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Bohao Dai,1,&ast; Xiaorong Peng,1,&ast; Jia Sun,1 Xueling Zhu,1 Xiang Liu,1 Ye Xiong,1 Zhikai Wan,1 Dairong Xiang,1 Jiangjin Hui,1 Chenxi Ying,2 Huiting Liu,1 Biao Zhu1,&ast; 1The Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Cardivascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Biao Zhu, The Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qing Chun Road, Hangzhou, 310006, People’s Republic of China, Email zhubiao1207@zju.edu.cnBackground: HIV-1 CRF01_AE is becoming the predominant HIV-1 subtype among patients in China. The distribution and characteristics of transmission clusters of HIV-1 CRF01_AE in Zhejiang, Eastern China remains unclear. This study analyzed the epidemiologic characteristics and transmission clusters of HIV-1 CRF01_AE in Zhejiang.Methods: Plasma samples obtained from 152 patients of HIV-1 CRF01_AE not undergoing ART were used to amplify HIV-1 pol and env gene. CRF01_AE drug resistance mutations (DRM) prevalence was analysed using Stanford University’s HIV Drug Resistance Database. A phylogenetic tree was constructed using FastTree (version 2.1.11) based on the GTR nucleotide substitution model and visualized using Figtree (version 1.4.4) and The Interactive Tree of Life; the Chinese HIV Gene Sequence Data Platform was used to construct genetic transmission networks.Results: Majority samples could be grouped into CRF01_AE transmission Clusters 1 (11.2%), 4 (64.5%), and 5 (7.2%). The CD4+ T-cell counts in Cluster 1, 4a, 4b are lower than 5 were 15, 38, 30, and 248 cells/mm3, respectively (P < 0.05). The high X4 tropism rates were 13.2%, 11.8%, 20.0%, and 0.0% in Clusters 1, 4a, 4b, and 5, respectively. DRM rates in Clusters 4a and 4b were 17.6%, and 25.45% respectively (P < 0.05), whereas they were 17.6% and 18.2% in Clusters 1 and 5, respectively. In total, 24 transmission genetic networks, comprising 72 sequences and 61 links, were discovered; of them, 61.2%, 11.7%, and 18.2% were from Clusters 4, 1, and 5, respectively (P < 0.05).Conclusion: In Zhejiang, different CRF01_AE clusters displayed unique clinic features. Cluster 4, particularly Cluster 4b, was considered a high-risk transmission cluster. The surveillance of epidemiology of HIV-1 should be enhanced to minimize its transmission.Keywords: HIV-1 CRF01_AE, drug resistance mutation, transmission cluster

Summary: A wide variety of electrophilic derivatives of itaconate, the Kreb’s cycle-derived metabolite, are immunomodulatory, yet these derivatives have overlapping and sometimes contradictory activities. Therefore, we generated a genetic system to interrogate the immunomodulatory functions of endogenously produced itaconate in human macrophages. Endogenous itaconate is driven by multiple innate signals restraining inflammatory cytokine production. Endogenous itaconate directly targets cysteine 13 in IRAK4 (disrupting IRAK4 autophosphorylation and activation), drives the degradation of nuclear factor κB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1β in response to these innate activators. In contrast, the production of interferon (IFN)β, downstream of LPS, requires the production of itaconate. These data demonstrate that itaconate is a critical arbiter of inflammatory cytokine production downstream of multiple innate signaling pathways, laying the groundwork for the development of itaconate mimetics for the treatment of autoimmunity.

A dual-band sleeve monopole antenna with the substrate-integrated coaxial line (SICL) technology is proposed in this paper. Both the radiation structure and the feeding network are modified from the SICL structure. The antenna provides dual-band operation for LoRa (Long Range Radio) applications covering 433 MHz and 868 MHz bands. This antenna operates as a quarter-wavelength monopole with practical omnidirectional radiation performance for each band. The antenna exhibits a gain of 2.0 dBi at 433 MHz with more than 90% radiation efficiency, and a gain of 1.7 dBi at 868 MHz with more than 90% radiation efficiency. The measured −10 dB impedance bandwidths are from $393 \sim 450$ MHz and $826 \sim 931$ MHz, respectively. A good agreement is observed between the measured and the simulated results, which demonstrates that the proposed scheme can be a possible candidate for LoRa applications.

Although most follicular-derived thyroid cancers are well differentiated and have an overall excellent prognosis following treatment with surgery and radioiodine, management of advanced thyroid cancers, including iodine refractory disease and poorly differentiated/undifferentiated subtypes, is more challenging. Over the past decade, better understanding of the genetic drivers and immune milieu of advanced thyroid cancers has led to significant progress in the management of these patients. Numerous targeted kinase inhibitors are now approved by the U.S Food and Drug administration (FDA) for the treatment of advanced, radioiodine refractory differentiated thyroid cancers (DTC) as well as anaplastic thyroid cancer (ATC). Immunotherapy has also been thoroughly studied and has shown promise in selected cases. In this review, we summarize the progress in the understanding of the genetic landscape and the cellular and molecular basis of radioiodine refractory-DTC and ATC, as well as discuss the current treatment options and future therapeutic avenues.

Summary: Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

Introduction Ovarian hyperstimulation syndrome (OHSS) is the most significant short-term complication of pharmacological ovarian stimulation. Symptoms range from mild abdominal discomfort to rare complications such as renal failure, thromboembolism and respiratory distress syndrome.Currently, clinical practice typically involves monitoring the patient until the condition becomes severe, at which point they are admitted to hospital, where drainage of ascitic fluid (paracentesis) may take place. Preliminary studies have indicated that earlier outpatient paracentesis may reduce the progression of OHSS and prevent hospitalisation in women.Methods and analysis This UK, multicentre, pragmatic, two-arm, parallel-group, adaptive (group sequential with one interim analysis), open-label, superiority, confirmatory, group sequential, individually randomised controlled trial, with internal pilot will assess the clinical and cost-effectiveness and safety of outpatient paracentesis versus conservative management (usual care) for moderate or severe OHSS. 224 women from 20 National Health Service and private fertility units will be randomised (1:1) and followed up for up to 13.5 months. The primary outcome is the rate of OHSS related hospital admission of at least 24 hours within 28 days postrandomisation. The primary analysis will be an intention to treat with difference in hospitalisation rates as measure of treatment effect. Secondary outcomes include time to resolution of symptoms, patient satisfaction, adverse events and cost-effectiveness. A qualitative substudy will facilitate the feasibility of recruitment. Participant recruitment commenced in June 2022.Ethics and dissemination London—Southeast Research Ethics Committee approved the protocol (reference: 22/LO/0015). Findings will be submitted to peer-reviewed journals and abstracts to relevant national and international conferences, as well as being disseminated to trial participants and patient groups.Trial registration number ISRCTN71978064.

Background: This study aims to provide evidence of factors that impact participant reported serious depression and serious anxiety among individuals receiving injectable opioid agonist treatment (iOAT). Methods: Data from an 18-month longitudinal retrospective cohort of individuals receiving iOAT was utilized. The outcomes of serious depression and serious anxiety were ascertained via self-report in the European Addiction Severity Index. Two Generalized Linear Mixed Models were formulated using Penalized Quasi-Likelihood method. Results: Analyses included 131 participants. Average age was 49.04 years, 31 % self-identified as female, and 30 % self-identified as Indigenous. Adjusted analysis identified the importance of poorer physical health (AOR:1.06; 95 % CI: 1.03, 1.08), illicit opioid use (AOR: 1.03; 95 %CI: 1.01, 1.06), emotional abuse (AOR: 2.01; 95 % CI: 1.17, 3.44), and social isolation (AOR: 1.95; 95 % CI: 1.06, 3.58) with serious depression. Adjusted analysis of serious anxiety identified associations with age (AOR: 0.95; 95 % CI: 0.92, 0.98), illicit benzodiazepine use (AOR:1.31 95 % CI: 1.06, 1.61), poorer physical health (AOR: 1.05; 95 % CI: 1.03, 1.07), and social problems (AOR: 2.09; 95 % CI: 1.18, 3.71). Limitations: Generalizability of study findings may be limited given the criteria used to enroll participants and to define depression and anxiety. Conclusion: Depression and anxiety are highly prevalent among clients receiving iOAT. While both disorders share several factors, there are distinct characteristics associated with each outcome. These include poorer physical health, experiences of abuse, illicit substance use, and social problems. Understanding factors that influence depression and anxiety in iOAT can assist providers in supporting iOAT clients' mental health and developing individualized care plans.

The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intratumor transformation process is poorly understood. We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single-cell transcriptomic and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stress-responsive DTC cells, inflammatory ATC cells (iATCs), and mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Furthermore, our analysis identified 2 important milestones: (a) a diploid stage, in which iATC cells were diploids with inflammatory phenotypes and (b) an aneuploid stage, in which mATCs gained aneuploid genomes and mesenchymal phenotypes, producing excessive amounts of collagen and collagen-interacting receptors. In parallel, cancer-associated fibroblasts showed strong interactions among mesenchymal cell types, macrophages shifted from M1 to M2 states, and T cells reprogrammed from cytotoxic to exhausted states, highlighting new therapeutic opportunities for the treatment of ATC.

Background:. Despite an increasing surge of exosome use throughout the aesthetic arena, a paucity of published exosome-based literature exists. Exosomes are membrane-bound extracellular vesicles derived from various cell types, exerting effects via intercellular communication and regulation of several signaling pathways. The purpose of this review was to summarize published articles elucidating mechanisms and potential applications, report available products and clinical techniques, and prompt further investigation of this emerging treatment within the plastic surgery community. Methods:. A literature review was performed using PubMed with keywords exosomes, secretomes, extracellular vesicles, plastic surgery, skin rejuvenation, scar revision, hair growth, body contouring, and breast augmentation. Publications from 2010 to 2021 were analyzed for relevance and level of evidence. A Google search identified exosome distributors, where manufacturing/procurement details, price, efficacy, and clinical indications for use were obtained by direct contact and summarized in table format. Results:. Exosomes are currently derived from bone marrow, placental, adipose, and umbilical cord tissue. Laboratory-based exosome studies demonstrate enhanced outcomes in skin rejuvenation, scar revision, hair restoration, and fat graft survival on the macro and micro levels. Clinical studies are limited to anecdotal results. Prices vary considerably from $60 to nearly $5000 based on company, source tissue, and exosome concentration. No exosome-based products are currently Food and Drug Administration–approved. Conclusions:. Administered alone or as an adjunct, current reports show promise in several areas of aesthetic plastic surgery. However, ongoing investigation is warranted to further delineate concentration, application, safety profile, and overall outcome efficacy.

Yuanyuan Dai,1 Wenjiao Chang,1 Xin Zhou,1 Wei Yu,2 Chen Huang,2 Yunbo Chen,2 Xiaoling Ma,1 Huaiwei Lu,1 Rujin Ji,2 Chaoqun Ying,2 Peipei Wang,2 Zhiying Liu,2 Qingfeng Yuan,1 Yonghong Xiao2 1Department of Laboratory, First Affiliated Hospital of University of Science and Technology of China, Hefei, People’s Republic of China; 2State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Yonghong Xiao Tel/Fax +865 718 723 6421Email xiao-yonghong@163.comPurpose: To evaluate the administration regimen of ceftazidime/avibactam (CZA) for bloodstream infections caused by Enterobacteriaceae and Pseudomonas aeruginosa.Methods: The minimal inhibitory concentrations (MICs) of CZA against Enterobacteriaceae and P. aeruginosa isolated from blood cultures at member hospitals in BRICS (Blood Bacterial Resistant Investigation Collaborative System) in 2019 were determined by broth micro-dilution methodology. A 10,000-patient Monte Carlo simulation (MCS) was used to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) for different CZA dosage regimens to evaluate their efficacies and optimize the best initial dosage regimen.Results: Altogether, 6487 Enterobacteriaceae and P. aeruginosa strains were isolated from the blood cultures. The overall CZA resistance rate was 2.31%, of which the Enterobacteriaceae and P. aeruginosa rates were 1.57% and 14.29%, respectively. The MCS showed that the greater the MIC value, the worse the therapeutic effect. When the CZA MIC was ≤ 8 mg/L, the standard dose (2.5g iv q8h) achieved 90% PTA in the subset of patients with creatinine clearance (CrCl) values from 51 to 120 mL/min. Although the high-dose regimen (3.75g iv q8h) achieved 90% PTA in patients with CrCl values from 121 to 190 mL/min, implementing the low-dose regimen (1.25g iv q8h) was also effective for patients in the 51– 89 mL/min CrCl range. Generally, the high-dose regimen (3.75g iv q8h) reached 90% CFR against all of the strains. Conversely, in patients with CrCl values of 121– 190 mL/min, the standard dose (2.5g iv q8h) failed to reach 90% CFR against some Enterobacteriaceae members and P. aeruginosa. When the dose was reduced to the low-dose regimen (1.25g iv q8h), no patients reached 90% CFR against some Enterobacteriaceae members and P. aeruginosa.Conclusion: CZA has good antibacterial activity against Enterobacteriaceae and P. aeruginosa in bloodstream infections. Clinicians could make individualized treatment regimens in accordance with the sensitivity of the strains and the level of renal function in their patients to best predict the drug-related clinical responses.Keywords: Gram-negative bacteria, extended-spectrum β-lactamase, dosage regimens, pharmacokinetics, pharmacodynamics, minimum inhibitory concentration

Abstract A physiologically based pharmacokinetic (PBPK) model was developed to evaluate and predict (1) the effect of concomitant cytochrome P450 3A (CYP3A) inhibitors or inducers on the exposures of zanubrutinib, (2) the effect of zanubrutinib on the exposures of CYP3A4, CYP2C8, and CYP2B6 substrates, and (3) the impact of gastric pH changes on the pharmacokinetics of zanubrutinib. The model was developed based on physicochemical and in vitro parameters, as well as clinical data, including pharmacokinetic data in patients with B‐cell malignancies and in healthy volunteers from two clinical drug‐drug interaction (DDI) studies of zanubrutinib as a victim of CYP modulators (itraconazole, rifampicin) or a perpetrator (midazolam). This PBPK model was successfully validated to describe the observed plasma concentrations and clinical DDIs of zanubrutinib. Model predictions were generally within 1.5‐fold of the observed clinical data. The PBPK model was used to predict untested clinical scenarios; these simulations indicated that strong, moderate, and mild CYP3A inhibitors may increase zanubrutinib exposures by approximately four‐fold, two‐ to three‐fold, and

Zanubrutinib is a potent, second‐generation Bruton’s tyrosine kinase inhibitor that is currently being investigated in patients with B‐cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the PKs of zanubrutinib and identify the potential impact of intrinsic and extrinsic covariates on zanubrutinib PK. Data across nine clinical studies of patients with B‐cell malignancies and data of healthy volunteers (HVs) were included in this analysis, at total daily doses ranging from 20 to 320 mg. In total, 4,925 zanubrutinib plasma samples from 632 subjects were analyzed using nonlinear mixed‐effects modeling. Zanubrutinib PKs were adequately described by a two‐compartment model with sequential zero‐order then first‐order absorption, and first‐order elimination. A time‐dependent residual error model was implemented in order to better capture the observed maximum concentration variability in subjects. Baseline alanine aminotransferase and health status (HVs or patients with B‐cell malignancies) were identified as statistically significant covariates on the PKs of zanubrutinib. These factors are unlikely to be clinically meaningful based on a sensitivity analysis. No statistically significant differences in the PKs of zanubrutinib were observed based on age, sex, race (Asian, white, and other), body weight, mild or moderate renal impairment (creatinine clearance ≥ 30 mL/minute as estimated by Cockcroft‐Gault), baseline aspartate aminotransferase, bilirubin, tumor type, or use of acid‐reducing agents (including proton pump inhibitors). These results support that no dose adjustment is considered necessary based on the aforementioned factors.

Objectives The study aims to determine the relative importance of key attributes of a novel intrauterine device. The device monitors uterine oxygen, pH and temperature in real time with the aim of improving our understanding and treatment of reproductive disorders.Design A discrete choice experiment was used to elicit preferences in this novel investigative tool. The attributes and levels used in the choice scenarios were length of time using the device (7, 14 or 28 days), information obtained to guide treatment (limited, majority or all cases), risk of complications (1% or 10%) and discreteness (completely discrete, moderately discrete or indiscrete).Setting Secondary care hospital in Hampshire, UK.Participants 361 women of reproductive age.Primary and secondary outcome measures Conditional logit and latent class logit regression models to determine the preference for each attribute.Results Conditional logit coefficients allow comparison between attributes; women placed most importance on obtaining information to guide treatment in all cases (2.771), followed by having a completely discrete device (1.104), reducing risk of complications by 1% (0.184) and decreased length of time by 1 day (0.0150). All coefficients p

This thorough QT (TQT) study evaluated the effect of zanubrutinib on electrocardiogram (ECG) parameters by using concentration‐QTc (C‐QTc) analysis as the primary analysis for this study. Part A of the study determined the safety and tolerability of a single supratherapeutic dose of zanubrutinib (480 mg) in healthy volunteers. Part B was a randomized, blinded, placebo‐controlled and positive‐controlled, four‐way crossover, TQT study of single therapeutic (160 mg) and supratherapeutic (480 mg) doses of zanubrutinib, placebo, and open‐label moxifloxacin 400 mg. Thirty‐two participants received at least 1 dose of zanubrutinib, and 26 participants completed all 4 periods. Zanubrutinib did not have any effect on heart rate or cardiac conduction (pulse rate, QRS interval, or T‐wave morphology) and was generally well‐tolerated. Using C‐QTc analysis, the predicted placebo‐corrected change‐from‐baseline QT interval using Fridericia’s formula (ΔΔQTcF) was −3.4 msec (90% confidence interval: −4.9 to −1.9 msec) at peak concentrations of the 480 mg dose. A QT effect (ΔΔQTcF) exceeding 10 msec could be excluded within the observed concentration range at 160 and 480 mg doses. Assay sensitivity was established by moxifloxacin with 90% lower bound exceeding 5 msec. Implementing a C‐QTc analysis prospectively in this TQT study resulted in a substantially smaller sample size to maintain a similar study power as shown in the traditional time‐point analysis. A single 160‐mg or 480‐mg zanubrutinib dose did not prolong the QTc interval or have any other clinically relevant effects on ECG parameters.

Abstract Zanubrutinib is a highly selective, potent, orally available, targeted covalent inhibitor (TCI) of Bruton's tyrosine kinase (BTK). This work investigated the in vitro drug metabolism and transport of zanubrutinib, and its potential for clinical drug–drug interactions (DDIs). Phenotyping studies indicated cytochrome P450 (CYP) 3A are the major CYP isoform responsible for zanubrutinib metabolism, which was confirmed by a clinical DDI study with itraconazole and rifampin. Zanubrutinib showed mild reversible inhibition with half maximal inhibitory concentration (IC50) of 4.03, 5.69, and 7.80 μM for CYP2C8, CYP2C9, and CYP2C19, respectively. Data in human hepatocytes disclosed induction potential for CYP3A4, CYP2B6, and CYP2C enzymes. Transport assays demonstrated that zanubrutinib is not a substrate of human breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP)1B1/1B3, organic cation transporter (OCT)2, or organic anion transporter (OAT)1/3 but is a potential substrate of the efflux transporter P‐glycoprotein (P‐gp). Additionally, zanubrutinib is neither an inhibitor of P‐gp at concentrations up to 10.0 μM nor an inhibitor of BCRP, OATP1B1, OATP1B3, OAT1, and OAT3 at concentrations up to 5.0 μM. The in vitro results with CYPs and transporters were correlated with the available clinical DDIs using basic models and mechanistic static models. Zanubrutinib is not likely to be involved in transporter‐mediated DDIs. CYP3A inhibitors and inducers may impact systemic exposure of zanubrutinib. Dose adjustments may be warranted depending on the potency of CYP3A modulators.

Chen Huang,1,2 Qingyi Shi,1 Beiwen Zheng,1 Jinru Ji,1 Chaoqun Ying,1 Xiao Yu,1 Hui Wang,2 Yonghong Xiao11State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Respiratory Medicine, Lihuili Hospital, Ningbo Medical Center, Ningbo, People’s Republic of ChinaObjectives: Monte Carlo simulation (MCS) was used to evaluate optimal dosage for cefepime (FEP), moxalactam (MOX), and cefperazone/sulbactam (CFZ/SBT) against extended-spectrum β-lactamase (ESBL) producers isolated from the Blood Bacterial Resistant Investigation Collaborative System.Methods: Minimum inhibitory concentration (MIC) was tested by agar dilution, and ESBL producers were identified by modified Clinical and Laboratory Standards Institute tests. Pharmacokinetic parameters were derived from data on healthy individuals, and probability of target attainment (PTA) and cumulative fraction of response (CFR) %fT >MIC values were estimated by MCS.Results: A total of 2032 Escherichia coli (875 ESBL-producing) and Klebsiella pneumoniae (157 ESBL-producing) strains, and 371 other Enterobacteriaceae strains, were isolated from patients with bloodstream infections (BSIs). MIC90 values for FEP, MOX, and CFZ/SBT against ESBL-producing E. coli and K. pneumoniae were 64/64 mg/L, 2/32 mg/L, and 64/128 mg/L, respectively. Conventional MOX and CFZ/SBT doses failed to reach 90% PTA against isolates with MICs ≥8 mg/L and ≥4 mg/L, respectively. Against ESBL producers, neither FEP nor CFZ/SBT achieved ≥90% CFR, while CFRs for MOX (1 g iv q6h, 2 g iv q12h, and 2 g iv q8h) exceeded 90% against ESBL-producing E. coli. Simulated CFRs for FEP and MOX were similar (>90%) against non-ESBL-producing Enterobacteriaceae, and higher than CFRs for CFZ/SBT.Conclusion: ESBL producers from BSIs were highly susceptible to MOX, and PTA values were generally higher for MOX than FEP or CFZ/SBT for conventional dosing regimens. This large MCS analysis shows that MOX but not FEP or CFZ/SBT can be used empirically to treat BSIs caused by ESBL-producing E. coli strains.Keywords: Monte Carlo simulation, Enterobacteriaceae, extended-spectrum β-lactamase, moxalactam, cefperazone/sulbactam, cefepime

Yigang Wang,1 Binrong Wang,1 Junnan Liang,2 Caixia Cui,3 Chang Ying,1 Fang Huang,4 Buyun Ma,1 Xiumei Zhou,1 Liang Chu21College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, People’s Republic of China; 2Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 3Department of Otorhinolaryngology, Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, People’s Republic of China; 4Department of Pathology, Zhejiang Provincal People’s Hospital, Hangzhou 310014, People’s Republic of ChinaBackground: Oncolytic virus can specifically replicate in and then lyse tumor cells, but seldom in normal cells. Further studies have shown the significant therapeutic effect of oncolytic virotherapy combining with other strategies, such as chemo-, radio-, and immunotherapy et al. In this study, we investigated the combinational effect of oncolytic virus ZD55-TRAIL and chemotherapy drug doxorubicin (DOX) on human laryngeal squamous cell carcinoma (LSCC).Methods: The effect of ZD55-TRAIL combined with DOX on cell growth was assessed in LSCC Hep2 cells and normal cells by MTT assay. Hochest 33342 staining was performed to observe cell morphological changes. Western blot was used to detect the expression of apoptotic activation proteins. The in vivo antitumor efficacy of combination treatment was estimated in laryngeal cancer xenograft models.Results: The combination of ZD55-TRAIL and DOX exhibited enhanced inhibitory effects on laryngocarcinoma cell growth, and had few side effects to normal cells in vitro. Chemotherapy drug increased the inducement of tumor cell apoptosis mediated by oncolytic virus. In vivo experiment confirmed that the combination treatment significantly inhibited Hep2 laryngocarcinoma xenografts growth in mice.Conclusion: The oncolytic viro-chemotherapy is a potent therapeutic approach for in vitro cytotoxicity evaluation of Hep2 cells and xenograft growth in vivo.Keywords: laryngocarcinoma, oncolytic virus, ZD55-TRAIL, doxorubicin

Azoospermia is divided into two categories of obstructive azoospermia and non-obstructive azoospermia. Before 1995, couples with a male partner diagnosed with non-obstructive azoospermia had to choose sperm donation or adoption to have a child. Currently, testicular sperm aspiration or micro-dissection testicular sperm extraction combined with intracytoplasmic sperm injection allows patients with non-obstructive azoospermia to have biological offspring. The sperm retrieval rate is significantly higher in micro-dissection testicular sperm extraction compared with testicular sperm aspiration. Additionally, micro-dissection testicular sperm extraction has the advantages of minimal invasion, safety, limited disruption of testicular function, a low risk of postoperative intratesticular bleeding, and low serum testosterone concentrations. Failed micro-dissection testicular sperm extraction has significant emotional and financial implications on the involved couples. Testicular sperm aspiration and micro-dissection testicular sperm extraction have the possibility of failure. Therefore, predicting the sperm retrieval rate before surgery is important. This narrative review summarizes the existing data on testicular sperm aspiration and micro-dissection testicular sperm extraction to identify the possible factor(s) that can predict the presence of sperm to guide clinical practice. The predictors of surgical sperm retrieval in patients with non-obstructive azoospermia have been widely studied, but there is no consensus.

Neural markers, such as the mismatch negativity (MMN), have been used to examine the phonological underspecification of English feature contrasts using the Featurally Underspecified Lexicon (FUL) model. However, neural indices have not been examined within the approximant phoneme class, even though there is evidence suggesting processing asymmetries between liquid (e.g., /ɹ/) and glide (e.g., /w/) phonemes. The goal of this study was to determine whether glide phonemes elicit electrophysiological asymmetries related to [consonantal] underspecification when contrasted with liquid phonemes in adult English speakers. Specifically, /ɹɑ/ is categorized as [+consonantal] while /wɑ/ is not specified [i.e., (–consonantal)]. Following the FUL framework, if /w/ is less specified than /ɹ/, the former phoneme should elicit a larger MMN response than the latter phoneme. Fifteen English-speaking adults were presented with two syllables, /ɹɑ/ and /wɑ/, in an event-related potential (ERP) oddball paradigm in which both syllables served as the standard and deviant stimulus in opposite stimulus sets. Three types of analyses were used: (1) traditional mean amplitude measurements; (2) cluster-based permutation analyses; and (3) event-related spectral perturbation (ERSP) analyses. The less specified /wɑ/ elicited a large MMN, while a much smaller MMN was elicited by the more specified /ɹɑ/. In the standard and deviant ERP waveforms, /wɑ/ elicited a significantly larger negative response than did /ɹɑ/. Theta activity elicited by /ɹɑ/ was significantly greater than that elicited by /wɑ/ in the 100–300 ms time window. Also, low gamma activation was significantly lower for /ɹɑ/ vs. /wɑ/ deviants over the left hemisphere, as compared to the right, in the 100–150 ms window. These outcomes suggest that the [consonantal] feature follows the underspecification predictions of FUL previously tested with the place of articulation and voicing features. Thus, this study provides new evidence for phonological underspecification. Moreover, as neural oscillation patterns have not previously been discussed in the underspecification literature, the ERSP analyses identified potential new indices of phonological underspecification.

The Featurally Underspecified Lexicon (FUL) theory predicts that [coronal] is the language universal default place of articulation for phonemes. This assumption has been consistently supported with adult behavioral and event-related potential (ERP) data; however, this underspecification claim has not been tested in developmental populations. The purpose of this study was to determine whether children demonstrate [coronal] underspecification patterns similar to those of adults. Two English consonants differing in place of articulation, [labial] /b/ and [coronal] /d/, were presented to 24 children (ages 4–6 years) characterized by either a typically developing phonological system (TD) or a phonological disorder (PD). Two syllables, /bɑ/ and /dɑ/, were presented in an ERP oddball paradigm where both syllables served as the standard and deviant stimulus in opposite stimulus sets. Underspecification was examined with three analyses: traditional mean amplitude measurements, cluster-based permutation tests, and single-trial general linear model (GLM) analyses of single-subject data. Contrary to previous adult findings, children with PD demonstrated a large positive mismatch response (PMR) to /bɑ/ while the children with TD exhibited a negative mismatch response (MMN); significant group differences were not observed in the /dɑ/ responses. Moreover, the /bɑ/ deviant ERP response was significantly larger in the TD children than in the children with PD. At the single-subject level, more children demonstrated mismatch responses to /dɑ/ than to /bɑ/, though some children had a /bɑ/ mismatch response and no /dɑ/ mismatch response. While both groups of children demonstrated similar responses to the underspecified /dɑ/, their neural responses to the more specified /bɑ/ varied. These findings are interpreted within a proposed developmental model of phonological underspecification, wherein children with PD are functioning at a developmentally less mature stage of phonological acquisition than their same-aged TD peers. Thus, phonological underspecification is a phenomenon that likely develops over time with experience and exposure to language.

Abstract ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disease characterized by the redistribution of the RNA binding protein TDP-43 in affected neurons: from predominantly nuclear to aggregated in the cytosol. However, the determinants of TDP-43 localization and the cellular insults that promote redistribution are incompletely understood. Here, we show that the putative Nuclear Export Signal (NES) is not required for nuclear egress of TDP-43. Moreover, when the TDP-43 domain which contains the putative NES is fused to a reporter protein, YFP, the presence of the NES is not sufficient to mediate nuclear exclusion of the fusion protein. We find that the previously studied “∆NES” mutant, in which conserved hydrophobic residues are mutated to alanines, disrupts both solubility and splicing function. We further show that nuclear export of TDP-43 is independent of the exportin XPO1. Finally, we provide evidence that nuclear egress of TDP-43 is size dependent; nuclear export of dTomato TDP-43 is significantly impaired compared to Flag TDP-43. Together, these results suggest nuclear export of TDP-43 is predominantly driven by passive diffusion.

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

Wei Yu,1,2,* Jinru Ji,1,* Tingting Xiao,1 Chaoqun Ying,1 Jiaheng Fang,3 Ping Shen,1 Yonghong Xiao1 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 2Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, 3Department of Gastroenterology, Hang Zhou Normal University Affiliated Hospital, Hangzhou, People’s Republic of China *These authors contributed equally to this work Background: Dicloxacillin, a semisynthetic isoxazolyl penicillin, exhibits antimicrobial activity against a wide variety of Gram-positive bacteria, as well as stability against penicillinases and low level of toxicity. The objective of this study was to obtain optimal dosing regimen of oral administration of dicloxacillin by analyzing the pharmacokinetic (PK) index in healthy volunteers and in vitro antibacterial activity by using Monte Carlo simulation. Materials and methods: A total of 867 clinical isolates from community-onset infections were collected from 31 secondary hospitals in People’s Republic of China. The minimum inhibitory concentration (MIC) values of dicloxacillin were determined by the agar dilution method. Based on the MICs and the PK parameters of different dosage regimens, Monte Carlo simulation was performed to simulate the PK/pharmacodynamic indices of 250 mg once-daily (qd), 500 mg qd, 1,000 mg qd, 2,000 mg qd, 250 mg every 6 hours (q6h), and 500 mg q6h, respectively. The probability of target attainment was estimated at each MIC value, and the cumulative fraction of response (CFR) was calculated to evaluate the efficacy of these regimens. Results: Dicloxacillin showed poor antibacterial activity against Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Resistance to dicloxacillin was observed in 7.5% of coagulase-negative Staphylococcus (CNS) isolates and 9.2% of other Streptococcus isolates, whereas 1.5% of methicillin-sensitive Staphylococcus aureus (MSSA) was resistant to dicloxacillin. Multiple-dose regimens could obtain higher CFR than single-dose regimens against H. influenza and S. pneumoniae. However, all dosing regimens against MSSA achieved CFR ≥90%. Meanwhile, dosing regimen of 2,000 mg qd, 250 mg q6h, and 500 mg q6h could achieve >90% of CFR for CNS. For other Streptococcus isolates, multiple-dose regimens achieved CFR ≥90%. Conclusion: Dicloxacillin has a significant antibacterial activity against MSSA, CNS, and other Streptococcus isolates. The simulation results suggest that dicloxacillin 250 mg q6h and 500 mg q6h dosing regimens may be recommended for clinical applications, especially for community-onset infections. Keywords: pharmacokinetics, pharmacodynamics, PK/PD index, dosage regimens, MSSA, CNS

Background and objectives: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted. Design and setting: A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites). Participants and interventions: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan®, Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks). Main outcome measures: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6–8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use. Methods: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth. Results: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence’s threshold of £20,000–30,000 per quality-adjusted life-year as between 0.7145 and 0.7341. Conclusions: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM. Limitations: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle. Future work: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM. Trial registration: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.

BACKGROUND: Although a variety of national organizations such as the Canadian Pain Society, the American Pain Society and the Joint Commission on Accreditation of Health Care Organizations have advanced the idea that pain should be assessed on a routine basis, there is little evidence that systematic pain assessment information is used routinely by clinicians even when it is readily available.

Biharmonic eigen-values arise in the study of static equilibrium of an elastic body which has been suitably secured at the boundary. This paper is concerned mainly with the existence of and Lp-estimates for the solutions of certain biharmonic boundary value problems which are related to the first eigen-values of the associated biharmonic operators. The methods used in this paper consist of the a-priori estimates due to Agmon-Douglas-Nirenberg and P. L. Lions along with the Fredholm theory for compact operators.

The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intratumor transformation process is poorly understood. We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single-cell transcriptomic and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stress-responsive DTC cells, inflammatory ATC cells (iATCs), and mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Furthermore, our analysis identified 2 important milestones: (a) a diploid stage, in which iATC cells were diploids with inflammatory phenotypes and (b) an aneuploid stage, in which mATCs gained aneuploid genomes and mesenchymal phenotypes, producing excessive amounts of collagen and collagen-interacting receptors. In parallel, cancer- associated fibroblasts showed strong interactions among mesenchymal cell types, macrophages shifted from M1 to M2 states, and T cells reprogrammed from cytotoxic to exhausted states, highlighting new therapeutic opportunities for the treatment of ATC., Introduction Anaplastic thyroid cancer (ATC), characterized by an undifferentiated morphology, is arguably one of the most lethal malignancies. According to Surveillance, Epidemiology and End Results (SEER) data (released April 2021) [...]