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Tong-Fu Wang,* De-Sheng Chen,* Jia-wang Zhu, Bo Zhu, Zeng-Liang Wang, Jian-Gang Cao, Cai-Hong Feng, Jun-Wei Zhao Department of Sports Medicine and Arthroscopy, Tianjin Hospital of Tianjin University, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jia-wang ZhuDepartment of Sports Medicine and Arthroscopy, Tianjin Hospital of Tianjin University, Tianjin, People’s Republic of ChinaEmail zhulingelou@126.comPurpose: We aim to present unsupervised machine learning-based analysis of clinical features, bone mineral density (BMD) features, and medical care costs of Rotator cuff tears (RCT).Patients and Methods: Fifty-three patients with RCT were reviewed, the clinical features, BMD features, and medical care costs were collected and analyzed by descriptive statistics. Furtherly, unsupervised machine learning (UML) algorithm was used for dimensionality reduction and cluster analysis of the RCT data.Results: There were 26 males and 27 females. The patients were divided into four subgroups using the UML algorithm. There were significant differences among four subgroups regarding trauma exposure, full-thickness supraspinatus tendon tears, infraspinatus tendon tear, subscapularis tendon tear, BMD distribution, medial row anchors, lateral row anchors, total medical care costs, and consumables costs. We observed the highest frequency of trauma exposure, infraspinatus tendon tear, subscapularis tendon tear, osteoporosis, the highest number of medial row anchors, lateral row anchors, total medical care costs, and consumables costs in subgroup II.Conclusion: The unsupervised machine learning-based analysis of RCT can provide clinically meaningful classification, which shows good interpretability and contribute to a better understanding of RCT. The significance of the results is limited due to the small number of samples, a larger follow-up study is needed to confirm the encouraging results.Keywords: unsupervised machine learning, clinical features, bone mineral density, medical care costs, rotator cuff tears

Courtship interactions are remarkably diverse in form and complexity among species. How neural circuits evolve to encode new behaviors that are functionally integrated into these dynamic social interactions is unknown. Here we report a recently originated female sexual behavior in the island endemic Drosophila species D. santomea, where females signal receptivity to male courtship songs by spreading their wings, which in turn promotes prolonged songs in courting males. Copulation success depends on this female signal and correlates with males' ability to adjust his singing in such a social feedback loop. Functional comparison of sexual circuitry across species suggests that a pair of descending neurons, which integrates male song stimuli and female internal state to control a conserved female abdominal behavior, drives wing spreading in D. santomea. This co-option occurred through the refinement of a pre-existing, plastic circuit that can be optogenetically activated in an outgroup species. Combined, our results show that the ancestral potential of a socially-tuned key circuit node to engage the wing motor circuit facilitates the expression of a new female behavior in appropriate sensory and motivational contexts. More broadly, our work provides insights into the evolution of social behaviors, particularly female behaviors, and the underlying neural mechanisms., (© 2024. The Author(s).)

Objective: To evaluate the efficacy of medial open wedge high tibial osteotomy (MOWHTO) combined with anterior cruciate ligament (ACL) reconstruction in the treatment of varus knee osteoarthritis (OA) with ACL injury. Methods: A follow-up study. The study retrospectively analyzed the patients underwent MOWHTO combined with ACL reconstruction for treatment of varus knee OA with ACL injury in Tianjin Hospital between April 2018 and September 2022. The preoperative and postoperative posterior slope angle (PSA), hip-knee-ankle angle (HKA), visual analog scale (VAS) pain scores, Lysholm score, International Knee Documentation Committee (IKDC) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Tegner score were compared. The follow-up indicators were recorded at 6 weeks, 3 months and 1 year after operation, and the complications were recorded. Results: The study included 32 patients (23 males, 9 females) with a mean age of (50.7±8.4) years. The mean follow-up time was (21.2±4.8) months. PSA increased from 9.2°±1.8° preoperatively to 11.1°±2.4° postoperatively, and HKA increased from 168.7°±2.2° to 181.5°±2.2° (both P <0.01). The indicators such as VAS score (6.8±1.1 vs 1.8±0.4), Lysholm score (52.6±7.1 vs 82.0±6.4), IKDC score (64.7±6.2 vs 80.3±10.0), WOMAC score (51.8±6.3 vs 81.8±6.5), and Tegner score (1.9±0.6 vs 5.0±1.0) were all improved after the operation (all P <0.01). Complications occurred in 5 patients (15.6%), including hematomas, sensory abnormalities, intermuscular vein thrombosis and correction angle loss. Conclusion: MOWHTO combined with ACL reconstruction is a safe and effective approach for the treatment of varus knee OA with ACL injury.

Aims: It is not clear whether there are differences in glycemic control between the Equil patch and the MMT-712 insulin pump. Our objective was to compare two types of insulin pumps in the treatment of type 2 diabetes mellitus (T2DM), using continuous glucose monitoring (CGM) metrics and profiles., Methods: This was a randomized case-crossover clinical trial. Participants were hospitalized and randomly allocated to two groups and underwent two types of insulin pump treatments (group A: Equil patch-Medtronic MMT-712 insulin pump; group B: Medtronic MMT-712-Equil patch insulin pump) separated by a 1-day washout period. Glycemic control was achieved after 7-8 days of insulin pump therapy. Each patient received CGM for 5 consecutive days (from day 1 to day 5). On day 3 of CGM performance, the Equil patch insulin pump treatment was switched to Medtronic MMT-712 insulin pump treatment at the same basal and bolus insulin doses or vice versa. CGM metrics and profiles including glycemic variability (GV), time in range (TIR, 3.9-10.0 mmol/L), time below range (TBR, <3.9 mmol/L), time above range (TAR, >10.0 mmol/L), and postprandial glucose excursions, as well as incidence of hypoglycemia., Results: Forty-six T2DM patients completed the study. There was no significant difference in parameters of daily GV and postprandial glucose excursions between the Equil patch insulin pump treatment and the Medtronic insulin pump treatment. Similarly, there was no between-treatment difference in TIR, TBR, and TAR, as well as the incidence of hypoglycemia., Conclusion: The Equil patch insulin pump was similar to the traditional MMT-712 insulin pump in terms of glycemic control. Equil patch insulin pump is a reliable tool for glycemic management of diabetes mellitus., (© 2024 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

The soldier caste is one of the most distinguished castes inside the termite colony. The mechanism of soldier caste differentiation has mainly been studied at the transcriptional level, but the function of microRNAs (miRNAs) in soldier caste differentiation is seldom studied. In this study, the workers of Coptotermes formosanus Shiraki were treated with methoprene, a juvenile hormone analog which can induce workers to transform into soldiers. The miRNomes of the methoprene-treated workers and the controls were sequenced. Then, the differentially expressed miRNAs (DEmiRs) were corrected with the differentially expressed genes DEGs to construct the DEmiR-DEG regulatory network. Afterwards, the DEmiR-regulated DEGs were subjected to GO enrichment and KEGG enrichment analysis. A total of 1,324 miRNAs were identified, among which 116 miRNAs were screened as DEmiRs between the methoprene-treated group and the control group. A total of 4,433 DEmiR-DEG pairs were obtained. No GO term was recognized as significant in the cellular component, molecular function, or biological process categories. The KEGG enrichment analysis of the DEmiR-regulated DEGs showed that the ribosome biogenesis in eukaryotes and circadian rhythm-fly pathways were enriched. This study demonstrates that DEmiRs and DEGs form a complex network regulating soldier caste differentiation in termites., Competing Interests: The authors declare that they have no competing interests., (© 2024 Du et al.)

Different aromatic components do indeed give different tea flavors. There is still little research on whether there is a certain regularity in the combination and content of aromatic components in different aroma types of Phoenix Dancong (PDC) tea. This potential regularity may be a key factor in unraveling the relationship between reproduction and evolution in PDC tea. Here, the 5 kinds of these 4 aroma types PDC tea (Zhuye, Tuofu, Jianghuaxiang, Juduo, Yashixiang) were used as research materials in this study, the headspace solid-phase microextraction combined with gas chromatography-mass spectrometry was used to analyze the aromatic components of these PDC teas. The results showed a total of 36 aromatic components identified in this study. When conducting cluster analysis, it was found that similarity degree arrangement sequence of 5 PDC teas was Juduo, Tuofu, Yashixiang, Zhuye and Jianghuaxiang. Among these aromatic components, the 7,9-Di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione, the 2-Cyclopenten-1-one, 3-methyl-2-(2-pentenyl)-,(Z)-, the 2,4-Di-tert-butylphenol, the 3,7-dimethyl-1,5,7-Octatrien-3-ol, and the 2-Furanmethanol,5-ethenyltetrahydro-.alpha.,.alpha.,5-trimethyl-,cis- are common to 5 PDC teas. This study aims to elucidate the similarities in the aromatic components of 5 PDC teas, revealing the major aroma-endowed substances of various aroma, and providing theoretical reference for further exploring the relationship between aroma type discrimination, variety selection, and evolution of PDC teas., (© 2024. The Author(s).)

Ribonucleic acid (RNA) drugs have shown promising therapeutic effects for various diseases in clinical and preclinical studies, owing to their capability to regulate the expression of genes of interest or control protein synthesis. Different strategies, such as chemical modification, ligand conjugation, and nanotechnology, have contributed to the successful clinical translation of RNA medicine, including small interfering RNA (siRNA) for gene silencing and messenger RNA (mRNA) for vaccine development. Among these, nanotechnology can protect RNAs from enzymatic degradation, increase cellular uptake and cytosolic transportation, prolong systemic circulation, and improve tissue/cell targeting. Here, a focused overview of stimuli-responsive nanotechnologies for RNA delivery, which have shown unique benefits in promoting RNA bioactivity and cell/organ selectivity, is provided. Many tissue/cell-specific microenvironmental features, such as pH, enzyme, hypoxia, and redox, are utilized in designing internal stimuli-responsive RNA nanoparticles (NPs). In addition, external stimuli, such as light, magnetic field, and ultrasound, have also been used for controlling RNA release and transportation. This review summarizes a wide range of stimuli-responsive NP systems for RNA delivery, which may facilitate the development of next-generation RNA medicines., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: The recovery time of hand wounds is long, which can easily result in chronic and refractory wounds, making the wounds unable to be properly repaired. The treatment cycle is long, the cost is high, and it is prone to recurrence and disability. Double layer artificial dermis combined with autologous skin transplantation has been used to repair hypertrophic scars, deep burn wounds, exposed bone and tendon wounds, and post tumor wounds., Aim: To investigate the therapeutic efficacy of autologous skin graft transplantation in conjunction with double-layer artificial dermis in treating finger skin wounds that are chronically refractory and soft tissue defects that expose bone and tendon., Methods: Sixty-eight chronic refractory patients with finger skin and soft tissue defects accompanied by bone and tendon exposure who were admitted from July 2021 to June 2022 were included in this study. The observation group was treated with double layer artificial dermis combined with autologous skin graft transplantation ( n = 49), while the control group was treated with pedicle skin flap transplantation ( n = 17). The treatment status of the two groups of patients was compared, including the time between surgeries and hospital stay. The survival rate of skin grafts/flaps and postoperative wound infections were evaluated using the Vancouver Scar Scale (VSS) for scar scoring at 6 mo after surgery, as well as the sensory injury grading method and two-point resolution test to assess the recovery of skin sensation at 6 mo. The satisfaction of the two groups of patients was also compared., Results: Wound healing time in the observation group was significantly longer than that in the control group ( P < 0.05, 27.92 ± 3.25 d vs 19.68 ± 6.91 d); there was no significant difference in the survival rate of skin grafts/flaps between the two patient groups ( P > 0.05, 95.1 ± 5.0 vs 96.3 ± 5.6). The interval between two surgeries (20.0 ± 4.3 d) and hospital stay (21.0 ± 10.1 d) in the observation group were both significantly shorter than those in the control group (27.5 ± 9.3 d) and (28.4 ± 17.7 d), respectively ( P < 0.05). In comparison to postoperative infection (23.5%) and subcutaneous hematoma (11.8%) in the control group, these were considerably lower at (10.2%) and (6.1%) in the observation group. When comparing the two patient groups at six months post-surgery, the excellent and good rate of sensory recovery (91.8%) was significantly higher in the observation group than in the control group (76.5%) ( P < 0.05). There was also no statistically significant difference in two point resolution ( P > 0.05). The VSS score in the observation group (2.91 ± 1.36) was significantly lower than that in the control group (5.96 ± 1.51), and group satisfaction was significantly higher ( P < 0.05, 90.1 ± 6.3 vs 76.3 ± 5.2)., Conclusion: The combination of artificial dermis and autologous skin grafting for the treatment of hand tendon exposure wounds has a satisfactory therapeutic effect. It is a safe, effective, and easy to operate treatment method, which is worthy of clinical promotion., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts of interest related to this study., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: This report details how one large medical center in the Metropolitan New York area re-purposed a drive-through COVID-19 vaccination structure to handle a surge in Mpox cases in July 2022.Methods/Results: Simultaneous to on-going COVID -19 vaccination and testing, Mpox vaccination was rolled out in the same drive through structure. More than 1,820 Jynneos (Smallpox and Monkeypox Vaccine, Live, Non-replicating) vaccine dosages were delivered subcutaneously and then intradermally to 1,123 individuals through the open window of their vehicles, averaging 8-10 patients an hour. Five vaccine recipients suffered Mpox rash; there was no exposure among healthcare providers., Conclusion: Drive-through vaccination is an efficient model to be redeployed for future unexpected vaccine initiatives., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Other acknowledgements: Jynneos ® – smallpox and monkeypox vaccine, live, nonreplicating, manufactured by Bavarian Nordic, Kvistgaard, Denmark., (© 2023 The Authors.)

The cancer-immunity cycle provides a framework to understand the series of events that generate anti-cancer immune responses. It emphasizes the iterative nature of the response where the killing of tumor cells by T cells initiates subsequent rounds of antigen presentation and T cell stimulation, maintaining active immunity and adapting it to tumor evolution. Any step of the cycle can become rate-limiting, rendering the immune system unable to control tumor growth. Here, we update the cancer-immunity cycle based on the remarkable progress of the past decade. Understanding the mechanism of checkpoint inhibition has evolved, as has our view of dendritic cells in sustaining anti-tumor immunity. We additionally account for the role of the tumor microenvironment in facilitating, not just suppressing, the anti-cancer response, and discuss the importance of considering a tumor's immunological phenotype, the "immunotype". While these new insights add some complexity to the cycle, they also provide new targets for research and therapeutic intervention., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Botulinum toxin is a potent neuromodulator commonly used for cosmetic applications in the clinic. In this article, we reviewed the various formulations of botulinum toxin type A commercially available in the United States, as well as clinical pearls for preprocedural planning, common in-office injections, and management of complications., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. World Journal of Otorhinolaryngology ‐ Head and Neck Surgery published by John Wiley & Sons Ltd on behalf of Chinese Medical Association.)

Background: Short-term (2 weeks to 3 months) insulin intensive therapy using continuous subcutaneous insulin infusion (CSII) can improve islet beta cell function and prolong glycemic remission in patients with newly diagnosed type 2 diabetes mellitus (T2DM). However, the total daily insulin dose (TDD, IU/kg/d) required to achieve near-normoglycemic control with CSII still needs to be frequently adjusted based on blood glucose monitoring. Although real-time continuous glucose monitoring (rtCGM), which measures the interstitial fluid glucose concentration continuously without much difficulty, facilitates the adjustment of insulin dosage, its adoption in the T2DM population is strictly limited by insurance coverage and lack of awareness of rtCGM among clinicians. Thus, it is of clinical significance to identify easy-to-use parameters that may allow a more rapid and accurate prediction of TDD requirement. This study aimed to explore the association between hand grip strength (HGS) and TDD requirement in patients with T2DM receiving CSII therapy., Methods: A total of 180 eligible patients with T2DM were enrolled in the study and divided into three groups based on their HGS: low (L), medium (M), and high (H). The TDD requirement was calculated on day 7 or 8 of CSII treatment. Anthropometric parameters, including HGS, skeletal muscle mass, skeletal muscle index (SMI) and 6-m gait speed, and laboratory data, were collected on the morning of the second day after admission, within the first 24 h of CSII therapy. These parameters were used to identify significant predictors of TDD requirement using Pearson or Spearman correlation test, and stepwise multiple regression analysis., Results: There were no significant differences in age, duration of T2DM, waist-to-hip ratio (WHR), body mass index (BMI), blood pressure, liver function, estimated glomerular filtration rate, triglyceride, total cholesterol, glycosylated hemoglobin A1c (HbA1c), homeostatic model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of beta cell function (HOMA-β) among the groups. The H group had higher body muscle mass-to-fat ratio (BMFR), skeletal muscle mass-to-fat ratio (SMFR), SMI, 6-m gait speed, and lower TDD requirement than the M and L groups. The HGS negatively correlated with TDD requirement (r = -0.33, p < 0.001) after adjusting for sex, age, BMI, WHR, HbA1c, Ln (HOMA-β), Ln (HOMA-IR), Ln (BMFR), Ln (SMFR), SMI, and 6-m gait speed. Multivariate stepwise regression analysis indicated that HGS was an independent predictor of TDD requirement in patients with T2DM (β = -0.45, p < 0 001)., Conclusion: Lower HGS is associated with an increased TDD requirement in T2DM patients. HGS may facilitate the prediction of TDD requirement in T2DM patients receiving CSII therapy., Competing Interests: The authors declare that they have no competing interests., (© 2023 Chen et al.)

The prognosis of biliary tract cancer (BTC) remains unsatisfactory. This single-arm, phase II clinical trial (ChiCTR2000036652) investigated the efficacy, safety, and predictive biomarkers of sintilimab plus gemcitabine and cisplatin as the first-line treatment for patients with advanced BTCs. The primary endpoint was overall survival (OS). Secondary endpoints included toxicities, progression-free survival (PFS), and objective response rate (ORR); multi-omics biomarkers were assessed as exploratory objective. Thirty patients were enrolled and received treatment, the median OS and PFS were 15.9 months and 5.1 months, the ORR was 36.7%. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Predefined biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations or loss-of-function mutations in chromatin remodeling genes presented better tumor response and survival outcomes. Furthermore, transcriptome analysis revealed a markedly longer PFS and tumor response were associated with higher expression of a 3-gene effector T cell signature or an 18-gene inflamed T cell signature. Sintilimab plus gemcitabine and cisplatin meets pre-specified endpoints and displays acceptable safety profile, multiomics potential predictive biomarkers are identified and warrant further verification., (© 2023. The Author(s).)

In order to improve the degradation activity of β-glucosidase (CpBgl) from Coniophora puteana, the structural modification was conducted. The enzyme activity of mutants CpBgl-Q20C and CpBgl-A240S was increased by 65.75% and 58.58%, respectively. These mutants exhibited maximum activity under the same conditions as wild-type CpBgl (65 ℃ and pH 5.0), slightly improved stabilities compared that of the wild-type, and remarkably enhanced activities in the presence of Mn 2+ or Fe 2+ . The V max of CpBgl-Q20C and CpBgl-A240S was increased to 138.18 and 125.14 μmol/mg/min, respectively, from 81.34 μmol/mg/min of the wild-type, and the catalysis efficiency (k cat /K m ) of CpBgl-Q20C (335.79 min -1 /mM) and CpBgl-A240S (281.51 min -1 /mM) was significantly improved compared with that of the wild-type (149.12 min -1 /mM). When the mutant CpBgl-Q20C were used in the practical degradation of different biomasses, the glucose yields of filter paper, corncob residue, and fungi mycelia residue were increased by 17.68%, 25.10%, and 20.37%, respectively. The spatial locations of the mutation residues in the architecture of CpBgl and their unique roles in the enzyme-substrate binding and catalytic efficiency were probed in this work. These results laid a foundation for evolution of other glycoside hydrolases and the industrial bio-degradation of cellulosic biomass in nature., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Epoxy (EP) was copolymerized with polyamic acid (PAA, precursor of polyimide (PI)) with termanil monomers of (1) 4,4'-Oxydianiline (ODA) and (2) pyromellitic dianhydride (PMDA) individually to form (PI-O-EP) and (PI-P-EP) copolymers. The FTIR spectrum of PI-O-EP copolymerization intermediates shows that some amide-EP linkages were formed at low temperature and were broken at higher temperature; in additoin, the released amide was available for subsequent imidization to form PI. The curing and imidization of the amide groups on PAA were determined by reaction temperature (kinetic vs. thermodynamic control). In PI-P-EP, the released amide group was very short-lived (fast imidization) and was not observed on FTIR spectra. Formation and breakage of the amide-EP linkages is the key step for EP homopolymerization and formation of the interpenetration network. PI contributed in improving thermal durability and mechanical strength without compromising EP's adhesion strength. Microphase separations were minimal at PI content less than 10 wt%. The copolymerization reaction in this study followed the "kinetic vs. thermodynamic control" principle. The copolymer has high potential for application in the field of higher-temperature anticorrosion.

Background: The optimal width of resection margin (RM) for hepatocellular carcinoma (HCC) remains controversial. This study aimed to investigate the value of imaging tumor capsule (ITC) and imaging tumor size (ITS) in guiding RM width for patients with HCC., Methods: Patients who underwent hepatectomy for HCC in our center were retrospectively reviewed. ITC (complete/incomplete) and ITS (≤ 3 cm/> 3 cm) were assessed by preoperative magnetic resonance imaging (MRI). Using subgroup analyses based on ITC and ITS, the impact of RM width [narrow RM (< 5 mm)/wide RM (≥ 5 mm)] on recurrence-free survival (RFS), overall survival (OS), and RM recurrence was analyzed., Results: A total of 247 patients with solitary HCC were included. ITC and ITS were independent predictors for RFS and OS in the entire cohort. In patients with ITS ≤ 3 cm, neither ITC nor RM width showed a significant impact on prognosis, and the incidence of RM recurrence was comparable between the narrow RM and wide RM groups (15.6% vs. 4.3%, P = 0.337). In patients with ITS > 3 cm and complete ITC, the narrow RM group exhibited comparable RFS, OS, and incidence of RM recurrence with the wide RM group (P = 0.606, 0.916, and 0.649, respectively). However, in patients with ITS > 3 cm and incomplete ITC, the wide RM group showed better RFS and OS and a lower incidence of RM recurrence compared with the narrow RM group (P = 0.037, 0.018, and 0.046, respectively)., Conclusions: As MRI-based preoperative markers, conjoint analysis of ITC with ITS aids in determining RM width for solitary HCC patients. Narrow RM is applicable in patients with ITS ≤ 3 cm regardless of ITC status and in those with ITS > 3 cm and complete ITC. Wide RM is preferred in those with ITS > 3 cm and incomplete ITC., (Copyright © 2021. Published by Elsevier B.V.)

Background: Immune checkpoint inhibitor (ICI)-combined chemotherapy in advanced intrahepatic cholangiocarcinoma has been proved to have more efficacy in a series of clinical trials. However, whether the tumor microenvironment (TME) plays a vital role in immune-combined therapy has not been rigorously evaluated., Methods: Firstly, we assayed the immunogenic properties of GEM-based chemotherapy. Then, 12 ICC patients treated with PD-1 inhibitor (sintilimab) combined with gemcitabine and cisplatin (GemCis) from a phase 2 clinical trial (ChiCTR2000036652) were included and their immune-related gene expression profiles were analyzed using RNA from baseline tumor samples. Immune-related signature correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in an ICC cohort with 26 patients. Multiplexed immunofluorescence (mIF) and flow cytometry (FCM) analysis were performed to evaluate the immune-related molecules with therapeutic outcomes., Results: GEM-based chemotherapy induced immunogenic cell death of cholangiocarcinoma cells, together with increased CD274 expression. In an ICC cohort, we found that upregulation of immune-checkpoint molecules and immune response-related pathways were significantly related to better clinical outcome. On the contrary, baseline immune-cell proportions in tumor tissues did not show any correlation with clinical benefit between responders and non-responders. Immune-related signature (including six genes) correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in a small ICC cohort with 26 patients., Conclusion: Immune-related RNA signature predicts the outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma, which could be tested as a biomarker for immune-chemotherapy in the future., Competing Interests: Authors YS and DC were employed by Jiangsu Simcere Diagnostics Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zeng, Pan, Yuan, Chen, Song and Gao.)

The broad activity of agents blocking the programmed cell death protein 1 and its ligand (the PD-(L)1 axis) revolutionized oncology, offering long-term benefit to patients and even curative responses for tumors that were once associated with dismal prognosis. However, only a minority of patients experience durable clinical benefit with immune checkpoint inhibitor monotherapy in most disease settings. Spurred by preclinical and correlative studies to understand mechanisms of non-response to the PD-(L)1 antagonists and by combination studies in animal tumor models, many drug development programs were designed to combine anti-PD-(L)1 with a variety of approved and investigational chemotherapies, tumor-targeted therapies, antiangiogenic therapies, and other immunotherapies. Several immunotherapy combinations improved survival outcomes in a variety of indications including melanoma, lung, kidney, and liver cancer, among others. This immunotherapy renaissance, however, has led to many combinations being advanced to late-stage development without definitive predictive biomarkers, limited phase I and phase II data, or clinical trial designs that are not optimized for demonstrating the unique attributes of immune-related antitumor activity-for example, landmark progression-free survival and overall survival. The decision to activate a study at an individual site is investigator-driven, and generalized frameworks to evaluate the potential for phase III trials in immuno-oncology to yield positive data, particularly to increase the number of curative responses or otherwise advance the field have thus far been lacking. To assist in evaluating the potential value to patients and the immunotherapy field of phase III trials, the Society for Immunotherapy of Cancer (SITC) has developed a checklist for investigators, described in this manuscript. Although the checklist focuses on anti-PD-(L)1-based combinations, it may be applied to any regimen in which immune modulation is an important component of the antitumor effect., Competing Interests: Competing interests: MBA—Consulting Fees: Aveo, BMS, Eisai, Exelixis, Genentech, Iovance, Merck, Novartis, Pfizer, Roche, Pyxis, Werewolf, Asher Bio, Calithera, Idera, Agenus, Apexigen, Neoleukin, Adagene, AstraZeneca, Elpis, ScholarRock, Surface, ValoHealth, Sanofi, Fathom; Ownership Interest (less than 5%): Werewolf, Pyxis, Elpis. HA-S—Nothing to disclose. PAA—Consulting Fees: BMS, Roche, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTEOS, Medicenna; Contracted Research: BMS, Roche-Genentech, Array, Sanofi. MRB—Consulting Fees: Novartis, Kite/Gilead, CRISPR Therapeutics, Autolus, Takeda, Agios, Iovance, Bluebird Bio, BMS; Fees for Non-CE Services: Agio, BMS, Incyte, Sanofi, Kite/Gilead; Contracted Research: Immatics, Novartis, Kite/Gilead, CRISPR Therapeutics, Autolus, TMUNITY. DSC—Ownership Interest (less than 5%): IGM Biosciences, Corvus. MD—Consulting Fees: Lava Therapeutics, Amgen, Janssen, Roche/Genentech. LAE—Consulting Fees: Genentech, F. Hoffmann-La Roche, Chugai, GPCR, Gilead, Immune Onc, Immutep, Shionogi, Mersana; Contracted Research: AbbVie, AstraZeneca, Bolt Therapeutics, Bristol Myers Squibb, Compugen, Corvus, CytomX, EMD Serono, Genentech, F. Hoffmann-La Roche, ImmuneOnc, Maxcyte, Merck, Next Cure, Silverback, Takeda, Tempest; Grants from Non-Industry Entities: HeritX Incorporated, NSABP Foundation, Translational Breast Cancer Research Consortium, Breast Cancer Research Foundation, National Cancer Institute, Department of Defense, Johns Hopkins University, University of California San Francisco, Cornell University, Dana Farber Cancer Institute. Royalties: Elsevier; IP Rights: Aduro Biotech. MSE—Nothing to Disclose. RLF—Consulting Fees: Achilles Therapeutics, Aduro Biotech, Bicara Therapeutics, BMS, Brooklyn Immunotherapeutic, Everest Clinical Research Corporation, F. Hoffman-La Roche, Genocea Biosciences, Hookipa Biotech GmbH, Instill Bio, Kowa Research Institute, Lifescience Dynamics Limited, MacroGenics, Merck, Mirati Therapeutics, Nanobiotix, Novasenta, Numab Therapeutics AG, OncoCyte Corporation, Pfizer, PPD Development, L.P., Rakuten Medical, Sanofi, Seagen, Vir Biotechnology, Zymeworks; Contracted Research: AstraZeneca/MedImmune, BMS, Merck, Novasenta, Tesaro; Stock: Novasenta. TFG—Contracted Research: AstraZeneca, BMS, Merck, Sillajen, Vascular Biogenics. JLG—Nothing to disclose. RSH—Consulting Fees: AbbVie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Bayer HealthCare Pharmaceuticals, Bolt Biotherapeutics, BMS, Candel Therapeutics, Cybrexa Therapeutics, eFFECTOR Therapeutics, Eli Lilly and Company, EMD Serono, Foundation Medicine, Genentech/Roche, Genmab, Gilead, Halozyme Therapeutics, Heat Biologics, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Loxo Oncology, Merck and Company, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Ocean Biomedical, Oncternal Therapeutics, Pfizer, Ribbon Therapeutics, Ventana Medical Systems, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, STCube Pharmaceuticals, Symphogen, Takeda, Tesaro, Tocagen, WindMIL Therapeutics, Xencor; Contracted Research: AstraZeneca, Eli Lilly and Company, Genentech/Roche, Merck and Company; Board Member (non-executive/independent): Immunocore Holdings Limited, Junshi Pharmaceuticals. RWH—Stock: Black Diamond, Xilio. JL—Consulting Fees: Iovance, Boston Biomedical, Pfizer, BMS, GSK, Novartis, Incyte, Immunocore, YKT Global, iOnctura, Apple Tree, Roche, Pierre Fabre, AstraZeneca, EUSA Pharma, MSD, Ervaxx, Merck, Ipsen, Aptitude, Eisai, Calithera, Ultmovacs, Seagen; Contracted Research: BMS, MSD, Novartis, Pfizer, Achilles, Roche, Nektar, Covance, Immunocore, Pharmacyclics, Aveo. KAM—Consulting Fees: Iovance DMC, ImaginAb SAB, Checkmate Pharma DSMB, Xilio advisor, Werewolf advisor, all except ImaginAb less than 10k/year;Temporary higher consulting fees: ImaginAb (to provide one time extra consulting up to 25k). LM—Consulting Fees: Tethis spa; Fees for Non-CE Services: Roche. SSR—Consulting Fees: Amgen, BMS, Genentech/Roch, Merck, AstraZeneca, Takeda, Eisai, Daiichi Sankyo, Sanofi, GSK, Lilly; Contracted Research: Tesaro, Merck, AstraZeneca, Advaxis, BMS, Amgen, Takeda, Genmab, GSK. MMR—Consulting Fees: BMS, Tolmar, WebMD; Contracted Research: Novartis, Pfizer, Ipsen, TerSera, Merck, Pierre Fabre, Roche, AstraZeneca, BMS, Bayer, DebioPharm. BIR—Consulting Fees: BMS, Pfizer, GNE/Roche, Aveo, Synthorx, Compugen, Merck, Corvus, Surface Oncology, 3DMedicines, Aravive, Alkermes, Arrowhead, GSK, Shionogi, Eisai; Contracted Research: Pfizer, F. Hoffmann-La Roche, Incyte, AstraZeneca, Taris, Seattle Genetics, Arrowhead Pharmaceuticals, Immunomedics, Bristol Myers Squibb, Mirati Therapeutics, Merck, Surface Oncology, Dragonfly Therapeutics, Aravive, Exelixis; Ownership Interest (less than 5%): PTC therapeutics. MS—Consulting Fees: Adaptimmune, Pfizer, Kadmon, Pierre-Fabre, Biond, Nextcure, Incyte, Alligator, Bristol Myers, Ocellaris, Simcha, Rootpath, Numab, Evolveimmune, Biontech, Immunocore, Glaxo Smith Kline, Adagene, Asher, Kanaph, iTEOS, Genocea, Trillium, Sapience, Targovax, Molecular Partners, Ontario Institute for Cancer Research, Jazz Pharmaceuticals, Gilead, Innate pharma, Tessa, Stcube, Oncosec, Regeneron, AstraZeneca, Agenus, Idera, Apexigen, Verastem, Rubius, Genentech-Roche, Boston Pharmaceutical, Servier, Dragonfly, Boehringer Ingelheim, Nektar, Pieris, AbbVie, Zelluna, Seattle Genetics; Stock options: Adaptive Biotechnologies, Amphivena, Intensity, Actym, Evolveimmune, Nextcure, Repertoire, Oncohost, Rootpath, Asher; Stock: Johnson and Johnson, Glaxo-Smith Kline. SITC staff: SMW—Shares owned: Pacific Biosciences, Editas Medicine. ME, AK—Nothing to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To investigate the surgical outcomes of patients with chronic angle-closure glaucoma (CACG) treated with phacoemulsification (phaco)/endocyclophotocoagulation (ECP) with and without endoscopic goniosynechialysis (E-GSL)., Methods: A retrospective, nonrandomized, comparative case series was conducted. Patients with CACG who underwent phaco in combination with either ECP alone (ECP group) or GSL with ECP (E-GSL group) from 2018 to 2019 were followed for 12mo and reviewed. Clinical features and outcomes were identified and analyzed. The ECP and E-GSL groups were matched in age and baseline intraocular pressure (IOP). Changes in IOP, mean of visual acuity (VA), peripheral anterior synechiae (PAS) formation, and the number of glaucoma medications was examined., Results: The ECP group included 32 eyes of 27 patients, and the E-GSL group included 32 eyes of 26 patients. The preoperative baseline IOP was 22.18±6.48 mm Hg in the ECP group and 22.95±6.71 mm Hg in the E-GSL group ( P =0.644). The mean IOP reduction was 26.2% in the ECP group and 41.6% in the E-GSL group at 12mo. The mean postoperative VA (logMAR units) at 12mo was 0.47 in the ECP group and 0.36 in the E-GSL group. The reduction in PAS formation and the number of glaucoma medications was also higher in the ECP group than E-GSL group at 12mo., Conclusion: The phaco/ECP and phaco/E-GSL groups both achieve a significant reduction in IOP without complications associated with traditional glaucoma filtration surgeries., (International Journal of Ophthalmology Press.)

In polyandrous internally fertilizing species, a multiply-mated female can use stored sperm from different males in a biased manner to fertilize her eggs. The female's ability to assess sperm quality and compatibility is essential for her reproductive success, and represents an important aspect of postcopulatory sexual selection. In Drosophila melanogaster, previous studies demonstrated that the female nervous system plays an active role in influencing progeny paternity proportion, and suggested a role for octopaminergic/tyraminergic Tdc2 neurons in this process. Here, we report that inhibiting Tdc2 neuronal activity causes females to produce a higher-than-normal proportion of first-male progeny. This difference is not due to differences in sperm storage or release, but instead is attributable to the suppression of second-male sperm usage bias that normally occurs in control females. We further show that a subset of Tdc2 neurons innervating the female reproductive tract is largely responsible for the progeny proportion phenotype that is observed when Tdc2 neurons are inhibited globally. On the contrary, overactivation of Tdc2 neurons does not further affect sperm storage, release or progeny proportion. These results suggest that octopaminergic/tyraminergic signaling allows a multiply-mated female to bias sperm usage, and identify a new role for the female nervous system in postcopulatory sexual selection., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Patients with early-stage laryngeal cancer, even stage T1-2N0, are at considerable risk of recurrence and death. The genetic and immunologic characteristics of recurrent laryngeal cancer remain unclear., Methods: A total of 52 T1-2N0 laryngeal cancer patients were enrolled. Of these, 42 tissue samples were performed by targeted DNA sequencing, and 21 cases were performed by NanoString immuno-oncology targeted RNA sequencing to identify the distinct molecular bases and immunologic features associated with relapse in patients with early laryngeal cancer, respectively., Results: To the best to our knowledge, we present for the first time an overview of the genomic mutation spectrum of early-stage laryngeal cancers. A total of 469 genomic alterations were detected in 211 distinct cancer-relevant genes, and the genes found to be mutated in more than five patients (>10%) included tumor protein p53 ( TP53 , 78.5%), FAT atypical cadherin 1 ( FAT1 , 26%), LDL receptor related protein 1B ( LRP1B , 19%), cyclin dependent kinase inhibitor 2A ( CDKN2A , 17%), tet methylcytosine dioxygenase 2 ( TET2 , 17%), notch receptor 1 ( NOTCH1 , 12%) and neuregulin 1 ( NRG1 , 12%). Recurrent laryngeal cancer demonstrated a higher tumor mutation burden (TMB), as well as higher LRP1B mutation and NOTCH1 mutation rates. Univariate and multivariate analyses revealed that high TMB (TMB-H) and NOTCH1 mutation are independent genetic factors that are significantly associated with shorter relapse-free survival (RFS). Simultaneously, the results of the transcriptome analysis presented recurrent tumors with NOTCH1 mutation displayed upregulation of the cell cycle pathway, along with decreased B cells score, T cells score, immune signature score and tumor-infiltrating lymphocytes (TILs) score. The Cancer Genome Atlas (TCGA)-laryngeal cancer dataset also revealed weakened immune response and impaired adhesion functions in NOTCH1 -mutant patients., Conclusions: Genomic instability and impaired immune response are key features of the immunosurveillance escape and recurrence of early laryngeal cancer after surgery. These findings revealed immunophenotypic attenuation in recurrent tumors and provided valuable information for improving the management of these high-risk patients. Due to the small number of patients in this study, these differences need to be further validated in a larger cohort., Competing Interests: Author Dongsheng Chen, Le-le Zhao, Yun-jie Song, Ming-zhe Xiao, Wang-long Deng and Chuang Qi are employed by The State Key Laboratory of Translational Medicine and Innovative Drug Development, Medical Department, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Gong, Chen, Zhang, Chen, Li, Chen, Xu, Zhou, Zhao, Song, Xiao, Deng, Qi, Wang and Chen.)

Due to the lack of an assessment approach, the image of in vivo nasal ciliary motion of allergic rhinitis (AR) has never been captured and analyzed to date. Here, we have used an optimized approach to analyze the nasal ciliary function in vivo in AR rats. The digital microscopy system, a method for direct observation of ciliary motion in a living AR rat model, was applied to visualize and measure ciliary motion in vivo , including ciliary beat frequency (CBF) and ciliary beat distance (CBD). The AR rat model was established by ovalbumin sensitization. Comparisons of nasal ciliary motion in vivo between the experimental group (ovalbumin sensitization, allergen, or histamine) and the control group were analyzed. In the living rat model of allergic rhinitis, CBF and CBD decreased to 57.8 and 73.1% of the control group, respectively, but were restored after administration of chlorpheniramine maleate. Ovalbumin (OVA) significantly inhibited the ciliary motion of normal mucosa in vivo . However, responding to the OVA challenge, the ciliary motion of OVA-sensitized mucosa would not decrease further and stay at a stable level. Histamine stimulated in vivo ciliary motion quickly within 30 min, but afterward, the ciliary motion gradually decreased below the baseline. These results have clarified that in vivo ciliary motion was impaired by nasal mucosal sensitization, and this impairment was most likely related to allergen challenge and histamine. In addition, the short-term stimulation and long-term inhibition effects of histamine on in vivo ciliary motion were first reported in this study.

Background: To explore the relationship between sleep time, sleep quality, and emotional and cognitive function in the elderly., Methods: A total of 150 elderly patients over 65 years old who were admitted to our hospital from February 2019 to April 2021 were divided into a normal cognitive function group (Mini-Mental State Examination (MMSE) score: illiteracy, >17; primary school, >20; and middle school and above, >24; N = 86) and cognitive impairment group (MMSE score: illiteracy, ≤17; primary school, ≤20; and middle school or above, ≤24; N = 64). The sleep quality was evaluated by the Pittsburgh Sleep Quality Index (PSQI), and anxiety and depression were evaluated by Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD), respectively. The cognitive function between the two groups was compared via the Montreal Cognitive Assessment (MoCA) score, visual spatial execution, and attention. Pearson correlation analysis was used to analyze the correlation between sleep quality, sleep time, and emotional and cognitive function., Results: In the comparison of sleep quality between the two groups, the total score of PSQI, sleep quality, falling asleep time, sleep time, and sleep efficiency of patients with cognitive impairment were higher than those of patients with normal cognitive function ( P < 0.05). There was no significant difference in the scores of hypnotic use and daytime dysfunction between the two groups, but the scores of nocturnal sleep disorders and ESS in the cognitive impairment group were significantly higher than those in the normal group ( P > 0.05). Compared between the two groups, the MoCA score, visual spatial execution, and attention in the cognitive impairment group were significantly lower than those in the normal group, and the difference was statistically significant ( P < 0.05). The delayed recall in the cognitive impairment group was significantly higher than that in the control group ( P < 0.05). There was no significant difference in orientation, naming, language, and abstract ability between the two groups ( P > 0.05). The scores of HAMA and HAMD in the cognitive impairment group were significantly higher than those in the normal group. Pearson correlation analysis was used to analyze the correlation between sleep therapy, sleep time, and the score of cognitive scale. The results showed that PSQI was negatively correlated with MoCA and MMSE, and ESS was negatively correlated with MoCA and MMSE. Pearson correlation analysis results indicated that PSQI was positively correlated with HAMA and HAMD, while ESS was negatively correlated with HAMA and HAMD., Conclusion: The sleep quality and sleep time of elderly patients are positively correlated with their cognitive function. The worse the sleep quality is, the worse their cognitive function is and the more serious their anxiety and depression are. In the course of clinical therapeutics, more attention should be paid to the sleep quality of elderly., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Heng Liao et al.)

Using bacteriophages (phages) as environmental sanitizers has been recognized as a potential alternative method to remove bacterial contamination in vitro; however, very few studies are available on the application of phages for infection control in hospitals. Here, we performed a 3-year prospective intervention study using aerosolized phage cocktails as biocontrol agents against carbapenem-resistant Acinetobacter baumannii (CRAB) infection in the hospital. When a CRAB-infected patient was identified in an intensive care unit (ICU), their surrounding environment was chosen for phage aerosol decontamination. Before decontamination, 501 clinical specimens from the patients were subjected to antibiotic resistance analysis and phage typing. The optimal phage cocktails were a combination of different phage families or were constructed by next-evolutionary phage typing with the highest score for the host lysis zone to prevent the development of environmental CRAB phage resistance. The phage infection percentage of the antibiotic-resistant A. baumannii strains was 97.1%, whereas the infection percentage in the antibiotic-susceptible strains was 79.3%. During the phage decontamination periods from 2017 to 2019, the percentage of carbapenem-resistant A. baumannii in test ICUs decreased significantly from 65.3% to 55%. The rate of new acquisitions of CRAB infection over the three years was 4.4 per 1000 patient-days, which was significantly lower than that in the control wards (8.9 per 1000 patient-days) where phage decontamination had never been performed. In conclusion, our results support the potential of phage cocktails to decrease CRAB infection rates, and the aerosol generation process may make this approach more comprehensive and time-saving., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Obesity is a well-known modified risk factor for isolated systolic hypertension (ISH), but evidence is lacking regarding whether the combination of anthropometric and lipid indicators could strengthen their correlation with ISH. Therefore, we compared the association of body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), visceral adiposity index (VAI), lipid accumulation product index (LAP), and cardiometabolic index (CMI) with ISH., Methods: A total of 106,248 adults who received routine health screening and did not have diastolic blood pressure ≥ 90 mmHg were recruited in this cross-sectional study. The associations between these indicators and ISH were evaluated using multivariate regression., Results: Each standard deviation (SD) increase in traditional obesity indicators (especially WHR and WHtR) had significantly higher multivariate-adjusted odds ratios (ORs) than each SD increase in lipid-related obesity indicators. In addition, multivariate-adjusted ORs for ISH in the third (vs. the first) tertile of traditional obesity indicators were also significantly higher than those of lipid-related indicators. Moreover, traditional obesity indicators exhibited a higher area under the ROC curve for discriminating ISH than lipid-related obesity indicators., Conclusions: Traditional obesity indicators were more strongly associated with ISH than lipid-related obesity indicators among Chinese adults., (© 2022. The Author(s).)

In order to improve the catalytic efficiency of cellulase for more effective utilization of lignocellulose, a novel endoglucanase (CgEndo) from Colletotrichum graminicola was expressed by Pichia pastoris X33 and modified by site-directed mutagenesis. Two mutants, Y63S and N20D/S113T, with 62.31% and 57.14% increased enzyme activities were obtained, respectively. On this basis, their biochemical properties, kinetic parameters, structural information as well as the application in biomass degradation were investigated and compared with the wild-type CgEngo. The results indicated that the mutation Y63S and N20D/S113T resulted in an improvement of proximity between enzyme and substrate through conformational changes of the catalytic region, which might contribute to the higher enzyme activities and catalysis efficiency (K cat /K m ) of Y63S and N20D/S113T. These findings laid important foundation for the further engineering of this endoglucanase and practical application in efficient degradation of cellulosic biomass in nature., (Copyright © 2021 Elsevier Inc. All rights reserved.)