Mechanoresponsive Protein Crystals for NADH Recycling in Multicycle Enzyme Reactions.

NAD(H)-dependent enzymes play a crucial role in the biosynthesis of pharmaceuticals and fine chemicals, but the limited recyclability of the NAD(H) cofactor hinders its more general application. Here, we report the generation of mechano-responsive PEI-modified Cry3Aa protein crystals and their use for NADH recycling over multiple reaction cycles. For demonstration of its practical utility, a complementary Cry3Aa protein particle containing genetically encoded and co-immobilized formate dehydrogenase for NADH regeneration and leucine dehydrogenase for catalyzing the NADH-dependent l-tert-leucine (l-tert-Leu) biosynthesis has been produced. When combined with the PEI-modified Cry3Aa crystal, the resultant reaction system could be used for the efficient biosynthesis of l-tert-Leu for up to 21 days with a 10.5-fold improvement in the NADH turnover number.

Safety and Effectiveness of COVID-19 Vaccines During Pregnancy: A Living Systematic Review and Meta-analysis.

BACKGROUND: Pregnant persons are susceptible to significant complications following COVID-19, even death. However, worldwide COVID-19 vaccination coverage during pregnancy remains suboptimal. OBJECTIVE: This study assessed the safety and effectiveness of COVID-19 vaccines administered to pregnant persons and shared this evidence via an interactive online website. METHODS: We followed Cochrane methods to conduct this living systematic review. We included studies assessing the effects of COVID-19 vaccines in pregnant persons. We conducted searches every other week for studies until October 2023, without restrictions on language or publication status, in ten databases, guidelines, preprint servers, and COVID-19 websites. The reference lists of eligible studies were hand searched to identify additional relevant studies. Pairs of review authors independently selected eligible studies using the web-based software COVIDENCE. Data extraction and risk of bias assessment were performed independently by pairs of authors. Disagreements were resolved by consensus. We performed random-effects meta-analyses of adjusted relative effects for relevant confounders of comparative studies and proportional meta-analyses to summarize frequencies from one-sample studies using R statistical software. We present the GRADE certainty of evidence from comparative studies. Findings are available on an interactive living systematic review webpage, including an updated evidence map and real-time meta-analyses customizable by subgroups and filters. RESULTS: We included 177 studies involving 638,791 participants from 41 countries. Among the 11 types of COVID-19 vaccines identified, the most frequently used platforms were mRNA (154 studies), viral vector (51), and inactivated virus vaccines (17). Low to very low-certainty evidence suggests that vaccination may result in minimal to no important differences compared to no vaccination in all assessed maternal and infant safety outcomes from 26 fewer to 17 more events per 1000 pregnant persons, and 13 fewer to 9 more events per 1000 neonates, respectively. We found statistically significant reductions in emergency cesarean deliveries (9%) with mRNA vaccines, and in stillbirth (75-83%) with mRNA/viral vector vaccines. Low to very low-certainty evidence suggests that vaccination during pregnancy with mRNA vaccines may reduce severe cases or hospitalizations in pregnant persons with COVID-19 (72%; 95% confidence interval [CI] 42-86), symptomatic COVID-19 (78%; 95% CI 21-94), and virologically confirmed SARS-CoV-2 infection (82%; 95% CI 39-95). Reductions were lower with other vaccine types and during Omicron variant dominance than Alpha and Delta dominance. Infants also presented with fewer severe cases or hospitalizations due to COVID-19 and laboratory-confirmed SARS-CoV-2 infection (64%; 95% CI 37-80 and 66%; 95% CI 37-81, respectively). CONCLUSIONS: We found a large body of evidence supporting the safety and effectiveness of COVID-19 vaccines during pregnancy. While the certainty of evidence is not high, it stands as the most reliable option available, given the current absence of pregnant individuals in clinical trials. Results are shared in near real time in an accessible and interactive format for scientists, decision makers, clinicians, and the general public. This living systematic review highlights the relevance of continuous vaccine safety and effectiveness monitoring, particularly in at-risk populations for COVID-19 impact such as pregnant persons, during the introduction of new vaccines. CLINICAL TRIAL REGISTRATION: PROSPERO: CRD42021281290.

A Prediction Nomogram for Fractured Vertebra Recollapse After Posterior Reduction and Pedicle Screw Fixation in Thoracolumbar Fractures.

OBJECTIVE: This study aimed to establish a predictive nomogram model for recollapse of fractured vertebra after posterior pedicle screw fixation in thoracolumbar fractures (TLFs). METHODS: Patients undergoing posterior pedicle screw fixation for TLFs at our hospital between January 2016 and December 2021 were retrospectively reviewed. Patients were divided into 2 groups according to the presence or absence of recollapse of the fractured vertebra at the final follow-up. The predictors for fractured vertebra recollapse were identified by univariate and multivariable logistic regression analysis, and a nomogram model was developed. The prediction performance and internal validation were established. RESULTS: A total of 224 patients were included in this study. Of these, 46 (20.5%) patients developed recollapse of fractured vertebra. Age, thoracic and lumbar injury severity score, screw distribution in the fractured vertebra, and anterior vertebral height compression ratio were associated with vertebral recollapse. These predictors were used to construct a predictive nomogram. The area under the receiver operating characteristic curve of the nomogram model was 0.891. The concordance index was 0.891, and it was 0.877 with bootstrapping validation. The calibration curves and decision curve analysis also suggested that the nomogram model had excellent predictive performances for fractured vertebra recollapse. CONCLUSIONS: A clinical nomogram incorporating 4 variables was constructed to predict fractured vertebra recollapse after posterior pedicle screw fixation for TLFs. The nomogram demonstrated good calibration and discriminative abilities, which may help clinicians to make better treatment decisions.

ExtraCorporeal Membrane Oxygenation in the therapy for REfractory Septic shock with Cardiac function Under Estimated (ECMO-RESCUE): study protocol for a prospective, multicentre, non-randomised cohort study.

INTRODUCTION: Severe septic cardiomyopathy (SCM) is one of the main causes of refractory septic shock (RSS), with a high mortality. The application of venoarterial extracorporeal membrane oxygenation (ECMO) to support the impaired cardiac function in patients with septic shock remains controversial. Moreover, no prospective studies have been taken to address whether venoarterial ECMO treatment could improve the outcome of patients with sepsis-induced cardiogenic shock. The objective of this study is to assess whether venoarterial ECMO treatment can improve the 30-day survival rate of patients with sepsis-induced refractory cardiogenic shock. METHODS AND ANALYSIS: ExtraCorporeal Membrane Oxygenation in the therapy for REfractory Septic shock with Cardiac function Under Estimated is a prospective, multicentre, non-randomised, cohort study on the application of ECMO in SCM. At least 64 patients with SCM and RSS will be enrolled in an estimated ratio of 1:1.5. Participants taking venoarterial ECMO during the period of study are referred to as cohort 1, and patients receiving only conventional therapy without ECMO belong to cohort 2. The primary outcome is survival in a 30-day follow-up period. Other end points include survival to intensive care unit (ICU) discharge, hospital survival, 6-month survival, quality of life for long-term survival (EQ-5D score), successful rate of ECMO weaning, long-term survivors' cardiac function, the number of days alive without continuous renal replacement therapy, mechanical ventilation and vasopressor, ICU and hospital length of stay, the rate of complications potentially related to ECMO treatment. ETHICS AND DISSEMINATION: The trial has been approved by the Clinical Research and Application Institutional Review Board of the Second Affiliated Hospital of Guangzhou Medical University (2020-hs-51). Participants will be screened and enrolled from ICU patients with septic shock by clinicians, with no public advertisement for recruitment. Results will be disseminated in research journals and through conference presentations. TRIAL REGISTRATION NUMBER: NCT05184296.

Phthalate exposure and subfecundity in preconception couples: A nested case-control study.

BACKGROUND: Phthalates (PAEs) are endocrine-disrupting chemicals ubiquitously found in the environment. This study aimed to examine the association between exposure of PAEs and subfecundity in preconception couples. METHODS: This is a nested case-control study based on preconception cohort. Preconception couples with intention to conceive were enrolled and followed up until a clinically confirmed pregnancy or 12 menstrual cycles of preparation for conception. A total of 107 couples with subfecundity- time to pregnancy (TTP) more than 12 menstrual cycles, and 144 couples ≤12 cycles were included in the analysis. The levels of PAE metabolites in one spot urine samples were detected and compared between the groups. The weighted quantile sum (WQS) regression model and Bayesian kernel machine regression (BKMR) model were used to examine the joint effects of couples' exposure to PAEs on subfecundity. RESULTS: Using the multivariate binary logistic regression model, compared to the lowest quartile of urinary ∑PAEs concentration group, both preconception females (aOR=2.42, 95% CI: 1.10-5.30, p=0.027) and males (aOR=2.99, 95% CI: 1.36-6.58, p=0.006) in the highest quartile group had an increased risk of subfecundity, and a dose-response relationship was observed between PAEs and the risk of subfecundity. The WQS analyses found that co-exposure to PAE mixture was a risk factor for subfecundity in preconception female (aOR=1.76, 95% CI: 1.38-2.26, p<0.001), male (aOR=1.58, 95% CI: 1.20-2.08, p=0.001), and couple (aOR=2.39, 95% CI: 1.61-3.52, p<0.001). The BKMR model found a positive combined effect of mixed exposure to PAEs on the risk of subfecundity. CONCLUSIONS: PAEs increase the risk of subfecundity in preconception couples. Our research reinforced the need of monitoring PAE exposure for the purpose of improving human reproductive health.

Non-target screening and prioritization of organic contaminants in seawater desalination and their ecological risk assessment.

The impact of desalination brine on the marine environment is a global concern. Regarding this, salinity is generally accepted as the major environmental factor in desalination concentrate. However, recent studies have shown that the influence of organic contaminants in brine cannot be ignored. Therefore, a non-targeted screening method based on comprehensive two-dimensional gas chromatography-quadrupole mass spectrometry (GC × GC-qMS) was developed for identifying organic contaminants in the desalination brine. A total of 404 compounds were tentatively identified from four seawater desalination plants (three reverse osmosis plants and one multiple effect distillation plant) in China. The identified compounds were prioritized based on their persistence, bioaccumulation, ecotoxicity, usage, and detection frequency. Twenty-one (21) compounds (seven phthalates, ten pesticides, four trihalomethanes) were then selected for further quantitative analysis and ecological risk assessment, including compounds from the priority list along with substances from the same chemical classes. Ecologically risky substances in brine include diisobutylphthalate and bis(2-Ethylhexyl) phthalate, atrazine and acetochlor, and bromoform. Most of the contaminants come from raw seawater, and no high risk contaminants introduced by the desalination process have been found except for disinfection by-products. In brine discharge management, people believed that all pollution in raw seawater was concentrated by desalination process. This study shows that not all pollutants are concentrated during the desalination process. In this study, the total concentration of pesticide in the brine increased by 58.42%. The concentration of ∑PAEs decreased by 13.65% in reverse osmosis desalination plants and increased by 10.96% in the multi-effect distillation plant. The concentration of trihalomethane increased significantly in the desalination concentrate. The change in the concentration of pollutants in the desalination concentrate was related to the pretreatment method and the chemical characteristics of the contaminants. The method and results given in this study hinted a new idea to identify and control the environmental impact factors of brine.

The association between preconception cannabis use and gestational diabetes mellitus: The Preconception Period Analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium.

BACKGROUND: The metabolic changes that ultimately lead to gestational diabetes mellitus (GDM) likely begin before pregnancy. Cannabis use might increase the risk of GDM by increasing appetite or promoting fat deposition and adipogenesis. OBJECTIVES: We aimed to assess the association between preconception cannabis use and GDM incidence. METHODS: We analysed individual-level data from eight prospective cohort studies. We identified the first, or index, pregnancy (lasting ≥20 weeks of gestation with GDM status) after cannabis use. In analyses of pooled individual-level data, we used logistic regression to estimate study-type-specific odds ratios (OR) and 95% confidence intervals (CI), adjusting for potential confounders using random effect meta-analysis to combine study-type-specific ORs and 95% CIs. Stratified analyses assessed potential effect modification by preconception tobacco use and pre-pregnancy body mass index (BMI). RESULTS: Of 17,880 participants with an index pregnancy, 1198 (6.7%) were diagnosed with GDM. Before the index pregnancy, 12.5% of participants used cannabis in the past year. Overall, there was no association between preconception cannabis use in the past year and GDM (OR 0.97, 95% CI 0.79, 1.18). Among participants who never used tobacco, however, those who used cannabis more than weekly had a higher risk of developing GDM than those who did not use cannabis in the past year (OR 2.65, 95% CI 1.15, 6.09). This association was not present among former or current tobacco users. Results were similar across all preconception BMI groups. CONCLUSIONS: In this pooled analysis of preconception cohort studies, preconception cannabis use was associated with a higher risk of developing GDM among individuals who never used tobacco but not among individuals who formerly or currently used tobacco. Future studies with more detailed measurements are needed to investigate the influence of preconception cannabis use on pregnancy complications.

Individualized 3D-printed navigation template-assisted tension band wiring for olecranon fractures.

PURPOSE: 3D printing techniques guide precision medicine and show great development potential in clinical applications. The purpose of this study was to compare the clinical outcomes of 3D-printed navigation templates versus free-hand in tension band wiring (TBW) procedures for olecranon fractures. METHODS: Patients who underwent TBW due to Mayo type II olecranon fractures between January 2019 and December 2021 in our hospital were prospectively enrolled in the study. The patients were divided into the 3D printed navigation template guiding TBW group (3D printed group) and the free-hand TBW group (free-hand group). The primary endpoint of this study was the success rate of the bicortical placement of Kirschner wires (K-wires). Times of intraoperative fluoroscopy, operation times, complications, VAS scores, and Mayo Elbow Performance Scores (MEPS) were analyzed as the secondary outcomes measure. RESULTS: The success rate of the bicortical placement of K-wires was 85.7% in the 3D Printed group was significantly higher than the free-hand group (60%). There were fewer times of intraoperative fluoroscopy in the 3D Printed group (1.43 ± 0.51) than that in the free-hand group (2.60 ± 1.00) with statistical significance (P < 0.05). At the date of the last follow-up, four patients suffer from pain and skin injury at the K-wires insertion site in the 3D Printed group and 14 patients in the free-hand group, a significant difference between the two groups (P < 0.05). No statistically significant differences were found in operation time, VAS scores, and MEPS between the two groups. CONCLUSIONS: The individualized 3D-printed navigation template-assisted TBW demonstrated good accuracy and resulted in reduced times of intraoperative fluoroscopy and complication compared to the free-hand TBW for olecranon fractures.

Outcomes of different zero-profile spacers in the treatment of two-level cervical degenerative disk disease.

PURPOSE: The purpose of this study was to analyze the clinical and radiological outcomes of two different zero-profile spacers (ROI-C and anchor-C) in contiguous two-level ACDF for CDDD patients. METHODS: We retrospectively analyzed patients who underwent contiguous two-level ACDF due to CDDD between January 2015 and December 2020 in our hospital. Patients who received ROI-C and anchor-C were included as the study groups, and those who underwent plate-cage construct (PCC) were included as the control group. The primary outcome measures were radiographical parameters, and the secondary outcome measures were dysphagia, JOA scores and VAS scores for these patients. RESULTS: A total of 91 patients were enrolled in the study; there were 31, 21 and 39 patients in the ROI-C, anchor-C and PCC groups, respectively. The mean follow-up duration was 24.52 months (range, 18-48 months) in the ROI-C group, 24.38 months (range, 16-52 months) in the anchor-C group and 25.18 months (range, 15-54 months) in the PCC group. The loss of the intervertebral space height and cage subsidence rate in the ROI-C group were significantly higher than those in the anchor-C group and PCC group at the final follow-up (P < 0.05). The ROI-C group showed a lower incidence of adjacent segment degeneration than the anchor-C group and PCC group, but the difference was not significant. The fusion rates were not different among these three groups. The early dysphagia rate was significantly lower in the patients with zero-profile spacers than in the PCC group (P < 0.05), but the difference was not significant at the last follow-up. No relevant differences were found in the JOA scores and VAS scores. CONCLUSIONS: Zero-profile spacers showed promising clinical outcomes in CDDD patients having contiguous two-level ACDF. However, ROI-C resulted in a higher intervertebral space height loss and a higher cage subsidence rate than anchor-C during the follow-up.

Clinical outcomes and prediction nomogram model for postoperative hemoglobin < 80 g/L in patients following primary lumbar interbody fusion surgery.

OBJECTIVE: To analyze the association between different postoperative hemoglobin (Hb) levels and postoperative outcomes in patients who have undergone primary lumbar interbody fusion, and to investigate the risk factors and establish a predictive nomogram mode for postoperative Hb < 80 g/L. METHODS: We retrospectively analyzed 726 cases who underwent primary lumbar interbody fusion surgery between January 2018 and December 2021in our hospital. All patients were divided into three groups according to the postoperative Hb levels (< 70 g/L, 70-79 g/L, ≥ 80 g/L). The postoperative outcomes among the three groups were compared, and the risk factors for postoperative Hb < 80 g/L were identified by univariate and multivariable logistic regression analysis. Based on these independent predictors, a nomogram model was developed. Predictive discriminative and accuracy ability of the predicting model was assessed using the concordance index (C-index) and calibration plot. Clinical application was validated using decision curve analysis. Internal validation was performed using the bootstrapping validation. RESULTS: Patients with postoperative Hb < 80 g/L had higher rates of postoperative blood transfusion, a greater length of stay, higher rates of wound complications, and higher hospitalization costs than those with postoperative Hb ≥ 80 g/L. Preoperative Hb, preoperative platelets, fusion segments, body mass index, operation time, and intraoperative blood loss independently were associated with postoperative Hb < 80 g/L. Intraoperative blood salvage was found to be a negative predictor for postoperative Hb < 80 g/L (OR, 0.21 [95% CI 0.09-0.50]). The area under the curve of the nomogram model was 0.950. After internal validations, the C-index of the model was 0.939. The DCA and calibration curve suggested that the nomogram model had a good consistency and clinical utility. CONCLUSIONS: Postoperative Hb < 80 g/L in patients following primary lumbar interbody fusion surgery increased blood transfusions requirement and was independently associated with poor outcomes. A novel nomogram model was established and could conveniently predict the risk of postoperative Hb < 80 g/L in patients after this type of surgery.

Safety of COVID-19 vaccines during pregnancy: A systematic review and meta-analysis.

BACKGROUND: Assessment of COVID-19 vaccines safety during pregnancy is urgently needed. METHODS: We conducted a systematic review and meta-analysis to evaluate the safety of COVID-19 vaccines, including their components and technological platforms used in other vaccines during pregnancy and animal studies to complement direct evidence. We searched literature databases from its inception to September 2021 without language restriction, COVID-19 vaccine websites, and reference lists of other systematic reviews and the included studies. Pairs of reviewers independently selected, data extracted, and assessed the risk of bias of the studies. Discrepancies were resolved by consensus. (PROSPERO CRD42021234185). RESULTS: We retrieved 8,837 records from the literature search; 71 studies were included, involving 17,719,495 pregnant persons and 389 pregnant animals. Most studies (94%) were conducted in high-income countries, were cohort studies (51%), and 15% were classified as high risk of bias. We identified nine COVID-19 vaccine studies, seven involving 309,164 pregnant persons, mostly exposed to mRNA vaccines. Among non-COVID-19 vaccines, the most frequent exposures were AS03 and aluminum-based adjuvants. A meta-analysis of studies that adjusted for potential confounders showed no association with adverse outcomes, regardless of the vaccine or the trimester of vaccination. Neither the reported rates of adverse pregnancy outcomes nor reactogenicity exceeded expected background rates, which was the case for ASO3- or aluminum-adjuvanted non-COVID-19 vaccines in the proportion meta-analyses of uncontrolled studies/arms. The only exception was postpartum hemorrhage after COVID-19 vaccination (10.40%; 95% CI: 6.49-15.10%), reported by two studies; however, the comparison with non-exposed pregnant persons, available for one study, found non-statistically significant differences (adjusted OR 1.09; 95% CI 0.56-2.12). Animal studies showed consistent results with studies in pregnant persons. CONCLUSION: We found no safety concerns for currently administered COVID-19 vaccines during pregnancy. Additional experimental and real-world evidence could enhance vaccination coverage. Robust safety data for non-mRNA-based COVID-19 vaccines are still needed.

Data collection systems for active safety surveillance of vaccines during pregnancy in low- and middle-income countries: developing and piloting an assessment tool (VPASS).

BACKGROUND: There is an urgent need for active safety surveillance to monitor vaccine exposure during pregnancy in low- and middle-income countries (LMICs). Existing maternal, newborn, and child health (MNCH) data collection systems could serve as platforms for post-marketing active surveillance of maternal immunization safety. To identify sites using existing systems, a thorough assessment should be conducted. Therefore, this study had the objectives to first develop an assessment tool and then to pilot this tool in sites using MNCH data collection systems through virtual informant interviews. METHODS: We conducted a rapid review of the literature to identify frameworks on population health or post-marketing drug surveillance. Four frameworks that met the eligibility criteria were identified and served to develop an assessment tool capable of evaluating sites that could support active monitoring of vaccine safety during pregnancy. We conducted semi-structured interviews in six geographical sites using MNCH data collection systems (DHIS2, INDEPTH, and GNMNHR) to pilot domains included in the assessment tool. RESULTS: We developed and piloted the "VPASS (Vaccines during Pregnancy - sites supporting Active Safety Surveillance) assessment tool" through interviews with nine stakeholders, including central-level systems key informants and site-level managers from DHIS2 and GNMNHR; DHIS2 in Kampala (Uganda) and Kigali (Rwanda); GNMNHR from Belagavi (India) and Lusaka (Zambia); and INDEPTH from Nanoro (Burkina Faso) and Manhica (Mozambique). The tool includes different domains such as the system's purpose, the scale of implementation, data capture and confidentiality, type of data collected, the capability of integration with other platforms, data management policies and data quality monitoring. Similarities among sites were found regarding some domains, such as data confidentiality, data management policies, and data quality monitoring. Four of the six sites met some domains to be eligible as potential sites for active surveillance of vaccinations during pregnancy, such as a routine collection of MNCH individual data and the capability of electronically integrating individual MNCH outcomes with information related to vaccine exposure during pregnancy. Those sites were: Rwanda (DHIS2), Manhica (IN-DEPTH), Lusaka (GNMNHR), and Belagavi (GNMNHR). CONCLUSION: This study's findings should inform the successful implementation of active safety surveillance of vaccines during pregnancy by identifying and using active individual MNCH data collection systems in LMICs.

Safety, immunogenicity, and effectiveness of COVID-19 vaccines for pregnant persons: A protocol for systematic review and meta analysis.

INTRODUCTION: Numerous vaccines have been evaluated and approved for coronavirus disease 2019 (COVID-19). Since pregnant persons have been excluded from most clinical trials of COVID-19 vaccines, sufficient data regarding the safety of these vaccines for the pregnant person and their fetus have rarely been available at the time of product licensure. However, as COVID-19 vaccines have been deployed, data on the safety, reactogenicity, immunogenicity, and efficacy of COVID-19 vaccines for pregnant persons and neonates are becoming increasingly available. A living systematic review and meta-analysis of the safety and effectiveness of COVID-19 vaccines for pregnant persons and newborns could provide the information necessary to help guide vaccine policy decisions. METHODS AND ANALYSIS: We aim to conduct a living systematic review and meta-analysis based on biweekly searches of medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries to systematically identify relevant studies of COVID-19 vaccines for pregnant persons. Pairs of reviewers will independently select, extract data, and conduct risk of bias assessments. We will include randomized clinical trials, quasi-experimental studies, cohort, case-control, cross-sectional studies, and case reports. Primary outcomes will be the safety, efficacy, and effectiveness of COVID-19 vaccines in pregnant persons, including neonatal outcomes. Secondary outcomes will be immunogenicity and reactogenicity. We will conduct paired meta-analyses, including prespecified subgroup and sensitivity analyses. We will use the grading of recommendations assessment, development, and evaluation approach to evaluate the certainty of evidence.

A 3D culture system improves the yield of MSCs-derived extracellular vesicles and enhances their therapeutic efficacy for heart repair.

BACKGROUND: Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs), due to their inner functional substances, have shown great value in treating acute myocardial infarction (AMI). However, their clinical application is limited by a low yield. In the present study, we cultured EVs using a hollow fiber bioreactor-based three-dimensional (3D) system, and assessed their therapeutic effectiveness on AMI. METHODS: The MSCs separated from fresh human umbilical cord were planted into the flasks of two systems: two-dimensional (2D) culture and hollow-fiber-bioreactor based 3D culture. EVs were extracted from the culture supernatants. Characteristics and yields of EVs from two culture systems, namely 2D-EVs and 3D-EVs, were compared. A rat model of AMI was built up to assess their therapeutic efficacy on AMI. RESULTS: The yield of 3D-EVs was higher, with biofunctions similar to those of 2D-EVs. 3D-EVs repressed the apoptosis of cardiomyocytes, facilitated angiogenesis, and regulated the transition of macrophage subpopulations after myocardial infarction, and eventually improved cardiac function in the AMI rats. CONCLUSIONS: The hollow fiber 3D culture system can increase the yield of MSCs-derived EVs to render a strong cardioprotective effect in AMI rats.

Alpinetin inhibits neuroinflammation and neuronal apoptosis via targeting the JAK2/STAT3 signaling pathway in spinal cord injury.

BACKGROUND: A growing body of research shows that drug monomers from traditional Chinese herbal medicines have antineuroinflammatory and neuroprotective effects that can significantly improve the recovery of motor function after spinal cord injury (SCI). Here, we explore the role and molecular mechanisms of Alpinetin on activating microglia-mediated neuroinflammation and neuronal apoptosis after SCI. METHODS: Stimulation of microglia with lipopolysaccharide (LPS) to simulate neuroinflammation models in vitro, the effect of Alpinetin on the release of pro-inflammatory mediators in LPS-induced microglia and its mechanism were detected. In addition, a co-culture system of microglia and neuronal cells was constructed to assess the effect of Alpinetin on activating microglia-mediated neuronal apoptosis. Finally, rat spinal cord injury models were used to study the effects on inflammation, neuronal apoptosis, axonal regeneration, and motor function recovery in Alpinetin. RESULTS: Alpinetin inhibits microglia-mediated neuroinflammation and activity of the JAK2/STAT3 pathway. Alpinetin can also reverse activated microglia-mediated reactive oxygen species (ROS) production and decrease of mitochondrial membrane potential (MMP) in PC12 neuronal cells. In addition, in vivo Alpinetin significantly inhibits the inflammatory response and neuronal apoptosis, improves axonal regeneration, and recovery of motor function. CONCLUSION: Alpinetin can be used to treat neurodegenerative diseases and is a novel drug candidate for the treatment of microglia-mediated neuroinflammation.

Multiparametric ultrasound for the assessment of testicular lesions with negative tumoral markers / 亚洲男科学杂志(英文版)

The purpose of this study was to evaluate the diagnostic performance of multiparametric ultrasound (mpUS; grayscale US, color Doppler US, strain elastography, and contrast-enhanced US) in the assessment of testicular lesions with negative tumoral markers. MpUS imaging data, patient age, serum tumor markers, scrotal pain, cryptorchidism, and related clinical information were retrospectively collected for patients who underwent mpUS examination between January 2013 and December 2019. Histologic results or follow-up examinations were used as the reference standard. In total, 83 lesions from 79 patients were included in the analysis. Fifty-six patients were finally diagnosed with benign tumors, and 23 patients were ultimately diagnosed with malignant tumors. Chi-square tests or Fisher's exact tests were used to assess the difference between the two groups. Stepwise multivariate logistic regression analysis showed that lesion diameter (odds ratio [OR] = 1.072, P = 0.005), vascularization on color Doppler US (OR = 4.066, P = 0.001), and hyperenhancement during the early phase (OR = 6.465, P = 0.047) were significant independent risk factors for malignancy; however, when compared with neoplastic lesions, pain (OR = 0.136, P < 0.001), absence of vascularization on color Doppler US (OR = 1.680, P = 0.042), and nonenhancement during the late phase (OR = 3.461, P = 0.031) were strongly associated with nonneoplastic lesions. MpUS features are useful for differentiating testicular lesions with negative tumoral markers and improving the preoperative diagnosis, which may avoid inappropriate radical orchiectomy.

Added value of shear-wave elastography in the prediction of extracapsular extension and seminal vesicle invasion before radical prostatectomy / 亚洲男科学杂志(英文版)

The purpose of this study was to analyze the value of transrectal shear-wave elastography (SWE) in combination with multivariable tools for predicting adverse pathological features before radical prostatectomy (RP). Preoperative clinicopathological variables, multiparametric magnetic resonance imaging (mp-MRI) manifestations, and the maximum elastic value of the prostate (Emax) on SWE were retrospectively collected. The accuracy of SWE for predicting adverse pathological features was evaluated based on postoperative pathology, and parameters with statistical significance were selected. The diagnostic performance of various models, including preoperative clinicopathological variables (model 1), preoperative clinicopathological variables + mp-MRI (model 2), and preoperative clinicopathological variables + mp-MRI + SWE (model 3), was evaluated with area under the receiver operator characteristic curve (AUC) analysis. Emax was significantly higher in prostate cancer with extracapsular extension (ECE) or seminal vesicle invasion (SVI) with both P < 0.001. The optimal cutoff Emax values for ECE and SVI were 60.45 kPa and 81.55 kPa, respectively. Inclusion of mp-MRI and SWE improved discrimination by clinical models for ECE (model 2 vs model 1, P = 0.031; model 3 vs model 1, P = 0.002; model 3 vs model 2, P = 0.018) and SVI (model 2 vs model 1, P = 0.147; model 3 vs model 1, P = 0.037; model 3 vs model 2, P = 0.134). SWE is valuable for identifying patients at high risk of adverse pathology.

Transrectal ultrasound examination of prostate cancer guided by fusion imaging of multiparametric MRI and TRUS: avoiding unnecessary mpMRI-guided targeted biopsy / 亚洲男科学杂志(英文版)

The purpose of this study was to explore transrectal ultrasound (TRUS) findings of prostate cancer (PCa) guided by multiparametric magnetic resonance imaging (mpMRI) and to improve the Prostate Imaging Reporting and Data System (PI-RADS) system for avoiding unnecessary mpMRI-guided targeted biopsy (TB). From January 2018 to October 2019, fusion mpMRI and TRUS-guided biopsies were performed in 162 consecutive patients. The study included 188 suspicious lesions on mpMRI in 156 patients, all of whom underwent mpMRI-TRUS fusion imaging-guided TB and 12-core transperineal systematic biopsy (SB). Univariate analyses were performed to investigate the relationship between TRUS features and PCa. Then, logistic regression analysis with generalized estimating equations was performed to determine the independent predictors of PCa and obtain the fitted probability of PCa. The detection rates of PCa based on TB alone, SB alone, and combined SB and TB were 55.9% (105 of 188), 52.6% (82 of 156), and 62.8% (98 of 156), respectively. The significant predictors of PCa on TRUS were hypoechogenicity (odds ratio [OR]: 9.595, P = 0.002), taller-than-wide shape (OR: 3.539, P = 0.022), asymmetric vascular structures (OR: 3.728, P = 0.031), close proximity to capsule (OR: 3.473, P = 0.040), and irregular margins (OR: 3.843, P = 0.041). We propose subgrouping PI-RADS score 3 into categories 3a, 3b, 3c, and 3d based on different numbers of TRUS predictors, as the creation of PI-RADS 3a (no suspicious ultrasound features) could avoid 16.7% of mpMRI-guided TBs. Risk stratification of PCa with mpMRI-TRUS fusion imaging-directed ultrasound features could avoid unnecessary mpMRI-TBs.

Ugi Cascade Sequence for the Construction of 3-Pyrrolin-2-one Scaffolds: Anti-proliferation in Prostate Cancer Cells.

Herein, a small series of 3-pyrrolin-2-ones was efficiently synthesized through a three-step Ugi cascade sequence. This method features readily available substrates, simple aqueous workup procedures and good yields, dramatically improving generality of reaction. Importantly, the newly product N-benzyl-2-(3-(4-chlorophenyl)-4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-2-phen-ylacetamide exhibited potent anti-proliferation in prostate cancer cell line through G1/S cell cycle arrest and targeted in PI3K/AKT/TSC2 signal pathway.