Crystal structure of a pre-chemistry viral RNA-dependent RNA polymerase suggests participation of two basic residues in catalysis.

The nucleic acid polymerase-catalyzed nucleotidyl transfer reaction associated with polymerase active site closure is a key step in the nucleotide addition cycle (NAC). Two proton transfer events can occur in such a nucleotidyl transfer: deprotonation of the priming nucleotide 3'-hydroxyl nucleophile and protonation of the pyrophosphate (PPi) leaving group. In viral RNA-dependent RNA polymerases (RdRPs), whether and how active site residues participate in this two-proton transfer reaction remained to be clarified. Here we report a 2.5 Šresolution crystal structure of enterovirus 71 (EV71) RdRP in a catalytically closed pre-chemistry conformation, with a proposed proton donor candidate K360 in close contact with the NTP γ-phosphate. Enzymology data reveal that K360 mutations not only reduce RdRP catalytic efficiency but also alter pH dependency profiles in both elongation and pre-elongation synthesis modes. Interestingly, mutations at R174, an RdRP-invariant residue in motif F, had similar effects with additional impact on the Michaelis constant of NTP (KM,NTP). However, direct participation in protonation was not evident for K360 or R174. Our data suggest that both K360 and R174 participate in nucleotidyl transfer, while their possible roles in acid-base or positional catalysis are discussed in comparison with other classes of nucleic acid polymerases.

Ferroptosis in brain microvascular endothelial cells mediates blood-brain barrier disruption after traumatic brain injury.

Ferroptosis is a newly recognized form of regulated cell death. Recently, growing evidence has shown that ferroptosis is involved in the pathogenesis of traumatic brain injury (TBI). However, less attention has been paid to its role in brain microvascular endothelial cells (BMVECs) and blood-brain barrier (BBB) damage, the central pathological process in secondary brain injury of TBI. Here, we established a mechanical stretch injury bEnd.3 model and a Controlled Cortical Impact (CCI) mouse model to explore the ferroptosis-related markers in brain endothelial cells after TBI in vitro and in vivo. From the results of RNA-seq analysis, RT-qPCR and immunostaining, glutathione peroxidase 4 (GPX4) downregulation, Cyclooxygenase-2 (COX-2) upregulation, and iron accumulation were observed in brain endothelial cells after TBI both in vitro and in vivo. Furthermore, we utilized Ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, to investigate the protective effects of ferroptosis inhibition on BBB disruption and neurological deficits. From the results of immunostaining, transmission electron microscopy (TEM), and western blotting, we demonstrated that Fer-1 significantly reduced BMVECs death, BBB permeability, and tight junction loss at 3 days after TBI. The neurological tests including grid walking, rotarod test, and wire-hanging test showed that Fer-1 administration exerted neuroprotective effects in the early stage of TBI. Our findings provided evidences for inhibition of BMVECs ferroptosis as a promising therapeutic target against TBI-induced BBB disruption.

Promotion of microRNA-146a by histone deacetylase 4 silencing contributes to radiosensitization of esophageal carcinoma.

BACKGROUND: Histone deacetylases (HDACs) have been identified to be implicated in the carcinogenesis and cancer progression. The present study was performed to probe into the effect of HDAC4 on radioresistance of esophageal carcinoma (EC). METHODS: The expression of HDAC4 in responders and non-responders to radiotherapy was characterized by RT-qPCR, immunohistochemistry, and Western blot analysis. EC cells were exposed to continuous fractionated X-ray irradiation, and their proliferation and apoptosis were evaluated by means of colony formation assay and flow cytometry based Annexin V-FITC/PI apoptosis assay in response to HDAC4 overexpression or silencing. Mechanistic investigation was conducted by means of in silico analysis and dual-luciferase reporter gene assay. Tumor xenografts derived from radioresistant EC cells were exposed to local X-ray irradiation in vivo for validation. RESULTS: High expression of HDAC4 was detected in either tumor tissues derived from radiotherapy responders or radioresistant EC cells. Loss of HDAC4 contributed to suppressed proliferation and enhanced apoptosis of radioresistant EC cells. Moreover, our findings revealed that HDAC4 conferred radioresistance of EC by downregulating microRNA-146a (miR-146a). Interleukin-1 receptor-associated kinase 1 (IRAK1) was a target of miR-146a, and its knockdown promoted radiosensitivity. Silencing of HDAC4 radiosensitized EC cells both in vitro and in vivo via the miR-146a/IRAK1 axis. CONCLUSION: Hence, loss of HDAC4 upregulated miR-146a to limit radioresistance. This study aids in the better understanding about mechanism responsible for radioresistance of EC.

Efficacy and safety of endovascular treatment with or without intravenous alteplase in acute anterior circulation large vessel occlusion stroke: a meta-analysis of randomized controlled trials.

OBJECTIVE: The current meta-analysis aimed to investigate the efficacy and safety of direct endovascular treatment (EVT) and bridging therapy (EVT with prior intravenous thrombolysis (IVT)) in patients with acute anterior circulation large vessel occlusion (LVO) stroke. METHODS: This meta-analysis followed PRISMA guidelines. Eligible RCTs were identified through a systemic search of electronic databases (PubMed, Ovid, Web of Science, and Cochrane Library) from the inception dates to January 10, 2022. The pooled analyses were performed using RevMan 5.3 software. The primary outcome was functional outcome on the modified Rankin Scale (mRS) (range 0 to 5) at 90 days. The secondary outcomes included successful reperfusion, intracranial hemorrhage, and mortality (mRS 6) within 90 days. RESULTS: A total of 4 RCTs involving 1633 patients were finally included. Findings of pooled analyses indicated that neither the primary outcomes (no disability (mRS 0), no significant disability despite some symptoms (mRS 1), slight disability (mRS 2), moderate disability (mRS 3), moderately severe disability (mRS 4), severe disability (mRS 5), excellent outcome (mRS 0-1), functional independence outcome (mRS 0-2), and poor outcome (mRS 3-5)) nor the secondary outcomes (successful reperfusion, intracranial hemorrhage, and mortality) in the EVT groups were not statistically significant compared with the IVT plus EVT groups (P > 0.05). In addition, the outcomes of sensitivity analysis implied that the findings of meta-analysis were credible. CONCLUSIONS: Among patients with acute ischemic stroke due to LVO of anterior circulation, EVT alone yielded efficacy and safety outcomes similar to IVT plus EVT.

A hybrid of long short-term memory neural network and autoregressive integrated moving average model in forecasting HIV incidence and morality of post-neonatal population in East Asia: global burden of diseases 2000-2019.

BACKGROUND: To forecast the human immunodeficiency virus (HIV) incidence and mortality of post-neonatal population in East Asia including North Korea, South Korea, Mongolia, Japan and China Mainland and Taiwan province. METHODS: The data on the incidence and mortality of HIV in post-neonatal population from East Asia were obtained from the Global Burden of Diseases (GBD). The morbidity and mortality of post-neonatal HIV population from GBD 2000 to GBD 2013 were applied as the training set and the morbidity and mortality from GBD 2014 to GBD 2019 were used as the testing set. The hybrid of ARIMA and LSTM model was used to construct the model for assessing the morbidity and mortality in the countries and territories of East Asia, and predicting the morbidity and mortality in the next 5 years. RESULTS: In North Korea, the incidence and mortality of HIV showed a rapid increase during 2000-2010 and a gradual decrease during 2010-2019. The incidence of HIV was predicted to be increased and the mortality was decreased. In South Korea, the incidence was increased during 2000-2010 and decreased during 2010-2019, while the mortality showed fluctuant trend. As predicted, the incidence of HIV in South Korea might be increased and the mortality might be decreased during 2020-2025. In Mongolia, the incidence and mortality were slowly decreased during 2000-2005, increased during 2005-2015, and rapidly decreased till 2019. The predicted incidence and mortality of HIV showed a decreased trend. As for Japan, the incidence of HIV was rapidly increased till 2010 and then decreased till 2015. The predicted incidence of HIV in Japan was gradually increased. The mortality of HIV in Japan was fluctuant during 2000-2019 and was slowly decreased as predicted. The incidence and mortality of HIV in Taiwan during 2000-2019 was increased on the whole. The predicted incidence of HIV during was stationary and the mortality was decreased. In terms of China Mainland, the incidence and mortality of HIV was fluctuant during 2000-2019. The predicted incidence of HIV in China Mainland was stationary while the mortality was rapidly decreased. CONCLUSION: On the whole, the incidence of HIV combined with other diseases in post-neonatal population was increased before 2010 and then decreased during 2010-2019 while the mortality of those patients was decreased in East Asia.

Exosomal lncRNA UCA1 from cancer-associated fibroblasts enhances chemoresistance in vulvar squamous cell carcinoma cells.

AIM: In the current work, we aimed to explore whether Cancer-associated fibroblasts (CAF) exosomes played crucial roles in vulvar squamous cell carcinoma (VSCC) chemoresistance via mediating long noncoding RNAs (lncRNA). METHODS: The IC50 value and cell apoptosis were assessed by the Cell Counting-8 Kit (CCK-8) assay and flow cytometry, respectively. Western blot analysis was used for the measurement of protein levels. The levels of urothelial cancer-associated 1 (UCA1), miR-103a and WEE1 G2 checkpoint kinase (WEE1) mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The target relationships among miR-103a, UCA1 and WEE1 were confirmed by dual-luciferase reporter assays. Xenograft model mice were established to observe the impact of exosomal UCA1 on cisplatin (CDDP) resistance in vivo. RESULTS: Our data indicated that CAF enhanced CDDP resistance of VSCC cells in vitro. Extracellular UCA1 was transferred by exosomes derived from CAF. Exosomal UCA1 derived from CAF conferred VSCC cell resistance to CDDP. Moreover, UCA1 functioned as a miR-103a sponge in VSCC cells. The promotion of exosomal UCA1 on VSCC cell resistance to CDDP was mediated by miR-103a. WEE1 was a direct target of miR-103a, and exosomal miR-103a from CAF weakened CDDP resistance of VSCC cells by WEE1. Furthermore, exosomal UCA1 regulated WEE1 expression through sponging miR-103a. Additionally, exosomal UCA1 enhanced tumor growth and CDDP resistance in vivo. CONCLUSION: Our findings suggested exosomal UCA1 derived from CAF conferred VSCC cell resistance to CDDP in vitro and in vivo at least partly through the miR-103a/WEE1 axis, highlighting a novel therapeutic method for improving the clinical benefits of CDDP chemotherapy in VSCC patients.

Twelve-week intradialytic cycling exercise improves physical functional performance with gain in muscle strength and endurance: a randomized controlled trial.

OBJECTIVE: To evaluate the effect of intradialytic cycling exercise on physical functional performance with gain in muscle strength and endurance in end-stage renal disease patients with haemodialysis. DESIGN: Randomized controlled trial, with repeated measurements at baseline and after 4, 8, and 12 weeks of intradialytic cycling exercise. SETTING: A 50-bed haemodialysis centre in a regional hospital in Taiwan. SUBJECTS: Seventy-six regular haemodialysis patients, recruited and equally and randomly assigned to exercise and control groups. INTERVENTION: The intradialytic cycling exercise was performed for 12 weeks and comprised warm-up, main, and cool-down exercise phases. A stationary cycling equipment was used, which involved aerobic and resistance modalities. The intensity was maintained at somewhat hard exertion. Each intradialytic cycling exercise was implemented for 30 minutes, starting at the second hour of treatment. MAIN MEASURE: Measured outcomes were 6-minute walk distance, time taken to complete 10 sit-to-stand-to-sit cycles and number of sit-to-stand-to-sit cycles in 60 seconds. RESULTS: Average (standard deviation) participant age was 55.47 (13.00) years. Therefore, the 6-minute walk distance was significantly different at weeks 8 (P = 0.01) and 12 (P < 0.001) in the exercise group compared with that in the control group at baseline. Notably, sit-to-stand-to-sit outcomes (P = 0.01) significantly influenced the 6-minute walk distance. Sit-to-stand-to-sit outcomes significantly improved in the exercise group (P < 0.05). CONCLUSION: Twelve-week intradialytic exercise for patients on haemodialysis can improve physical functional performance with gain muscle strength and endurance. This is a safe and effective method for improving health.

PAK4, a target of miR-9-5p, promotes cell proliferation and inhibits apoptosis in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. P21-activated kinase 4 (PAK4) and miR-9-5p have emerged as attractive therapeutic targets in several tumor types, but in CRC, the regulation of their biological function and their target association remain unclear. METHODS: The expression of PAK4 in CRC tissues was determined using quantitative real-time PCR and immunohistochemistry analyses. The targeted regulation between miR-9-5p and PAK4 was predicted and confirmed with bioinformatics analysis and the dual-luciferase reporter assay. Functional experiments, including the MTT assay and flow cytometry, were performed to investigate the impact of PAK4 knockdown and miR-9-5p overexpression on cell proliferation and apoptosis in CRC cells. RESULTS: We found that the expression of PAK4 was upregulated in CRC tissues. PAK4 knockdown significantly suppressed cell proliferation and promoted apoptosis in cells of the CRC cell lines HCT116 and SW1116. We also found that miR-9-5p directly targeted the 3'-UTR of PAK4 mRNA and negatively regulated its expression. The degree of downregulation of miR-9-5p inversely correlated with PAK4 expression. Intriguingly, enforced expression of miR-9-5p suppressed cell proliferation and promoted apoptosis. This could be partially reversed by PAK4 overexpression. CONCLUSION: These results suggest that miR-9-5p targeting of PAK4 could have therapeutic potential for CRC treatment.

Cloud Computing for Infectious Disease Surveillance and Control: Development and Evaluation of a Hospital Automated Laboratory Reporting System.

BACKGROUND: Outbreaks of several serious infectious diseases have occurred in recent years. In response, to mitigate public health risks, countries worldwide have dedicated efforts to establish an information system for effective disease monitoring, risk assessment, and early warning management for international disease outbreaks. A cloud computing framework can effectively provide the required hardware resources and information access and exchange to conveniently connect information related to infectious diseases and develop a cross-system surveillance and control system for infectious diseases. OBJECTIVE: The objective of our study was to develop a Hospital Automated Laboratory Reporting (HALR) system based on such a framework and evaluate its effectiveness. METHODS: We collected data for 6 months and analyzed the cases reported within this period by the HALR and the Web-based Notifiable Disease Reporting (WebNDR) systems. Furthermore, system evaluation indicators were gathered, including those evaluating sensitivity and specificity. RESULTS: The HALR system reported 15 pathogens and 5174 cases, and the WebNDR system reported 34 cases. In a comparison of the two systems, sensitivity was 100% and specificity varied according to the reported pathogens. In particular, the specificity for Streptococcus pneumoniae, Mycobacterium tuberculosis complex, and hepatitis C virus were 99.8%, 96.6%, and 97.4%, respectively. However, the specificity for influenza virus and hepatitis B virus were only 79.9% and 47.1%, respectively. After the reported data were integrated with patients' diagnostic results in their electronic medical records (EMRs), the specificity for influenza virus and hepatitis B virus increased to 89.2% and 99.1%, respectively. CONCLUSIONS: The HALR system can provide early reporting of specified pathogens according to test results, allowing for early detection of outbreaks and providing trends in infectious disease data. The results of this study show that the sensitivity and specificity of early disease detection can be increased by integrating the reported data in the HALR system with the cases' clinical information (eg, diagnostic results) in EMRs, thereby enhancing the control and prevention of infectious diseases.

Production of water-soluble yellow pigments via high glucose stress fermentation of Monascus ruber CGMCC 10910.

Monascus pigments are secondary metabolites of Monascus species and are mainly composed of yellow pigments, orange pigments and red pigments. In this study, a larger proportion of Monascus yellow pigments could be obtained through the selection of the carbon source. Hydrophilic yellow pigments can be largely produced extracellularly by Monascus ruber CGMCC 10910 under conditions of high glucose fermentation with low oxidoreduction potential (ORP). However, keeping high glucose levels later in the culture causes translation or a reduction of yellow pigment. We presume that the mechanism behind this phenomenon may be attributed to the redox level of the culture broth and the high glucose stress reaction of M. ruber CGMCC 10910 during high glucose fermentation. These yellow pigments were produced via high glucose bio-fermentation without citrinin. Therefore, these pigments can act as natural pigments for applications as food additives.

Porous TiO2 Nanotubes with Spatially Separated Platinum and CoOx Cocatalysts Produced by Atomic Layer Deposition for Photocatalytic Hydrogen Production.

Efficient separation of photogenerated electrons and holes, and associated surface reactions, is a crucial aspect of efficient semiconductor photocatalytic systems employed for photocatalytic hydrogen production. A new CoOx /TiO2 /Pt photocatalyst produced by template-assisted atomic layer deposition is reported for photocatalytic hydrogen production on Pt and CoOx dual cocatalysts. Pt nanoclusters acting as electron collectors and active sites for the reduction reaction are deposited on the inner surface of porous TiO2 nanotubes, while CoOx nanoclusters acting as hole collectors and active sites for oxidation reaction are deposited on the outer surface of porous TiO2 nanotubes. A CoOx /TiO2 /Pt photocatalyst, comprising ultra-low concentrations of noble Pt (0.046 wt %) and CoOx (0.019 wt %) deposited simultaneously with one atomic layer deposition cycle, achieves remarkably high photocatalytic efficiency (275.9 µmol h-1 ), which is nearly five times as high as that of pristine TiO2 nanotubes (56.5 µmol h-1 ). The highly dispersed Pt and CoOx nanoclusters, porous structure of TiO2 nanotubes with large specific surface area, and the synergetic effect of the spatially separated Pt and CoOx dual cocatalysts contribute to the excellent photocatalytic activity.

Ultrathin Coating of Confined Pt Nanocatalysts by Atomic Layer Deposition for Enhanced Catalytic Performance in Hydrogenation Reactions.

Metal-support interfaces play a prominent role in heterogeneous catalysis. However, tailoring the metal-support interfaces to realize full utilization remains a major challenge. In this work, we propose a graceful strategy to maximize the metal-oxide interfaces by coating confined nanoparticles with an ultrathin oxide layer. This is achieved by sequential deposition of ultrathin Al2 O3 coats, Pt, and a thick Al2 O3 layer on carbon nanocoils templates by atomic layer deposition (ALD), followed by removal of the templates. Compared with the Pt catalysts confined in Al2 O3 nanotubes without the ultrathin coats, the ultrathin coated samples have larger Pt-Al2 O3 interfaces. The maximized interfaces significantly improve the activity and the protecting Al2 O3 nanotubes retain the stability for hydrogenation reactions of 4-nitrophenol. We believe that applying ALD ultrathin coats on confined catalysts is a promising way to achieve enhanced performance for other catalysts.

Mature dendritic cells cause Th17/Treg imbalance by secreting TGF-ß1 and IL-6 in the pathogenesis of experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is generally acknowledged to be an autoimmune disease, but its etiology remains unknown. The most intensively studied animal model of MS is experimental autoimmune encephalomyelitis (EAE). Dendritic cells (DCs), the professional antigen presenting cells (APCs), have gained increasing attention because they connect innate and adaptive immunity. The aim of this study was to determine the role of mature DCs in the pathogenesis of EAE. It was found that the number of mature DCs in the EAE spleen increased compared to the control group (p < 0.05). And there was an imbalance between Th17 (effector) and Treg (regulatory) in EAE. The data showed that mature DCs can regulate the differentiation of Th17 and Treg in EAE. In addition, there was a significant difference in secretion of TGF-ß1 and IL-6 between mature DCs from mice with EAE and controls. The present data suggest that mature DCs cause an imbalance between Th17 and Treg by secreting TGF-ß1 and IL-6 in the pathogenesis of EAE disease. Thus, targeting DC may be an effective strategy for treating MS.

Evaluation of program success for programs with multiple trials in binary outcomes.

A late-stage clinical development program typically contains multiple trials. Conventionally, the program's success or failure may not be known until the completion of all trials. Nowadays, interim analyses are often used to allow evaluation for early success and/or futility for each individual study by calculating conditional power, predictive power and other indexes. It presents a good opportunity for us to estimate the probability of program success (POPS) for the entire clinical development earlier. The sponsor may abandon the program early if the estimated POPS is very low and therefore permit resource savings and reallocation to other products. We provide a method to calculate probability of success (POS) at an individual study level and also POPS for clinical programs with multiple trials in binary outcomes. Methods for calculating variation and confidence measures of POS and POPS and timing for interim analysis will be discussed and evaluated through simulations. We also illustrate our approaches on historical data retrospectively from a completed clinical program for depression.

High prevalence of metallo-ß-lactamase among carbapenem-resistant Klebsiella pneumoniae in a teaching hospital in China.

The aim of this study was to characterize the carbapenemases in carbapenem-resistant Klebsiella pneumoniae (CR-KP) from a Chinese teaching hospital. A total of 40 CR-KPs were screened for the presence of carbapenemases. Minimum inhibitory concentrations were determined by agar dilution. The modified Hodge test was used for the detection of carbapenemase production. Carbapenemase, extended-spectrum ß-lactamase, and AmpC genes were detected using polymerase chain reaction (PCR) and sequencing. A conjugation test was performed using a broth culture mating method, transferred plasmids were typed by PCR-based replicon typing, and clonal relatedness was investigated by enterobacterial repetitive intergenic consensus sequences PCR (ERIC-PCR) and multilocus sequence typing (MLST). The results revealed that modified Hodge test was positive for 28 CR-KPs, and CR-KPs exhibited high resistance rates against various antibiotics, except colistin (5.0%) and tigecycline (22.5%). ERIC and MLST profiles showed no clonal outbreak. PCR demonstrated a high prevalence rate (55.0%, 22/40) of metallo-ß-lactamases (MBLs) in CR-KPs. IMP-4, IMP-8, NDM-1, and KPC-2 were identified in 14 (35.0%), 7 (17.5%), 2 (5.0%), and 7 (17.5%) isolates, respectively. Notably, 2 CR-KPs coproduced 2 carbapenemases simultaneously (IMP-8/NDM-1 and IMP-4/KPC-2). In vitro transfer of carbapenem resistance was successful for 11 MBL-producing CR-KPs. The extended spectrum ß-lactamase genes were detected in 30 (75.0%) of these CR-KPs. To the best of our knowledge, this is the first report focusing on carbapenem resistance in K. pneumoniae due to metalloenzymes in China. Screening and surveillance of MBLs in Enterobacteriaceae is urgently needed in this region to control and prevent the spread of these resistance determinants.

Safety and Tolerability of Starting Aripiprazole Lauroxil With Aripiprazole Lauroxil NanoCrystal Dispersion in 1 Day Followed by Aripiprazole Lauroxil Every 2 Months Using Paliperidone Palmitate Monthly as an Active Control in Patients With Schizophrenia: A Post Hoc Analysis of a Randomized Controlled Trial.

Background: Aripiprazole lauroxil (AL) 1064 mg every 2 months following initiation using the AL NanoCrystal Dispersion formulation (ALNCD) plus 30-mg oral aripiprazole was efficacious and well tolerated in a 25-week, randomized, double-blind phase 3 trial in adults with acute schizophrenia. This post hoc analysis further characterized the safety of AL 1064 mg administered every 2 months and that of active control paliperidone palmitate (PP) 156 mg monthly based on occurrence, timing, and severity of adverse events (AEs) associated with antipsychotic medications.Methods: This study was conducted between November 2017 and March 2019. AL or PP was initiated during an inpatient stay of ≥ 2 weeks with transition to outpatient treatment thereafter. Rates of AEs of clinical interest, including injection site reactions (ISRs), motor AEs, sedation, hypotension, prolactin level increase, weight gain, and suicidal ideation/behavior, were summarized through weeks 4, 9, and 25 for each treatment.Results: Of 200 patients who received ≥ 1 dose of study treatment, 99 (49.5%) completed the study (AL, 57%; PP, 43%). Mean (SD) baseline Positive and Negative Syndrome Scale total scores were 94.1 (9.04) and 94.6 (8.41) in the AL and PP treatment groups, respectively. AEs were reported by 69/99 (70%) patients administered AL and 72/101 (71%) administered PP; most AEs were mild or moderate in severity. ISRs (AL, 18.2%; PP, 26.7%) occurred primarily on days 1 and 8. All akathisia/restlessness AEs (AL, 10.1%; PP, 11.9%) occurred during the first 4 weeks; <10% of patients (either treatment) experienced hypotension, sedation, or suicidal ideation/behavior events. Weight gain of ≥ 7% from baseline occurred in 9.3% of AL- and 23.8% of PP-treated patients. Median prolactin concentrations changed by -4.60 and -3.55 ng/mL among AL-treated males and females, respectively, and did not exceed 2 times normal levels in any AL-treated patients. In PP-treated patients, changes were 21.20 and 80.40 ng/mL and concentrations exceeded 2 times normal in 38% and 88% of males and females, respectively.Conclusions: No new early- or late-emerging safety concerns were observed through 25 weeks of treatment with AL 1064 mg every 2 months following initiation using ALNCD plus 30-mg oral aripiprazole. Results were consistent with known safety profiles of AL and PP and support the safety of AL 1064 mg every 2 months initiated using ALNCD plus 30-mg oral aripiprazole.Trial Registration: ClinicalTrials.gov identifier: NCT03345979.

Immune Checkpoint Inhibitors Serve as the First-Line Treatment for Advanced Head and Neck Cancer.

OBJECTIVES: Immune checkpoint inhibitor (ICI) therapy has demonstrated substantial benefits for certain patients. We try to evaluate the merits and demerits of each immunotherapy to aid clinical treatment. METHODS: We conducted a comprehensive search of the PubMed, Embase, and Cochrane databases for randomized clinical trials published as of June 10, 2023. Our study included published clinical trials of ICI monotherapy or combination therapy, along with data on treatment-related adverse events (TRAE). Data regarding survival efficacy and adverse events of each randomized controlled trial (RCT) were collected. The Bayesian random effects model was utilized for the network meta-analysis (NMA). RESULTS: This study incorporated 19 RCTs, involving 5900 patients. Among 14 treatment regimens, Pembrolizumab combined with chemotherapy emerged as the most promising primary treatment for overall survival (OS) and objective response rate (ORR). Toripalimab combined with chemotherapy exhibited the highest likelihood of becoming the primary treatment for extending progression-free survival (PFS). Durvalumab showed the lowest probability of adverse events, suggesting a safer profile compared with other drugs. Camrelizumab combined with chemotherapy demonstrated a heightened risk of adverse events. Dual ICI Nivolumab/Ipilimumab surpassed Durvalumab/Tremelimumab in terms of ORR and adverse events. The standard of care (SOC) regimen did not exhibit strong performance across the four outcome indicators. CONCLUSION: Our analysis suggests that the integration of chemotherapy agents with ICIs enhances its efficacy as a first-line treatment for patients with advanced head and neck cancer (HNC). LEVEL OF EVIDENCE: 1 Laryngoscope, 134:749-761, 2024.

Effects of traditional Chinese medicine-assisted intervention on improving postpartum lactation: A systematic review and meta-analysis.

Importance: Breast milk is the safest food for infants and has many psychological and physical benefits for infants and mothers. However, problems encountered during the breastfeeding process can reduce postpartum women's willingness to breastfeed. Lactation and engorgement may be improved through Traditional Chinese Medicine auxiliary therapy. However, the overall efficacy of various Traditional Chinese Medicine auxiliary therapies and the relevant meridians and acupuncture points for treating breast milk deficiency remain unclear. Objective: To investigate Traditional Chinese Medicine auxiliary therapy's effectiveness and acupoints for postpartum women who experience problems during the breastfeeding process. Methods: Data were sourced from Embase, Web of Science, CINAHL, Cochrane, CNKI, PubMed, and the Airiti Library Central Register of Controlled Trials and Clinical Trials from the database inception to October 2022. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Main outcome measures: The primary outcomes were overall efficiency, prolactin level, milk volume, and breast engorgement in postpartum women with lactation deficiency after-assisted therapies and the correlation between meridian points and milk secretion. Results: A total of 1,516 studies were initially identified, and 357 articles were assessed. In the final analysis, 20 studies were included, covering various Traditional Chinese Medicine therapies (acupuncture, acupressure, scrapping, moxibustion cupping, etc.) to stimulate relative acupoints without any acupoint stimulation. The overall efficiency (odds ratio [OR] = 14.17, 95% confidence interval [CI] = 6.49 to 30.92), prolactin level (standardized mean difference [SMD] = 0.36, 95% CI = 0.074 to 0.64), improvement of milk volume (SMD = 0.94, 95% CI = 0.59 to 1.29), reduction of engorgement level (OR= 18, 95% CI = 8.34 to 38.82) demonstrated that Traditional Chinese Medicine therapies can effectively improve lactation and breast fullness, thereby helping patients with breast milk deficiency. The most common acupuncture points used to treat agalactia were classified as the Stomach Meridian, Small Intestine Meridian, and Conception Vessel, with the common acupoints CV17: Danzhong, ST18: Rugen, SI1: Shaoze, ST36: Zusanli, and ST16: Yingchuang. Conclusion: Adjuvant Traditional Chinese Medicine therapy can improve lactation and breast engorgement, thereby increasing the willingness to breastfeed. Clinical Finding: 1. The best time for Traditional Chinese Medicine acupoint intervention for breast deficiency treatment is within 24 h 2. The most effective acupuncture points for improving milk deficiency and bloating pain are ST18: Rugen, ST16: Yingchuang, ST36: Zusanli, SI1: Shaoze, CV17: Danzhong. 3. Traditional Chinese Medicine is non-invasive and effective techniques such as scraping, cupping, acupressure and ear peas. 4. Traditional Chinese Medicine can be combined with other different acupuncture points according to the different constitutions of post-partum women. Breast acupressure, ear acupuncture, scrapping, cupping, and moxibustion are noninvasive treatments that can effectively help patients during lactation, and their clinical practice should be considered and widely promoted.

Larotrectinib versus infigratinib for adult patients with both glioma and tyrosine kinase alterations after failure of initial therapies: Efficacy and safety analysis.

OBJECTIVES: To compare the efficacy and safety of larotrectinib with those of infigratinib in adult glioma patients with tyrosine kinase alterations. METHODS: Patients received oral infigratinib 125 mg (IN cohort, n = 125) or oral larotrectinib (LB cohort, n = 105) until unacceptable toxicity or disease progression. RESULTS: Duration of treatment was longer in the LB cohort than in the IN cohort (8 [9.5-6.25] months vs. 5.5 [6-5.25] months, p < 0.0001). Patients with partial responses (p = 0.0424) and overall survival (p = 0.03) were higher in the IN cohort than those in the LB cohort. The number of patients with disease progression was higher in the LB cohort (p = 0.0015). All the patients reported diarrhea, fatigue, vomiting, constipation, and decreased appetite. Patients in the IN cohort reported hyperphosphatemia, hyperlipasemia, stomatitis, dry skin, alopecia, dyspepsia, onycholysis, palmar-plantar erythrodysesthesia, nail disorders, and dry eyes. Patients in the LB cohort reported upper respiratory tract infections, pyrexia, cough, anemia, bacterial/viral infections, conjunctivitis, urinary tract infections, headaches, ataxia, dizziness, and muscle tremors. A total of 30 (24 %) and 40 (38 %) patients from the IN and the LB cohorts died at the follow-up of 18 months (p = 0.03). Patients who received bevacizumab initial therapy had higher overall survival (p = 0.048). CONCLUSIONS: Infigratinib has higher efficacy and overall survival than larotrectinib but has higher adverse effects in the management of both glioma and tyrosine kinase alterations after failure of initial therapies. Initial bevacizumab therapy is associated with a higher overall survival.