285, 95% CI: 0.921–1.791, P=0.14). Conclusion: An SVR following PEG-IFN combination treatment can reduce the risk of liver cirrhosis in elderly CHC patients. Keywords: hepatitis C, sustained virologic response, pegylated interferon, ribavirin, liver cirrhosis

Charged multivesicular body protein 1A (CHMP1A; also known as chromatin-modifying protein 1A) is a member of the ESCRT-III (endosomal sorting complex required for transport-III) complex but is also suggested to localize to the nuclear matrix and regulate c

In rats respiratory tract infections due to Sendai virus and coronavirus usually are transient, but they can have long-lasting consequences when accompanied by Mycoplasma pulmonis infections. Morphological alterations in the tracheal epithelium and a potentiation of the inflammatory response evoked by sensory nerve stimulation ("neurogenic inflammation") are evident nine weeks after the infections begin, but the extent to which these changes are present at earlier times is not known. In the present study we characterized these abnormalities in the epithelium and determined the extent to which they are present 3 and 6 weeks after the infections begin. We also determined the magnitude of the potentiation of neurogenic inflammation at these times, whether the potentiation can be reversed by glucocorticoids, and whether a proliferation of blood vessels contributes to the abnormally large amount of plasma extravasation associated with this potentiation. To this end, we studied Long-Evans rats that acquired these viral and mycoplasmal infections from other rats. We found that the tracheal epithelium of the infected rats had ten times as many Alcian blue-PAS positive mucous cells as did that of pathogen-free rats; but it contained none of the serous cells typical of pathogen-free rats, so the total number of secretory cells was not increased. In addition, the epithelium of the infected rats had three times the number of ciliated cells and had only a third of the number of globule leukocytes. In response to an injection of capsaicin (150 micrograms/kg i.v.), the tracheas of the infected rats developed an abnormally large amount of extravasation of two tracers, Evans blue dye and Monastral blue pigment, and had an abnormally large number of Monastral blue-labeled venules, particularly in regions of mucosa overlying the cartilaginous rings. This abnormally large amount of extravasation was blocked by dexamethasone (1 mg/day i.p. for 5 days). We conclude that M. pulmonis infections, exacerbated at the outset by viral infections, result within three weeks in the transformation of epithelial serous cells into mucous cells, the proliferation of ciliated cells, and the depletion of globule leukocytes. They also cause a proliferation of mediator-sensitive blood vessels in the airway mucosa, which is likely to contribute to the potentiation of neurogenic inflammation that accompanies these infections.

Background and Purpose: Chemoradiotherapy (CRT) for locally-advanced non-small cell lung cancer (LA-NSCLC) has undergone advances, including increased overall survival (OS) when combined with immune checkpoint blockade (ICB), and using cardiac-sparing techniques to reduce the radiotoxicity. This research investigated 1) how radiotherapy schedules can be optimised with CRT-ICB schemes, and 2) how cardiac-sparing might change the OS for concurrent CRT (cCRT)., Methods and Materials: Survival data and dosimetric indices were sourced from published studies, with 2-year OS standardised and the hazard ratio of mean heart dose (MHD) against radiotoxicity tabulated in purpose. A published CRT dose-response model was selected, then modified with ICB and cardiac-sparing hypotheses. Models were maximum likelihood fitted, then visualised the prediction outcomes after bootstrapping., Results: The modelled 2-year OS rate of cCRT-ICB reached 71 % (95 % confidence intervals, CI 62 %, 84 %) and 66 % (95 % CI: 53 %, 81 %) for stage IIIA and IIIB/C, respectively, given 60 Gy in 2 Gy-per-fraction. 60 Gy in 30 fractions remained the best schedule for cCRT-ICB, whereas modest dose de-escalation to 55 Gy only reduced the OS in 2 %. Sequential CRT (sCRT)-ICB provided 6 % OS increases versus the best OS rate achieved by sCRT alone. Photon MHD-sparing achieved a 5-10 % increase in modelled 2-year OS, with protons providing a further roughly 5-10 % increase., Conclusion: Neither dose-escalation nor de-escalation relative to 60 Gy in 30 fractions influenced the survival with cCRT-ICB, while 5 Gy dose de-escalation might benefit patients with heavily irradiated organs at risk. Cardiac-sparing improved OS, and protons provided advantages for tumours anatomically overlapped or lay below the heart., 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 © 2024 Elsevier B.V. All rights reserved.)

Evaluating the risk factors for the conversion from robotic-assisted partial nephrectomy (RAPN) to radical nephrectomy (RN). Through a comprehensive database search encompassing PubMed, Web of Science, Embase, and the Cochrane Library, we identified pertinent English-language research published by June 2024. We utilized the NOS scale for quality assessment. The aggregate effect was quantified via the odds ratio (OR), alongside a 95% confidence interval (CI). Sensitivity analyses were conducted using both fixed-effects and random-effects models to evaluate reliability. The meta-analytical process was facilitated by the Stata 18 software suite. Our meta-analysis encompassed a total of 8 retrospective studies and 3 prospective studies, totaling 4056 patients. We found that increasing patient age (OR: 1.04; 95% CI 1.00-1.08; P = 0.005), higher American Society of Anesthesiologists (ASA) scores (3 or above) (OR: 2.74; 95% CI 1.52-4.93; P = 0.001), elevated R.E.N.A.L. scores (7 or above) (OR: 2.49; 95% CI 1.57-3.95; P < 0.001), and the use of off-clamp RAPN (OR: 7.21; 95% CI 2.60-19.93; P < 0.001) significantly raised the odds of surgical conversion. On the other hand, male sex (OR: 1.04; 95% CI 0.67-1.62; P = 0.858), the side of the tumor (OR: 0.97; 95% CI 0.48-1.95; P = 0.936), tumor size (OR: 3.43; 95% CI 0.57-20.55; P = 0.177), body mass index (BMI) (OR: 1.03; 95% CI 0.96-1.11; P = 0.426), clinical stage (OR: 3.78; 95% CI 0.46-30.70; P = 0.214), and the use of single-port RAPN (OR: 0.54; 95% CI 0.16-1.78; P = 0.31) did not show a statistically significant link to an increased conversion risk. This meta-analysis elucidates the critical risk factors for the conversion from robotic-assisted partial nephrectomy to radical nephrectomy, providing significant guidance for preoperative risk assessment and clinical decision-making. However, our findings necessitate validation through studies with larger sample sizes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

This study investigated the effect of substances on nonspecific immune responses of head kidney leukocytes, the antimicrobial activity against Vibrio sp., as well as the time-kill of Vibrio sp. by combining the substances with lactic acid bacteria (LAB) and Pediococcus sp. The substances are B. pilosa hot water extract, B. pilosa powder extract, B. pilosa methanol extract, B. pilosa ethanol extract, B. alba hot water extract, B. alba powder extract, B. alba methanol extract, B. alba ethanol extract, and bioactive compounds, namely cytopiloyne, flavonoid, phenol, ethyl caffeate, luteolin, chlorogenic acid, butein, and linoleic acid. The results showed that some of them were nontoxic to the head kidney leukocytes, which can increase the phagocytic rate, phagocytic index, and respiratory burst. These substances were able to inhibit the growth of Vibrio sp.; they can even completely kill the pathogenic bacteria. The largest of the inhibition zone formed from the EC group at a concentration range of 5-50 µg/mL against V. parahaemolyticus , V. alginolyticus , and V. harveyi with a value of 19.7 ± 0.56, 19.3 ± 1.53, and 20.6 ± 1.53 mm. Furthermore, the time-kill studies showed that the LAB and P. acidilactici can completely kill the Vibrio sp. at 6 h incubation time, mainly in the group of combination with EC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that may influence the work reported in this paper.

Objectives: Obstructive sleep apnea is associated with alterations in slow-wave activity during sleep, potentially increasing the risk of Alzheimer's disease. This study investigated the associations between obstructive sleep apnea manifestations such as respiratory events, hypoxia, arousal, slow-wave patterns, and neurochemical biomarker levels., Methods: Individuals with suspected obstructive sleep apnea underwent polysomnography. Sleep disorder indices, oxygen metrics, and slow-wave activity data were obtained from the polysomnography, and blood samples were taken the following morning to determine the plasma levels of total tau (T-Tau) and amyloid beta-peptide 42 (Aβ 42 ) by using an ultrasensitive immunomagnetic reduction assay. Subsequently, the participants were categorized into groups with low and high Alzheimer's disease risk on the basis of their computed product Aβ 42 × T-Tau. Intergroup differences and the associations and mediation effects between sleep-related parameters and neurochemical biomarkers were analyzed., Results: Forty-two participants were enrolled, with 21 assigned to each of the low- and high-risk groups. High-risk individuals had a higher apnea-hypopnea index, oxygen desaturation index (≥3%, ODI-3%), fraction of total sleep time with oxygen desaturation (SpO 2- 90% TST ), and arousal index and greater peak-to-peak amplitude and slope in slow-wave activity, with a correspondingly shorter duration, than did low-risk individuals. Furthermore, indices such as the apnea-hypopnea index, ODI-3% and SpO 2- 90% TST were found to indirectly affect slow-wave activity, thereby raising the Aβ 42 × T-Tau level., Conclusions: Obstructive sleep apnea manifestations, such as respiratory events and hypoxia, may influence slow-wave sleep activity (functioning as intermediaries) and may be linked to elevated neurochemical biomarker levels. However, a longitudinal study is necessary to determine causal relationships among these factors., Statement of Significance: This research aims to bridge gaps in understanding how obstructive sleep apnea is associated with an elevated risk of Alzheimer's disease, providing valuable knowledge for sleep and cognitive health., Competing Interests: Declaration of conflicts of interest The authors declare that they have no competing interests., (Copyright © 2024 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Brief rationale: Zoledronic acid treatment against osteoporosis is limited by APR. Main result: Combination therapy (hydrocortisone plus non-steroidal anti-inflammatory drugs, acetaminophen, and prednisolone) reduced intolerable APR levels and provided complete symptom relief in most patients. Significance of the paper: Combination therapy can enhance patient outcomes in osteoporosis management., Purpose: Osteoporosis is a common condition associated with high morbidity rates, often requiring treatment with bisphosphonates such as zoledronic acid. However, the persistence to zoledronic acid infusion is commonly limited by acute phase response (APR). This retrospective study aimed to evaluate the efficacy of a novel combination therapy in preventing APR symptoms., Methods: A retrospective case-control study was conducted on 931 patients who received their first zoledronic acid infusion between 2011 and 2021. We evaluated the efficacy of combination therapy comprising a single dose of hydrocortisone prior to the infusion and a 3-d oral regimen of non-steroidal anti-inflammatory drugs, acetaminophen, and prednisolone following the infusion. Patients were divided into protocol (receiving combination therapy) and control groups (without treatment). Baseline characteristics, APR incidence, and the efficacy of symptom control were compared between groups using Fisher's exact test and Student's t-test., Results: There was no difference in APR incidence between the protocol (n = 507) and control group (n = 407; p = 0.1442). However, the protocol group exhibited lower intolerable APR levels (3.72% vs. 16.71%; p < 0.0001) and complete symptom relief in 96.28% of cases., Conclusion: The combination therapy protocol effectively reduced intolerable APR and relieved symptoms in most patients following zoledronic acid infusion. This study highlights the importance of proactive management strategies for APR and emphasizes the potential of combination therapy in alleviating APR symptoms and reducing the occurrence of severe APR in patients undergoing osteoporosis management., (© 2024. The Author(s).)

Purpose: This research aims to use a data-driven analytical method to compare the effectiveness of High-Intensity Focused Ultrasound (HIFU) partial gland ablation with Robot-Assisted Radical Prostatectomy (RARP) for treating localized prostate cancer, evaluating variations in treatment results., Methods: We performed a systematic review of the literature, covering key databases including the Cochrane Library, PubMed, EMBASE, Web of Science, and Google Scholar, with the latest information updated until August 2024. We utilized Stata 18 for data analysis, computing weighted mean differences (WMDs) for continuous data and odds ratios (ORs) for categorical data, with all results reported alongside 95% confidence intervals (CIs). Additionally, the studies included were evaluated using the Newcastle-Ottawa Scale (NOS)., Results: This meta-analysis incorporated data from three paired studies, encompassing a total of 1,503 patients. Patients treated with HIFU experienced a shorter hospital stay (WMD = -2.78, 95%CI -5.14,-0.43; p = 0.02) compared to those who received RARP. Additionally, evaluations at 3 and 12 months post-surgery revealed that the HIFU group exhibited better recovery in urinary continence and sexual function than the RARP group. However, there were no notable disparities in complication rates (OR = 1.48, 95%CI 0.92,2.40; p = 0.110) and the requirement for salvage therapy (OR = 2.92, 95%CI 0.60,14.33; p = 0.186) between the two treatment methods., Conclusion: In conclusion, this meta-analysis appears to suggest potential benefits of HIFU partial gland ablation in possibly reducing the length of hospital stays and seems to indicate that it might be associated with improved recovery in terms of urinary incontinence and sexual function, particularly during the early to mid-term postoperative period. Although the differences in complication rates and the requirement for salvage therapy between the two surgical methods were not statistically significant, the findings provided by this analysis are instrumental in guiding clinical decision-making., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Temporomandibular joint (TMJ) diseases are common clinical conditions. The number of patients with TMJ diseases is large, and the etiology, epidemiology, disease spectrum, and treatment of the disease remain controversial and unknown. To understand and master the current situation of the occurrence, development and prevention of TMJ diseases, as well as to identify the patterns in etiology, incidence, drug sensitivity, and prognosis is crucial for alleviating patients'suffering.This will facilitate in-depth medical research, effective disease prevention measures, and the formulation of corresponding health policies. Cohort construction and research has an irreplaceable role in precise disease prevention and significant improvement in diagnosis and treatment levels. Large-scale cohort studies are needed to explore the relationship between potential risk factors and outcomes of TMJ diseases, and to observe disease prognoses through long-term follw-ups. The consensus aims to establish a standard conceptual frame work for a cohort study on patients with TMJ disease while providing ideas for cohort data standards to this condition. TMJ disease cohort data consists of both common data standards applicable to all specific disease cohorts as well as disease-specific data standards. Common data were available for each specific disease cohort. By integrating different cohort research resources, standard problems or study variables can be unified. Long-term follow-up can be performed using consistent definitions and criteria across different projects for better core data collection. It is hoped that this consensus will be facilitate the development cohort studies of TMJ diseases.

High-fat diet (HFD)-induced obesity induces peripheral inflammation and hypothalamic pathogenesis linking the activation of astrocytes and microglia. Clinical evidence indicates a positive correlation between obesity and psychiatric disorders, such as depression. The connectivity of the frontal-striatal (FS) circuit, involving the caudate putamen (CPu) and anterior cingulate cortex (ACC) within the prefrontal cortex (PFC), is known for its role in stress-induced depression. Thus, there is a need for a thorough investigation into whether chronic obesity-induced gliosis, characterized by the activation of astrocytes and microglia, in these brain regions of individuals with chronic obesity. The results revealed increased S100β + astrocytes and Iba1 + microglia in the CPu and ACC of male obese mice, along with immune cell accumulation in meningeal lymphatic drainage. Activated GFAP + astrocytes and Iba1 + microglia were observed in the corpus callosum of obese mice. Gliosis in the CPu and ACC was linked to elevated cleaved caspase-3 levels, indicating potential neural cell death by chronic HFD feeding. There was a loss of myelin and adenomatous polyposis coli (APC) + oligodendrocytes (OLs) in the corpus callosum, an area known to be linked with injury to the CPu. Additionally, reduced levels of aquaporin-4 (AQP4), a protein associated within the glymphatic systems, were noted in the CPu and ACC, while ciliary neurotrophic factor (CNTF) gene expression was upregulated in these brain regions of obese mice. The in vitro study revealed that high-dose CNTF causing a trend of reduced astrocytic AQP4 expression, but it significantly impaired OL maturation. This pathological evidence highlights that prolonged HFD consumption induces persistent FS gliosis and demyelination in the corpus callosum. An elevated level of CNTF appears to act as a potential regulator, leading to AQP4 downregulation in the FS areas and demyelination in the corpus callosum. This cascade of events might contribute to neural cell damage within these regions and disrupt the glymphatic flow., (© 2024 International Society for Neurochemistry.)

Nitrogen (N) utilisation efficiency (NUE, milk N yield [g/d]/N intake [g/d]) is an important performance indicator in dairy farming. Determining the NUE-associated blood metabolite profile will contribute to the optimisation of nutritional strategies to further improve NUE among dairy cows. Here, 20 primiparous lactating cows with days in milk ranging from 95 to 115 days were selected from a total of 1 221 cows. Each cow's N intake and milk N yield were measured for 7 days. Subsequently, blood samples were collected before morning feeding. Based on analysis and calculations, cows were retrospectively classified into two groups based on their NUE values, namely, a low NUE group (LNUE, NUE = 24.8 ± 1.6%, n = 10, mean ± SD) and a high NUE group (HNUE, NUE = 35.2 ± 1.7%, n = 10, mean ± SD). Plasma samples were selected from six cows in each group for metabolomics and amino acid profiling. Among the 41 differential metabolites (DMs) identified in the metabolomic analysis, sucrose, MG(0:0/22:1(13Z)/0:0), 2-amino-6-hydroxyhexanoic acid, and L-glutamine exhibited significant correlations with NUE, milk yield, and BW (P < 0.05). Moreover, the five differential amino acids and amino acid metabolites (DAAs) identified in the amino acid profiling and 5 of the 6 differential amino acids and amino acid conjugates identified by plasma metabolomics were found to be less abundant in the HNUE group (P < 0.05). Specifically, there was a 39.4% decrease in L-arginine content and a 29.2% decrease in L-glutamine content (P < 0.05). Pathway analysis indicated that the DMs and DAAs were mainly involved in arginine biosynthesis, glutathione metabolism, arginine and proline metabolism, and tryptophan metabolism (pathway impact > 0.1). These results provided new insights into the new blood metabolite profile associated with NUE in dairy cows. These new insights can provide foundational information for the formulation of new strategies to further enhance NUE in dairy cows., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Adding immune checkpoint blockade (ICB) to concurrent chemoradiotherapy (cCRT) has improved overall survival (OS) for inoperable locally advanced non-small cell lung cancer. Trials of cCRT-ICB are heterogeneous for factors such as tumor stage and histology, programmed cell death ligand-1 (PDL-1) status, and cCRT-ICB schedules. We therefore aimed to determine the ICB contribution to survival across studies and identify factors associated with survival gain., Methods and Materials: Data were collated from cCRT-ICB clinical studies published 2018 to 2022 that treated 2196 patients with non-small cell lung cancer (99% stage 3). Associations between 2-year OS and ICB, CRT, patient and tumor factors were investigated using metaregression. A published model of survival after radiation therapy (RT) or CRT was extended to include ICB effects. The model was fitted simultaneously to the cCRT-ICB data and data previously compiled for RT/CRT treatments alone. The net ICB contribution (OS gain) and its associations with factors were described by fitted values of ICB terms added to the model. Statistical significance was determined by likelihood-ratio testing., Results: The gain in 2-year OS from ICB was 9.9% overall (95% CI, 7.6%, 12.2%; P = .018). Both OS gain and 2-year OS itself rose with increasing planned ICB duration (P = .008, .002, respectively) and with tumor PDL-1 ≥ 1% (P = .034, .023). Fitted OS gains were also greater for patients with stage 3B/C disease (P = .021). OS gain was not associated with tumor histology, patient performance status, radiation therapy dose, ICB drug type (anti-PDL-1 vs anti-programmed cell death-1), or whether ICB began concurrently with or after cCRT., Conclusions: Fitted gains in 2-year OS due to ICB were higher in cohorts with greater fractions of stage 3B/C patients and patients with tumor PDL-1 ≥ 1%. OS gain was also significantly higher in a single cohort with a planned ICB duration of 2 years rather than 1, but was not associated with whether ICB treatment began during versus after CRT., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The lifelong administration of immunosuppressants remains the largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model., Methods: Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term antilymphocyte serum (ALS) and cyclosporine A (CsA). Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis., Results: The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared with the control (group 1). However, in group 4, FBLT combined with short-term ALS/CsA, median composite tissue allograft survival time (266 days) was significantly prolonged compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) ( P < 0.01). Group 4 also showed a significant increase in regulatory T cells ( P = 0.04) and transforming growth factor-β1 levels ( P = 0.02), and a trend toward a decrease in interleukin-1β levels ( P = 0.03) at 16 weeks after transplantation as compared with control (group 1)., Conclusions: FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and antiinflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival., Clinical Relevance Statement: Full-spectrum light therapy could be a potential strategy to increase vascularized composite allotransplant survival., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Plantago asiatica seeds (PS) are commonly used as a medicinal plant. This study investigates the efficacy of PS against heavy metal toxicity in white shrimp (Penaeus vannamei). After feeding PS diet (5 g/kg) or basal diet (control group) for 7 days, shrimps were exposed to sublethal concentrations of heavy metals in seawater (As: 12 mg/L, Pb: 250 mg/L, Hg: 0.4 mg/L). The 7-day survival observation showed that the survival in groups fed with PS were significantly higher than that in the control group, revealing that dietary PS had the efficacy to mitigate heavy metal toxicity in white shrimp. Under the same feeding condition, white shrimps were exposed to safety dose of heavy metals (1/10 of sublethal concentrations) to understand the mechanism of mitigation. The metal accumulations in haemolymph, gills, hepatopancreas, and muscle tissues as well as the immune, anti-oxidative, stress related gene expressions in haemocytes, gills and hepatopancreas were measured for 14 days. The As accumulation in gills and hepatopancreas of groups fed with PS were significantly lower than those of control group on day 7 and 14, respectively; The Pb concentration in haemolymph of group fed with PS was significantly lower than that of control group on day 7 and 14; The Hg concentration in hepatopancreas of the group fed with PS was significantly lower than that of control group on day 7. Dietary PS could mitigate heavy metal-induced immune suppression, oxidative stress, and stress response by positively regulating immune (proPO I, Toll, IMD), antioxidant (SOD, GST, Trx), and negatively regulating stress response genes (HSP70, MT). The present study demonstrated that dietary PS could protect white shrimp against metal toxicity by reducing metal accumulations and regulating the immune, antioxidant, and stress response gene expressions in specific tissue. Therefore, PS may serve as a beneficial feed additive in the aquaculture., Competing Interests: Declaration of competing interest No conflicts of interest are declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Assessing the perioperative, oncological, and functional results of robotic-assisted radical prostatectomy (RARP) versus three-dimensional laparoscopic radical prostatectomy (3D LRP), a comprehensive exploration of the Cochrane Library, PubMed, EMBASE, and Web of Science databases was carried out until July 2024. The combined results were evaluated by utilizing the weighted mean differences (WMDs) and odds ratios (ORs) through the application of Stata version 18, where data were gathered and scrutinized. In addition, sensitivity analyses were performed to ensure the robustness of our findings. In the meta-analysis we conducted, four studies were incorporated in total, which comprised two randomized controlled trials, one study that was retrospective and another that was prospective. The findings revealed that RARP was associated with a significantly reduced estimated blood loss (EBL) (WMD - 31.04, 95%CI - 54.57, - 7.51; p = 0.01) compared to 3D LRP. Nonetheless, there were no notable statistical variances seen between the two groups regarding operative time (OT), nerve-sparing rates, positive surgical margin (PSM) rates, biochemical recurrence (BCR) rates, or the restoration of urinary continence and potency 3 or 6 months after the surgery. In conclusion, our comprehensive meta-analysis has offered a detailed contrast between the results of RARP and 3D LRP in the treatment of prostate cancer. The findings highlight a considerable decrease in projected blood loss linked with RARP, yet no notable variances were detected between the two methods regarding other perioperative, oncological, and functional results., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Objective: The influence of robot-assisted radical prostatectomy (RARP) in obese (OB) and non-obese (NOB) prostate cancer patients remains a topic of debate. The objective of this study was to juxtapose the perioperative, functional, and oncologic outcomes of RARP in OB and NOB cohorts., Materials and Methods: We systematically searched the databases such as PubMed, Embase, Web of Science, and the Cochrane Library database to identify relevant studies published in English up to September 2023. Review Manager was used to compare various parameters. The study was registered with PROSPERO (CRD42023473136). Sixteen comparative trials were included for 8434 obese patients compared with 55,266 non-obese patients., Results: The OB group had a longer operative time (WMD 17.8 min, 95% CI 9.7,25.8; p < 0.0001), a longer length of hospital stay (WMD 0.18 day, 95% CI 0.12,0.24; p < 0.00001, a higher estimated blood loss (WMD 50.6 ml, 95% CI 11.7,89.6; p = 0.01), and higher pelvic lymphadenectomy rate (RR 1.08, 95% CI 1.04,1.12; p < 0.0001)and lower nerve sparing rate (RR 0.95, 95% CI 0.91,0.99; p < 0.01), but there was no difference between unilateral (RR 1.0, 95% CI 0.8,1.3; p = 0.8)and bilateral (RR 0.9, 95% CI 0.9,1.0; p = 0.06)nerve sparing rate. Then, complication rates (RR 1.6, 95% CI 1.5,1.7; p < 0.00001) were higher in the OB group, and both major (RR 1.4, 95% CI 1.1,1.8; p = 0.01)and minor (RR 1.4, 95% CI 1.1,1.7; p < 0.01)complication rates were higher in the OB group. Moreover, obese patients showed significantly higher probabilities of incontinence (RR 1.17, 95% CI 1.03,1.33; p = 0.01) and impotency (RR 1.08, 95% CI 1.01,1.15; p = 0.02) at 1 year. Last, the positive surgical margin (RR 1.2, 95% CI 1.1,1.3; p < 0.01) was higher in the OB group., Conclusion: In the obese group, perioperative outcomes, total complications, functional outcomes, and oncologic outcomes were all worse for RARP. Weight loss before RARP may be a feasible strategy to improve the prognosis of patients., (© 2024. The Author(s).)

Bifunctional molecules such as targeted protein degraders induce proximity to promote gain-of-function pharmacology. These powerful approaches have gained broad traction across academia and the pharmaceutical industry, leading to an intensive focus on strategies that can accelerate their identification and optimization. We and others have previously used chemical proteomics to map degradable target space, and these datasets have been used to develop and train multiparameter models to extend degradability predictions across the proteome. In this study, we now turn our attention to develop generalizable chemistry strategies to accelerate the development of new bifunctional degraders. We implement lysine-targeted reversible-covalent chemistry to rationally tune the binding kinetics at the protein-of-interest across a set of 25 targets. We define an unbiased workflow consisting of global proteomics analysis, IP/MS of ternary complexes and the E-STUB assay, to mechanistically characterize the effects of ligand residence time on targeted protein degradation and formulate hypotheses about the rate-limiting step of degradation for each target. Our key finding is that target residence time is a major determinant of degrader activity, and this can be rapidly and rationally tuned through the synthesis of a minimal number of analogues to accelerate early degrader discovery and optimization efforts., Competing Interests: K.A.D receives or has received consulting fees from Kronos Bio and Neomorph Inc. H.-T.H has no conflict of interest. W.R.S. is a Board or SAB member and holds equity in Delphia Therapeutics, Ideaya Biosciences, Red Ridge Bio, Scorpion Therapeutics and has consulted for Array, Astex, CJ Biosciences, Epidarex Capital, Ipsen, Merck Pharmaceuticals, Pierre Fabre, Sanofi, Servier and Syndax Pharmaceuticals and receives research funding from Bayer Pharmaceutical, Bristol-Myers Squibb, Boehringer-Ingelheim, Ideaya Biosciences, Calico Biosciences, and Servier Pharmaceuticals. W.R.S. is a co-patent holder on EGFR mutation diagnostic patents. F.M.F. is a scientific co-founder and equity holder in Proximity Therapeutics, and was previously a scientific advisory board member (SAB) of Triana Biomedicines. F.M.F. is or was recently a consultant or received speaking honoraria from RA Capital, Eli Lilly and Co., Sorrento Pharma, Plexium Inc, Sygnature Discovery, Neomorph Inc. and Tocris BioTechne. The Ferguson lab receives or has received research funding or resources in kind from Ono Pharmaceutical Co. Ltd, Promega Corp, Eli Lilly and Co., and Merck and Co. F.M.F.’s interests have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies. E.S.F. is a founder, scientific advisory board (SAB) member, and equity holder of Civetta Therapeutics, Proximity Therapeutics, Stelexis Biosciences, and Neomorph, Inc. (also board of directors). He is an equity holder and SAB member for Avilar Therapeutics, Photys Therapeutics, and Ajax Therapeutics and an equity holder in Lighthorse Therapeutics and Anvia Therapeutics. E.S.F. is a consultant to Novartis, EcoR1 capital, Odyssey and Deerfield. The Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Interline, Bayer and Astellas.

Protein ubiquitylation controls diverse processes within eukaryotic cells, including protein degradation, and is often dysregulated in disease. Moreover, small-molecule degraders that redirect ubiquitylation activities toward disease targets are an emerging and promising therapeutic class. Over 600 E3 ubiquitin ligases are expressed in humans, but their substrates remain largely elusive, necessitating the development of new methods for their discovery. Here we report the development of E3-substrate tagging by ubiquitin biotinylation (E-STUB), a ubiquitin-specific proximity labeling method that biotinylates ubiquitylated substrates in proximity to an E3 ligase of interest. E-STUB accurately identifies the direct ubiquitylated targets of protein degraders, including collateral targets and ubiquitylation events that do not lead to substrate degradation. It also detects known substrates of E3 ligase CRBN and VHL with high specificity. With the ability to elucidate proximal ubiquitylation events, E-STUB may facilitate the development of proximity-inducing therapeutics and act as a generalizable method for E3-substrate mapping., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The objective of this research was to investigate how the combination of semen coicis extract and PD-1 inhibitors can potentially work together to enhance the anti-tumor effects, with a focus on understanding the underlying mechanism., Methods: We obtained the active components and specific targets of semen coicis in the treatment of NSCLC from various databases, namely TCMSP, GeneCard, and OMIM. By utilizing the STRING database and Cytoscape software, we established a protein interaction network (PPI) for the active ingredient of semen coicis and the target genes related to NSCLC. To explore the potential pathways involved, we conducted gene ontology (GO) and biological pathway (KEGG) enrichment analyses, which were further supported by molecular docking technology. Additionally, we conducted cyto-inhibition experiments to verify the inhibitory effects of semen coicis alone or in combination with a PD-1 inhibitor on A549 cells, along with examining the associated pathways. Furthermore, we investigated the synergistic mechanism of these two drugs through cytokine release experiments and the PD-L1 expression study on A549 cells., Results: Semen coicis contains two main active components, Omaine and (S)-4-Nonanolide. Its primary targets include PIK3R1, PIK3CD, PIK3CA, AKT2, and mTOR. Molecular docking experiments confirmed that these ingredients and targets form stable bonds. In vitro experiments showed that semen coicis demonstrates inhibitory effects against A549 cells, and this effect was further enhanced when combined with PD-1 inhibitors. PCR and WB analysis confirmed that the inhibition of the PI3K-AKT-mTOR pathway may contribute to this effect. Additionally, semen coicis was observed to decrease the levels of IFN-γ, IL-6, and TNF-α, promoting the recovery of the human anti-tumor immune response. And semen coicis could inhibit the induced expression of PD‑L1 of A549 cells stimulated by IFN‑γ as well., Conclusion: Semen coicis not only has the ability to kill tumor cells directly but also alleviates the immunosuppression found in the tumor microenvironment. Additionally, it collaboratively enhances the effectiveness of PD-1 inhibitors against tumors by blocking the activation of PI3K-AKT-mTOR., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Vaccination strategies that can induce a broad spectrum immune response are important to enhance protection against SARS-CoV-2 variants. We conducted a randomized, double-blind and parallel controlled trial to evaluate the safety and immunogenicity of the bivalent (5×10 10 viral particles) and B.1.1.529 variant (5×10 10 viral particles) adenovirus type-5 (Ad5) vectored COVID-19 vaccines administrated via inhalation. 451 eligible subjects aged 18 years and older who had been vaccinated with three doses inactivated COVID-19 vaccines were randomly assigned to inhale one dose of either B.1.1.529 variant Ad5 vectored COVID-19 vaccine (Ad5-nCoVO-IH group, N=150), bivalent Ad5 vectored COVID-19 vaccine (Ad5-nCoV/O-IH group, N=151), or Ad5 vectored COVID-19 vaccine (5×10 10 viral particles; Ad5-nCoV-IH group, N=150). Adverse reactions reported by 37 (24.67%) participants in the Ad5-nCoVO-IH group, 28 (18.54%) in the Ad5-nCoV/O-IH group, and 26 (17.33%) in the Ad5-nCoV-IH group with mainly mild to moderate dry mouth, oropharyngeal pain, headache, myalgia, cough, fever and fatigue. No serious adverse events related to the vaccine were reported. Investigational vaccines were immunogenic, with significant difference in the GMTs of neutralizing antibodies against Omicron BA.1 between Ad5-nCoV/O-IH (43.70) and Ad5-nCoV-IH (29.25) at 28 days after vaccination (P=0.0238). The seroconversion rates of neutralizing antibodies against BA.1 in Ad5-nCoVO-IH, Ad5-nCoV/O-IH, and Ad5-nCoV-IH groups were 56.00%, 59.60% and 48.67% with no significant difference among the groups. Overall, the investigational vaccines were demonstrated to be safe and well tolerated in adults, and was highly effective in inducing mucosal immunities in addition to humoral and cellular immune responses defending against SARS-CoV-2 variants.Trial registration: Chictr.org identifier: ChiCTR2200063996.

Background: Survival analysis has been used to characterize the time-to-event data. In medical studies, a typical application is to analyze the survival time of specific cancers by using high-dimensional gene expressions. The main challenges include the involvement of non-informaive gene expressions and possibly nonlinear relationship between survival time and gene expressions. Moreover, due to possibly imprecise data collection or wrong record, measurement error might be ubiquitous in the survival time and its censoring status. Ignoring measurement error effects may incur biased estimator and wrong conclusion., Results: To tackle those challenges and derive a reliable estimation with efficiently computational implementation, we develop the R package AFFECT, which is referred to Accelerated Functional Failure time model with Error-Contaminated survival Times., Conclusions: This package aims to correct for measurement error effects in survival times and implements a boosting algorithm under corrected data to determine informative gene expressions as well as derive the corresponding nonlinear functions., (© 2024. The Author(s).)

Non-CpG methylation is associated with several cellular processes, especially neuronal development and cancer, while its effect on DNA structure remains unclear. We have determined the crystal structures of DNA duplexes containing -CGCCG- regions as CCG repeat motifs that comprise a non-CpG site with or without cytosine methylation. Crystal structure analyses have revealed that the mC:G base-pair can simultaneously form two alternative conformations arising from non-CpG methylation, including a unique water-mediated cis Watson-Crick/Hoogsteen, (w)cWH, and Watson-Crick (WC) geometries, with partial occupancies of 0.1 and 0.9, respectively. NMR studies showed that an alternative conformation of methylated mC:G base-pair at non-CpG step exhibits characteristics of cWH with a syn-guanosine conformation in solution. DNA duplexes complexed with the DNA binding drug echinomycin result in increased occupancy of the (w)cWH geometry in the methylated base-pair (from 0.1 to 0.3). Our structural results demonstrated that cytosine methylation at a non-CpG step leads to an anti→syntransition of its complementary guanosine residue toward the (w)cWH geometry as a partial population of WC, in both drug-bound and naked mC:G base pairs. This particular geometry is specific to non-CpG methylated dinucleotide sites in B-form DNA. Overall, the current study provides new insights into DNA conformation during epigenetic regulation., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

This study investigated the effects of Cinnamomum osmophloeum leaf hot-water extract (CLWE) on nonspecific immune responses and resistance to Vibrio parahaemolyticus in white shrimp (Penaeus vannamei). Firstly, a cell viability assay demonstrated that the CLWE is safe to white shrimp heamocytes in the concentration of 0-500 mg L -1 . Haemocytes incubated in vitro with 10 and 50 mg L -1 of CLWE showed significantly higher response in superoxide anion production, PO activity, and phagocytic activity. In the in vivo trials, white shrimp were fed with 0, 0.5, 1, 5, and 10 g kg -1 CLWE supplemented feeds (designated as CLWE 0, CLWE 0.5, CLWE 1, CLWE 5, and CLWE 10, respectively) over a period of 28 days. In vivo experiments demonstrated that CLWE 0.5 feeding group resulted in the highest total haemocyte count, superoxide anion production, phenoloxidase activity, and phagocytic activity. Moreover, CLWE 0.5 supplemented feed significantly upregulated the clotting system, antimicrobial peptides, pattern recognition receptors, pattern recognition proteins, and antioxidant defences in white shrimp. Furthermore, the shrimp were infected with V. parahaemolyticus injections after 14 days of feeding as challenge test. Based on the challenge test result, both CLWE 0.5 and CLWE 5 demonstrated a strong resistance to V. parahaemolyticus. These two dosages effectively reduced the number of nonviable cells and activated different haemocyte subpopulations. These findings indicated that treatment with CLWE 0.5 could promote nonspecific immune responses, immune-related gene expression, and resistance to V. parahaemolyticus in white shrimp., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Hepatoblastoma (HB) is the most common pediatric liver tumor, presenting significant therapeutic challenges due to its high rates of recurrence and metastasis. While Inosine Monophosphate Dehydrogenase 2(IMPDH2) has been associated with cancer progression, its specific role and clinical implications in HB have not been fully elucidated., Methods: This study utilized Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Tissue Microarray (TMA) for validation. Following this, IMPDH2 was suppressed, and a series of in vitro assays were conducted. Flow cytometry was employed to assess apoptosis and cell cycle arrest. Additionally, the study explored the synergistic therapeutic effects of mycophenolate mofetil (MMF) and doxorubicin (DOX) on HB cell lines., Results: The study identified a marked overexpression of IMPDH2 in HB tissues, which was strongly correlated with reduced Overall Survival (OS) and Event-Free Survival (EFS). IMPDH2 upregulation was also found to be associated with key clinical-pathological features, including pre-chemotherapy alpha-fetoprotein (AFP) levels, presence of preoperative metastasis, and the pre-treatment extent of tumor (PRETEXT) staging system. Knockdown of IMPDH2 significantly inhibited HB cell proliferation and tumorigenicity, inducing cell cycle arrest at the G0/G1 phase. Notably, the combination of MMF, identified as a specific IMPDH2 inhibitor, with DOX, substantially enhanced the therapeutic response., Conclusion: The overexpression of IMPDH2 was closely linked to adverse outcomes in HB patients and appeared to accelerate cell cycle progression. These findings suggest that IMPDH2 may serve as a valuable prognostic indicator and a potential therapeutic target for HB., Impact: The present study unveiled a significant overexpression of inosine monophosphate dehydrogenase 2 (IMPDH2) in hepatoblastoma (HB) tissues, particularly in association with metastasis and recurrence of the disease. The pronounced upregulation of IMPDH2 was found to be intimately correlated with adverse outcomes in HB patients. This overexpression appears to accelerate the progression of the cell cycle, suggesting that IMPDH2 may serve as a promising candidate for both a prognostic marker and a therapeutic target in the context of HB., (© 2024. The Author(s).)

The spirohydantoin-containing cucurbitane-type triterpenoid, kaguacidine A ( 1 ), was isolated and purified from 95% ethanol extract of vines of Momordica charantia L. (Cucurbitaceae). Its unprecedented chemical structure, a spirohydantoin substituent at C-23 of cucurbitane, was elucidated by extensive spectroscopic analyses, including HRESIMS, IR, optical rotation, 1 D- and 2 D-NMR spectra. The possible biosynthetic pathway is deduced and may be attributed to the metabolic activity of microbial symbionts in M. charantia L. Compound 1 was evaluated for anti-inflammatory activity against LPS-induced NO production in RAW 264.7 cells and anti-proliferative activity against four cancer cell lines, including HEp-2, MCF-7, Hep-G2, and WiDr. Compound 1 showed moderate anti-inflammatory activity with an IC 50 value of 18.5 ± 0.4 μg/mL and weak anti-proliferative activity against MCF-7, HEp-2, Hep-G2, and WiDr with IC 50 values of >40, 33.8 ± 0.6, 31.0 ± 0.7, and 27.0 ± 0.7 μM, respectively.

The long noncoding DANCR functions as a tumor oncogene in many cancers, including colorectal cancer (CRC). However, the molecular mechanism of DANCR in CRC has not been explored. This study probed the function and potential mechanism by which DANCR contributes to the progression of CRC. The obtained data indicated that DANCR is overexpressed in CRC tissues and cell lines. Knockdown of DANCR hindered CRC cell proliferation, which was mediated by cyclin D1 and CDK4. Bioinformatic analysis, luciferase reporter assays and subcellular fractionation verified that DANCR directly binds to miR-508-5p. Moreover, DANCR acts as a miR-508-5p ceRNA to regulate expression of ATF1. In addition, upregulation of DANCR is attributed to H3K27 acetylation at the promoter region. In conclusion, our study confirmed that activation of lncRNA DANCR by H3K27 acetylation has an oncogenic role in CRC progression and provides a potential therapeutic target for CRC., (© 2024. The Author(s).)

This study aims to compare the perioperative, oncological, and functional outcomes of perineal hydrodissection (HD) with standard treatment (ST) in patients undergoing robot-assisted radical prostatectomy. We performed an exhaustive search in databases such as PubMed, Embase, Web of Science, and the Cochrane Library, seeking English-language studies relevant to our research question, with a cutoff date of April 2024. The pooled results were assessed using the weighted mean differences (WMDs), standardized mean differences (SMDs), and odds ratios (ORs) metrics. We also performed a sensitivity analysis. The meta-analysis was conducted utilizing Stata/MP version 18 software. The study was registered with PROSPERO (ID: CRD 42024536400). We included a total of five studies (three RCTs and two retrospective studies). According to the data from the Meta-analysis, the HD group showed positive effects in promoting urinary continence (OR 2.64, 95% CI 1.36, 5.12; p = 0.004 < 0.05) and erectile function (SMD 0.92, 95%CI 0.56, 1.27; p < 0.05) within 3 months after surgery. However, no notable disparities were observed in terms of operative time, estimated blood loss, bilateral nerve-sparing rate, or the rate of positive surgical margin. Perineal hydrodissection can be safely applied in robot-assisted radical prostatectomy (RARP), offering a distinct advantage in functional outcomes compared to those who undergo standard robot-assisted prostatectomy alone., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Introduction: Most COVID-19 survivors are troubled with chronic persistent symptoms, which have currently no definitive treatments. Bufei Huoxue (BFHX) capsule exerts clinical benefit, while the material basis and molecular mechanism remain unclear., Aim: The study aimed to elucidate the protective mechanisms of BFHX capsules against COVID-19 convalescence. UHPLC-HRMS and various databases were employed to explore potential compounds and targets. PPI, MCODE, transcription factor (TF), and miRNA analyses were conducted to receive hub targets and corresponding upstream regulators., Method: Molecular docking was applied to verify the binding activity of compound and target. Further, GO, KEGG, WIKI, and Reactome analyses were performed, and compound-targetsymptom and gene-disease networks were constructed. A total of 127 compounds and 313 targets were acquired. A sum of 10 hub targets were screened and showed good binding affinities with critical compounds., Result: MLLT1, CBFB, and EZH2 were identified as key TFs, and hsa-mir-146a-5p, hsa-mir- 26b-5p, and hsa-mir-24-3p were predicted to be important miRNAs. BFHX capsule may alleviate the symptoms by targeting TNF, IL-6, IFNG, and TGF-β1. Besides, BFHX capsule may exert a therapeutic effect on respiratory disease (especially pulmonary fibrosis and lung infection) and multi-system damage during COVID-19 convalescence by regulating cytokine-cytokine receptor interaction, as well as TGF-β, TNF, and Toll-like receptor signaling pathways., Conclusion: In summary, BFHX capsule may exert a therapeutic effect on multi-system damages during COVID-19 convalescence through multiple compounds (such as albiflorin, isopsoralen, and neobavaisoflavone), multiple targets (such as TNF, IL-6, and EGF) and multiple pathways (TGF-β, TNF, and Toll-like receptor signaling pathways)., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The purpose of this study was to conduct a comparative analysis of the perioperative outcomes associated with robot-assisted laparoscopic prostatectomy (RARP) versus open radical prostatectomy (ORP) in the obese population diagnosed with prostate cancer. We performed a comprehensive search in key databases such as PubMed, Embase, Web of Science, and the Cochrane Library, encompassing studies of all languages, with a final search date of April 2024. We also omitted articles that consisted of conference abstracts and content that was not pertinent to our study. The aggregated outcomes were evaluated utilizing the metrics of weighted mean differences (WMDs) and odds ratios (ORs). A sensitivity analysis was also integrated into our assessment. The meta-analysis was facilitated by employing Stata/MP version 18 software. Additionally, the study was duly registered with PROSPERO under the identifier: CRD 42024540216. This meta-analysis, which included five trials, shows that compared to ORP, RARP is associated with a reduced estimated blood loss (EBL) (WMD -445.77, 95%CI -866.08, -25.45; p = 0.038), a decreased transfusion rate (OR 0.17, 95%CI 0.13, 0.21; p < 0.001), and a diminished overall complication rate (OR 0.71, 95%CI 0.58, 0.86; p = 0.001). No statistically significant differences were found in operative time (OT) (WMD 1.88, 95%CI -46.53, 50.28; p = 0.939) or length of stay (LOS) (WMD -0.41, 95%CI -1.07, 0.25; p = 0.221). Among patients with obesity and prostate cancer, RARP demonstrates advantages over ORP by reducing estimated blood loss, transfusion requirements, and the incidence of complications. Notably, there were no significant differences in operative duration and hospital stay between the two surgical approaches. These findings suggest that RARP could be a preferable surgical option for obese individuals with prostate cancer., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Background: The comparison between the mini-midvastus (mini-MV) and mini-parapatellar (mini-MPP) approach in total knee arthroplasty (TKA) remains a subject of debate. The present study compared quadriceps activation, pain levels, and clinical outcomes between the two approaches; quadricep activation was assessed using surface electromyography (sEMG). Methods: This retrospective cross-sectional study comprised a total of 78 patients aged between 50 and 85 years with primary osteoarthritis. Patients were divided into a mini-MV (n = 38) group and a mini-MPP (n = 40) group according to the surgical approach. Results: The two groups exhibited no significant differences in sEMG for the vastus medialis (VM) or rectus femoris (RF) at the follow-up time points, with the exception that the mini-MV group exhibited superior strength of RF during extensions at the 2-week follow-up. However, the mini-MPP group had superior Western Ontario and McMaster Universities Index (WOMAC) total and function scores at the 2- and 6-week follow-ups. The mini-MPP group also had superior WOMAC stiffness scores at the 2-week follow-up. The two groups did not differ significantly in terms of pain levels or morphine consumption. Conclusions: The sEMG data of quadriceps muscle would not differ significantly between the mini-MV and mini-MPP approaches for TKA. Moreover, the mini-MPP approach may yield superior WOMAC scores when compared with the mini-MV approach.