HMGB1/TREM2 positive feedback loop drives the development of radioresistance and immune escape of glioblastoma by regulating TLR4/Akt signaling.

BACKGROUND: Radioresistance and immune escape are crucial reasons for unsatisfactory therapeutic effects of glioblastoma (GBM). Although triggering receptor expressed on myeloid cells-2 (TREM2) involved in forming immunosuppressive microenvironment, but the underlying mechanism and its roles in mediating cancer radioresistance remain unclear, moreover, the efficient delivery of drugs targeting TREM2 to GBM encounters serious challenges. Hence, this study aimed to elucidate the effect and mechanisms of targeted TREM2 silencing on reversing the radioresistance and immune escape of GBM aided by a glutathione-responsive biomimetic nanoparticle (NP) platform. METHODS: Radioresistant GBM cell lines and TREM2 stable knockdown GBM cell lines were firstly established. RNA sequencing, colony formation assay, western blot, enzyme-linked immunosorbent assay and co-immunoprecipitation assay were used to detect the molecular mechanisms of TREM2 in regulating the radioresistance and immune escape of GBM. The glutathione-responsive biomimetic NP, angiopep-2 (A2)- cell membrane (CM)-NP/siTREM2/spam1, was then constructed to triply and targeted inhibit TREM2 for in vivo study. Orthotopic GBM-bearing mouse models were established to evaluate the anti-GBM effect of TREM2 inhibition, multiplex immunofluorescence assay was conducted to detect the infiltration of immune cells. RESULTS: TREM2 was a regulator in accelerating the radioresistance and immune escape of GBM through participating in DNA damage repair and forming a positive feedback loop with high mobility group box 1 (HMGB1) to cascade the activation of Toll-like receptor 4 (TLR4)/protein kinase B (Akt) signaling. A2-CM-NP/siTREM2/spam1 was successfully synthesized with excellent passive targeting, active targeting and homologous targeting, and the in vivo results exhibited its remarkable anti-GBM therapeutic effect through promoting the infiltration of type 1 helper T cells and CD8+T cells, reducing the infiltration of type 2 helper T cells and regulatory T cells, repolarizing macrophages to M1-type, and decreasing the secretion of pro-tumor and immunosuppressive cytokines. CONCLUSIONS: Targeting TREM2 therapy is a promising avenue for optimizing radiotherapy and immunotherapy to improve the prognosis of GBM patients.

Platelet Transfusion in Cardiac Surgery: An Entropy-Balanced, Weighted, Multicenter Analysis.

BACKGROUND: Platelet transfusion is common in cardiac surgery, but some studies have suggested an association with harm. Accordingly, we investigated the association of perioperative platelet transfusion with morbidity and mortality. METHODS: We conducted a retrospective analysis of prospectively collected data from the Australian Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database. We included consecutive adults from 2005 to 2018 across 40 centers. We used inverse probability of treatment weighting via entropy balancing to investigate the association of perioperative platelet transfusion with our 2 primary outcomes, operative mortality (composite of both 30-day and in-hospital mortality) and 90-day mortality, as well as multiple other clinically relevant secondary outcomes. RESULTS: Among 119,132 eligible patients, 25,373 received perioperative platelets and 93,759 were considered controls. After entropy balancing, platelet transfusion was associated with reduced operative mortality (odds ratio [OR], 0.63; 99% confidence interval [CI], 0.47-0.84; P < .0001) and 90-day mortality (OR, 0.66; 99% CI, 0.51-0.85; P < .0001). Moreover, it was associated with reduced odds of deep sternal wound infection (OR, 0.57; 99% CI, 0.36-0.89; P = .0012), acute kidney injury (OR, 0.84; 99% CI, 0.71-0.99; P = .0055), and postoperative renal replacement therapy (OR, 0.71; 99% CI, 0.54-0.93; P = .0013). These positive associations were observed despite an association with increased odds of return to theatre for bleeding (OR, 1.55; 99% CI, 1.16-2.09; P < .0001), pneumonia (OR, 1.26; 99% CI, 1.11-1.44; P < .0001), intubation for longer than 24 hours postoperatively (OR, 1.13; 99% CI, 1.03-1.24; P = .0012), inotrope use for >4 hours postoperatively (OR, 1.14; 99% CI, 1.11-1.17; P < .0001), readmission to hospital within 30 days of surgery (OR, 1.22; 99% CI, 1.11-1.34; P < .0001), as well as increased drain tube output (adjusted mean difference, 89.2 mL; 99% CI, 77.0 mL-101.4 mL; P < .0001). CONCLUSIONS: In cardiac surgery patients, perioperative platelet transfusion was associated with reduced operative and 90-day mortality. Until randomized controlled trials either confirm or refute these findings, platelet transfusion should not be deliberately avoided when considering odds of death.

A single-center, open label, randomized, controlled study of hydroxychloroquine sulfate in the treatment of low risk PLA2R-associated membranous nephropathy.

OBJECTIVE: To evaluate the efficacy and safety of hydroxychloroquine sulfate (HCQ) in the treatment of low risk phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN). METHODS: A total of 110 patients with low risk PLA2R-associated MN were included in the study. Patients who met the inclusion and exclusion criteria were assigned randomly to two groups: the HCQ treatment group and the control group. The control group received standard supportive treatment according to the guidelines, while the HCQ treatment group received HCQ in addition to the supportive treatment. The clinical data of the patients were analyzed, with comparisons made at baseline and during the six-month follow-up period. Any adverse reactions were recorded. RESULTS: The baseline data were comparable between the HCQ treatment group and the control group. At the end of the six-month follow-up period, the reductions in urine protein excretion and serum PLA2R antibody titer were more notable in the HCQ treatment group than those in the control group, with these differences being statistically significant (p < 0.05). Compared to the control group, the HCQ treatment group had fewer patients who were converted from low risk to moderate-to-high risk (p = 0.084). There were also no severe adverse reactions in the HCQ treatment group. CONCLUSION: In patients with low risk PLA2R-associated MN, adequate supportive therapy combined with HCQ is superior to supportive therapy alone in controlling proteinuria and reducing serum PLA2R antibody titers. Additionally, our study demonstrated that the incidence of adverse reactions did not increase. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (Registration No.: ChiCTR1900021757, Date of registration: 2019-03-08).

Sex Differences in Opioid Administration After Cardiac Surgery.

OBJECTIVES: To assess whether there are sex-based differences in the administration of opioid analgesic drugs among inpatients after cardiac surgery. DESIGN: A retrospective cohort study. SETTING: At a tertiary academic referral center. PARTICIPANTS: Adult patients who underwent cardiac surgery from 2014 to 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the cumulative oral morphine equivalent dose (OMED) for the postoperative admission. Secondary outcomes were the daily difference in OMED and the administration of nonopioid analgesics. The authors developed multivariate regression models controlling for known confounders, including weight and length of stay. A total of 3,822 patients (1,032 women and 2,790 men) were included. The mean cumulative OMED was 139 mg for women and 180 mg for men, and this difference remained significant after adjustment for confounders (adjusted mean difference [aMD], -33.21 mg; 95% CI, -47.05 to -19.36 mg; p < 0.001). The cumulative OMED was significantly lower in female patients on postoperative days 1 to 5, with the greatest disparity observed on day 5 (aMD, -89.83 mg; 95% CI, -155.9 to -23.80 mg; p = 0.009). By contrast, women were more likely to receive a gabapentinoid (odds ratio, 1.91; 95% CI, 1.42-2.58; p < 0.001). The authors found no association between patient sex and the administration of other nonopioid analgesics or specific types of opioid analgesics. The authors found no association between patient sex and pain scores recorded within the first 48 hours after extubation, or the number of opioids administered in close proximity to pain assessments. CONCLUSIONS: Female sex was associated with significantly lower amounts of opioids administered after cardiac surgery.

Enhancement of Astaxanthin Bioaccessibility by Encapsulation in Liposomes: An In Vitro Study.

Astaxanthin was encapsulated in liposomes by a thin layer dispersion and ultrasound method using soybean phospholipid. The digestion properties of liposomes for encapsulating astaxanthin were investigated in light of particle size, size distribution, zeta potential, and microstructure during in vitro digestion as a function of time. These results exhibited that the average particle size increased gradually with liposomal vesicles retained round shapes and a fairly uniform distribution after passage through the simulated gastric fluid digestion. The result revealed that astaxanthin-loaded liposomes were stable in low pH conditions. It was also found that the mixed micelles formed in a simulated intestinal fluid. The zeta potential of astaxanthin-loaded liposomes had a decrease in negativity after digestion. In comparison with free astaxanthin, there was an appreciable increase in the bioaccessibility of astaxanthin after encapsulation in liposomes. This enhancement can be attributed to more soluble astaxanthin in the mixed micelles for astaxanthin-loaded liposomes. It indicated that the barrier of the liposomal bilayer could inhibit astaxanthin fading and leaking after encapsulation in liposomes. These results provide useful information for designing more stable delivery systems in the gastrointestinal tract and improving the bioaccessibility of lipophilic nutraceuticals.

Heterogeneous Dynamics of Sheared Particle-Laden Fluid Interfaces with Janus Particle Doping.

The formation of particle clusters can substantially modify the dynamics and mechanical properties of suspensions in both two and three dimensions. While it has been well established that large network-spanning clusters increase the rigidity of particle systems, it is still unclear how the presence of localized nonpercolating clusters affects the dynamics and mechanical properties of particle suspensions. Here, we introduce self-assembled localized particle clusters at a fluid-fluid interface by mixing a fraction of Janus particles in a monolayer of homogeneous colloids. Each Janus particle binds to a few nearby homogeneous colloids, resulting in numerous small clusters uniformly distributed across the interface. Using a custom magnetic rod interfacial stress rheometer, we apply linear oscillatory shear to the particle-laden fluid interface. By analyzing the local affine deformation of particles from optical microscopy, we show that particles in localized clusters experience substantially lower shear-induced stretching than their neighbors outside clusters. We hypothesize that such heterogeneous dynamics induced by particle clusters increase the effective surface coverage of particles, which in turn enhances the shear moduli of the interface, as confirmed by direct interfacial rheological measurements. Our study illustrates the microscopic dynamics of small clusters in a shear flow and reveals their profound effects on the macroscopic rheology of particle-laden fluid interfaces. Our findings open an avenue for designing interfacial materials with improved mechanical properties via the control of formation of localized particle clusters.

Engineering Double Sulfur-Vacancy in CoS1.097@MoS2 Core-Shell Heterojunctions for Hydrogen Evolution in a Wide pH Range.

Heterostructured nanomaterials have arisen as electrocatalysts with great potential for hydrogen evolution reaction (HER), considering their superiority in integrating different active components but are plagued by their insufficient active site density in a wide pH range. In this report, double sulfur-vacancy-decorated CoS1.097@MoS2 core-shell heterojunctions are designed, which contain a primary structure of hollow CoS1.097 nanocubes and a secondary structure of ultrathin MoS2 nanosheets. Taking advantage of the core-shell type heterointerfaces and double sulfur-vacancy, the CoS1.097@MoS2 catalyst exhibits pH-universal HER performance, achieving the overpotentials at 10 mA cm-2 of 190, 139, and 220 mV in 0.5 M H2SO4, 1.0 M KOH, and 1.0 M PBS, respectively. Systematic theoretical results show that the double sulfur-vacancy can endow the CoS1.097@MoS2 core-shell heterojunctions with promoted electron/mass transfer and enhanced reactive kinetics, thus boosting HER performance. This work clearly demonstrates an indispensable role of double sulfur-vacancy in enhancing the electrocatalytic HER performance of core-shell type heterojunctions under a wide pH operating condition.

The prognostic value of elevated neutrophil-lymphocyte ratio for cardiac surgery-associated acute kidney injury: A systematic review and meta-analysis.

BACKGROUND: Patients undergoing cardiac surgery are at significant risk of developing postoperative acute kidney injury (AKI). Neutrophil-lymphocyte ratio (NLR) is a widely available inflammatory biomarker which may be of prognostic value in this setting. METHODS: We conducted a systematic review and meta-analysis of studies reporting associations between perioperative NLR with postoperative AKI. We searched Medline, Embase and the Cochrane Library, without language restriction, from inception to May 2022 for relevant studies. We meta-analysed the reported odds ratios (ORs) with 95% confidence intervals (CIs) for both elevated preoperative and postoperative NLR with risk of postoperative AKI and need for renal replacement therapy (RRT). We conducted a meta-regression to explore inter-study statistical heterogeneity. RESULTS: Twelve studies involving 10,724 participants undergoing cardiac surgery were included, with eight studies being deemed at high risk of bias using PROBAST modelling. We found statistically significant associations between elevated preoperative NLR and postoperative AKI (OR 1.45, 95% CI 1.18-1.77), as well as postoperative need for RRT (OR 2.37, 95% CI 1.50-3.72). Postoperative NLR measurements were not of prognostic significance. CONCLUSIONS: Elevated preoperative NLR is a reliable inflammatory biomarker for predicting AKI following cardiac surgery.

The Prognostic Significance of Red Cell Distribution Width in Cardiac Surgery: A Systematic Review and Meta-Analysis.

RED CELL DISTRIBUTION WIDTH (RDW) is a routinely available biomarker of likely erythropoietic dysfunction, which may be associated with adverse outcomes after cardiac surgery. This systematic review and meta-analysis aimed to clarify the prognostic value of RDW in patients undergoing cardiac surgery. The authors searched MEDLINE, Embase, and the Cochrane Library from inception to May 10, 2022 for studies investigating the association between elevated RDW (as defined by the authors of included studies) and adverse outcomes after cardiac surgery. Herein, the authors extracted maximally adjusted hazard ratios (HRs) and odds ratios (ORs) with associated CIs, and pooled them using random-effects inverse- variance modeling. The authors explored interstudy heterogeneity using metaregression. The authors included 26 studies involving 48,092 patients who had undergone cardiac surgery. Elevated preoperative RDW was associated with long-term mortality (pooled HR 1.63, 95% CI 1.05-2.52), short-term mortality (pooled OR 2.16, 95% CI 1.21-3.87), acute kidney injury (AKI; pooled OR 1.30, 95% CI 1.19-1.41) and postoperative atrial fibrillation (POAF; pooled OR 1.44, 95% CI 1.05-1.96). Some studies suggested a significant association between preoperative RDW elevation and neurologic complications; however, their number was insufficient for meta-analysis. The postoperative RDW levels were less consistently reported and could not be meta-analyzed. In conclusion, the authors found that elevated preoperative RDW was associated with increased short- and long-term mortality, POAF, and AKI after cardiac surgery. Further research is needed to investigate its role in the risk stratification of patients undergoing cardiac surgery.

Platelet Transfusion After Cardiac Surgery.

OBJECTIVES: To investigate the independent association of platelet transfusion with hospital mortality and key relevant clinical outcomes in cardiac surgery. DESIGN: A single-center, propensity score-matched, retrospective, cohort study. SETTING: At an American tertiary teaching hospital data from the Medical Information Mart for Intensive Care III and IV databases from 2001 to 2019. PARTICIPANTS: Consecutive adults undergoing coronary artery bypass graft and/or cardiac valvular surgery. INTERVENTIONS: Platelet transfusion during perioperative intensive care unit (ICU) admission. MEASUREMENTS AND MAIN RESULTS: Overall, 12,043 adults met the study inclusion criteria. Of these, 1,621 (13.5%) received apheresis-leukoreduced platelets, with a median of 1.19 units per recipient (IQR: 0.93-1.19) at a median of 1.78 hours (IQR: 0.75-4.25) after ICU admission. The platelet count was measured in 1,176 patients (72.5%) before transfusion, with a median count of 120 × 109/L (IQR: 89.0-157.0), and only 53 (3.3%) had platelet counts below 50 × 109/L. After propensity matching of 1,046 platelet recipients with 1,046 controls, perioperative platelet transfusion carried no association with in-hospital mortality (odds ratio [OR]: 1.28; 99% CI: 0.49-3.35; p = 0.4980). However, it was associated with a pattern of decreased odds of suspected infection (eg, respiratory infection, urinary tract infection, septicaemia, or other; OR: 0.70; 99% CI: 0.50-0.97; p = 0.0050), days in the hospital (adjusted mean difference [AMD]: 0.86; 99% CI: -0.27 to 1.98; p = 0.048), or days in intensive care (AMD 0.83; 99% CI: -0.15 to 1.82; p = 0.0290). CONCLUSIONS: Platelet transfusion was not associated with hospital mortality, but it was associated with decreased odds of suspected infection and with shorter ICU and hospital stays.

Fresh frozen plasma transfusion after cardiac surgery.

INTRODUCTION: Fresh frozen plasma (FFP) transfusion in the intensive care unit (ICU) is commonly used to treat coagulopathy and bleeding in cardiac surgery, despite suggestion that it may increase the risk of morbidity and mortality through mechanisms such as fluid overload and infection. METHODS: We retrospectively studied consecutive adults undergoing cardiac surgery from the Medical Information Mart for Intensive Care III and IV databases. We applied propensity score matching to investigate the independent association of within-ICU FFP transfusion with mortality and other key clinical outcomes. RESULTS: Of our 12,043 adults who met inclusion criteria, 1585 (13.2%) received perioperative FFP with a median of 2.48 units per recipient (interquartile range [IQR]: 2.04, 4.33) at a median time of 1.83 h (IQR: 0.75, 3.75) after ICU admission. After propensity matching of 952 FFP recipients to 952 controls, we found no significant association between FFP use and hospital mortality (odds ratio (OR): 1.58; 99% confidence interval (CI): 0.57, 3.71), suspected infection (OR: 0.72; 99% CI: 0.49, 1.08), or acute kidney injury (OR: 1.23; 99% CI: 0.91, 1.67). However, FFP was associated with increased days in hospital (adjusted mean difference (AMD): 1.28; 99% CI: 0.27, 2.41; p = .0050), days in intensive care (AMD: 1.28; 99% CI: 0.27, 2.28; p = .0011), and chest tube output in millilitres up to 8 h after transfusion (AMD: 92.98; 99% CI: 52.22, 133.74; p < .0001). CONCLUSIONS: After propensity matching, FFP transfusion was not associated with increased hospital mortality, but was associated with increased length of stay and no decrease in bleeding in the early post-transfusion period.

Development of Terminator-Promoter Bifunctional Elements for Application in Saccharomyces cerevisiae Pathway Engineering.

The construction of a genetic circuit requires the substitution and redesign of different promoters and terminators. The assembly efficiency of exogenous pathways will also decrease significantly when the number of regulatory elements and genes is increased. We speculated that a novel bifunctional element with promoter and terminator functions could be created via the fusion of a termination signal with a promoter sequence. In this study, the elements from a Saccharomyces cerevisiae promoter and terminator were employed to design a synthetic bifunctional element. The promoter strength of the synthetic element is apparently regulated through a spacer sequence and an upstream activating sequence (UAS) with a ~5-fold increase, and the terminator strength could be finely regulated by the efficiency element, with a ~5-fold increase. Furthermore, the use of a TATA box-like sequence resulted in the adequate execution of both functions of the TATA box and the efficiency element. By regulating the TATA box-like sequence, UAS, and spacer sequence, the strengths of the promoter-like and terminator-like bifunctional elements were optimally fine-tuned with ~8-fold and ~7-fold increases, respectively. The application of bifunctional elements in the lycopene biosynthetic pathway showed an improved pathway assembly efficiency and higher lycopene yield. The designed bifunctional elements effectively simplified pathway construction and can serve as a useful toolbox for yeast synthetic biology.

Cryoprecipitate Transfusion After Cardiac Surgery.

OBJECTIVES: The association of cryoprecipitate transfusion with patient outcomes after cardiac surgery is unclear. We aimed to investigate the predictors of, and outcomes associated with, postoperative cryoprecipitate transfusion in cardiac surgery patients. METHODS: We used the Medical Information Mart for Intensive Care III and IV databases. We included adults undergoing cardiac surgery, and propensity score matched cryoprecipitate-treated patients to controls. Using the matched cohort, we investigated the association of cryoprecipitate use with clinical outcomes. The primary outcome was in-hospital mortality. Secondary outcomes were infection, acute kidney injury, intensive care unit length of stay, hospital length of stay, and chest tube output at 2-hour intervals. RESULTS: Of 12,043 eligible patients, 283 (2.35%) patients received cryoprecipitate. The median dose was 5.83 units (IQR 4.17-7.24) given at a median first transfusion time of 1.75 hours (IQR 0.73-4.46) after intensive care unit admission. After propensity scoring, we matched 195 cryoprecipitate recipients to 743 controls. Postoperative cryoprecipitate transfusion was not significantly associated with in-hospital mortality (odds ratio [OR] 1.10; 99% confidence interval [CI] 0.43-2.84; p=0.791), infection (OR 0.77; 99% CI 0.45-1.34; p=0.220), acute kidney injury (OR 1.03; 99% CI 0.65-1.62; p=0.876) or cumulative chest tube output (adjusted mean difference 8 hrs post transfusion, 11 mL; 99% CI -104 to 125; p=0.804). CONCLUSIONS: Although cryoprecipitate was typically given to sicker patients with more bleeding, its administration was not associated with worse outcomes. Large, multicentred studies are warranted to further elucidate cryoprecipitate's safety profile and patterns of use in cardiac surgery.

Crack patterns of drying dense bacterial suspensions.

Drying of bacterial suspensions is frequently encountered in a plethora of natural and engineering processes. However, the evaporation-driven mechanical instabilities of dense consolidating bacterial suspensions have not been explored heretofore. Here, we report the formation of two different crack patterns of drying suspensions of Escherichia coli (E. coli) with distinct motile behaviors. Circular cracks are observed for wild-type E. coli with active swimming, whereas spiral-like cracks form for immotile bacteria. Using the elastic fracture mechanics and the poroelastic theory, we show that the formation of the circular cracks is determined by the tensile nature of the radial drying stress once the cracks are initiated by the local order structure of bacteria due to their collective swimming. Our study demonstrates the link between the microscopic swimming behaviors of individual bacteria and the mechanical instabilities and macroscopic pattern formation of drying bacterial films. The results shed light on the dynamics of active matter in a drying process and provide useful information for understanding various biological processes associated with drying bacterial suspensions.

Elevated Cardiac Troponin to Detect Acute Cellular Rejection After Cardiac Transplantation: A Systematic Review and Meta-Analysis.

Cardiac troponin is well known as a highly specific marker of cardiomyocyte damage, and has significant diagnostic accuracy in many cardiac conditions. However, the value of elevated recipient troponin in diagnosing adverse outcomes in heart transplant recipients is uncertain. We searched MEDLINE (Ovid), Embase (Ovid), and the Cochrane Library from inception until December 2020. We generated summary sensitivity, specificity, and Bayesian areas under the curve (BAUC) using bivariate Bayesian modelling, and standardised mean differences (SMDs) to quantify the diagnostic relationship of recipient troponin and adverse outcomes following cardiac transplant. We included 27 studies with 1,684 cardiac transplant recipients. Patients with acute rejection had a statistically significant late elevation in standardised troponin measurements taken at least 1 month postoperatively (SMD 0.98, 95% CI 0.33-1.64). However, pooled diagnostic accuracy was poor (sensitivity 0.414, 95% CrI 0.174-0.696; specificity 0.785, 95% CrI 0.567-0.912; BAUC 0.607, 95% CrI 0.469-0.723). In summary, late troponin elevation in heart transplant recipients is associated with acute cellular rejection in adults, but its stand-alone diagnostic accuracy is poor. Further research is needed to assess its performance in predictive modelling of adverse outcomes following cardiac transplant. Systematic Review Registration: identifier CRD42021227861.

Epidemiology of persistent postoperative opioid use after cardiac surgery: a systematic review and meta-analysis.

BACKGROUND: The epidemiology of persistent postoperative opioid use at least 3 months after cardiac surgery is poorly characterised despite its potential public health importance. METHODS: We searched MEDLINE, Embase, and Google Scholar from inception to December 2021 and included studies reporting the rate and risk factors of persistent postoperative opioid use after cardiac surgery in opioid-naive and opioid-exposed patients. We recorded incidence rates and odds ratios (ORs) with 95% confidence intervals (CIs) for risk factors from individual studies and used random-effects inverse variance modelling to generate pooled estimates. RESULTS: From 10 studies involving 112 298 patients, the pooled rate of persistent postoperative opioid use in opioid-naive patients was 5.7% (95% CI: 4.2-7.2%). Risk factors included female sex (OR 1.18; 95% CI: 1.09-1.29), smoking (OR 1.34; 95% CI: 1.06-1.69), alcohol use (OR 1.43; 95% CI: 1.17-1.76), congestive cardiac failure (OR 1.17; 95% CI: 1.08-1.27), diabetes mellitus (OR 1.21; 95% CI: 1.07-1.37), chronic lung disease (OR 1.42; 95% CI: 1.16-1.75), chronic kidney disease (OR 1.35; 95% CI: 1.08-1.68), and length of hospital stay (per day) (OR 1.03; 95% CI: 1.02-1.04). CONCLUSIONS: Persistent postoperative opioid use after cardiac surgery affects at least one in 20 patients. The identification of risk factors, such as female sex, smoking, alcohol use, congestive cardiac failure, diabetes mellitus, chronic lung disease, chronic kidney disease, and length of hospital stay, should help target interventions aimed at decreasing its prevalence.

Perioperative Neutrophil-Lymphocyte Ratio Predicts Mortality After Cardiac Surgery: Systematic Review and Meta-Analysis.

OBJECTIVES: Neutrophil-lymphocyte ratio (NLR) is an inflammatory biomarker that has been evaluated across a variety of surgical disciplines and is widely predictive of poor postoperative outcome, but its value in cardiac surgery is unclear. The authors did this systematic review and meta-analysis to determine the impact of elevated perioperative NLR on survival after cardiac surgery. DESIGN: Systematic review and meta-analysis of study-level data. SETTING: Multiple hospitals involved in an international pool of studies. PARTICIPANTS: Adults undergoing cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors searched multiple databases from inception until November 2020. They generated summary hazard ratios (HR) and odds ratios (OR) for the association of elevated preoperative NLR with long-term and short-term mortality following cardiac surgery. They separately reported on elevated postoperative NLR. Between-study heterogeneity was explored using metaregression. The authors included 12 studies involving 13,262 patients undergoing cardiac surgery. Elevated preoperative NLR was associated with worse long-term (>30 days) (hazard ratio [HR] 1.56; 95% CI [confidence interval], 1.18-2.06; 8 studies) and short-term (<30 days) mortality (OR 3.18; 95% CI, 1.90-5.30; 7 studies). One study reported the association of elevated postoperative NLR with long-term mortality (HR 8.58; 95% CI, 2.55-28.85). There was considerable between-study heterogeneity for the analysis of long-term mortality (I2 statistic 94.39%), which mostly was explained by study-level variables, such as the number of variables adjusted for by included studies and how many of these significantly increased the risk of long-term mortality, high risk of bias, and number of study centers, as well as participant level factors, such as average participant age and hypertension prevalence. CONCLUSIONS: Perioperative NLR is an independent predictor of short-term and long-term postoperative mortality following cardiac surgery. Further research is required to determine which patient-level factors modify the prognostic value of NLR and to evaluate its role in routine clinical practice.

CMTM7 plays key roles in TLR-induced plasma cell differentiation and p38 activation in murine B-1 B cells.

Terminal differentiation of B cells into antibody-secreting cells is the foundation of humoral immune response. B-1 cells, which are different from B-2 cells, preferentially differentiate into plasma cells. CMTM7 is a MARVEL-domain-containing membrane protein predominantly expressed in B cells that plays an important role in B-1a cell development. The present study assessed CMTM7 function in response to antigen stimulation. Following immunization with T cell-dependent and T cell-independent antigens, Cmtm7-deficient mice exhibited decreased IgM but normal IgG responses in vivo. In vitro stimulation with LPSs induced Cmtm7-/- B-1 cell activation, whereas proliferation was marginally reduced. Notably, Cmtm7 deficiency markedly suppressed plasma cell differentiation in response to TLR agonists, accompanied by a decrease in IgM and IL-10 production. At the molecular level, loss of Cmtm7 repressed the downregulation of Pax5 and the upregulation of Xbp1, Irf4, and Prdm1. Furthermore, p38 phosphorylation was inhibited in Cmtm7-/- B-1 cells. Experiments using a p38 inhibitor revealed that p38 activation was essential for the terminal differentiation of B-1 cells, suggesting that Cmtm7 contributes to B-1 cell differentiation by maintaining p38 activation. Overall, the data reveal the crucial functions of CMTM7 in TLR-induced terminal differentiation and p38 activation in B-1 cells.

Density fluctuations and energy spectra of 3D bacterial suspensions.

Giant number fluctuations are often considered as a hallmark of the emergent nonequilibrium dynamics of active fluids. However, these anomalous density fluctuations have only been reported experimentally in two-dimensional dry active systems heretofore. Here, we investigate density fluctuations of bulk Escherichia coli suspensions, a paradigm of three-dimensional (3D) wet active fluids. Our experiments demonstrate the existence and quantify the scaling relation of giant number fluctuations in 3D bacterial suspensions. Surprisingly, the anomalous scaling persists at small scales in low-concentration suspensions well before the transition to active turbulence, reflecting the long-range nature of hydrodynamic interactions of 3D wet active fluids. To illustrate the origin of the density fluctuations, we measure the energy spectra of suspension flows and explore the density-energy coupling in both the steady and transient states of active turbulence. A scale-invariant density-independent correlation between density fluctuations and energy spectra is uncovered across a wide range of length scales. In addition, our experiments show that the energy spectra of bacterial turbulence exhibit the scaling of 3D active nematic fluids, challenging the common view of dense bacterial suspensions as active polar fluids.

Integrated Analyses of Phenotype and Quantitative Proteome of CMTM4 Deficient Mice Reveal Its Association with Male Fertility.

The chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) is a gene family that has been implicated in male reproduction. CMTM4 is an evolutionarily conserved member that is highly expressed in the testis. However, its function in male fertility remains unknown. Here, we demonstrate that CMTM4 is associated with spermatogenesis and sperm quality. Using Western blotting and immunohistochemical analyses, we found CMTM4 expression to be decreased in poor-quality human spermatozoa, old human testes, and testicular biopsies with nonobstructive azoospermia. Using CRISPR-Cas9 technology, we knocked out the Cmtm4 gene in mice. These Cmtm4 knockout (KO) mice showed reduced testicular daily sperm production, lower epididymal sperm motility and increased proportion of abnormally backward-curved sperm heads and bent sperm midpieces. These mice also had an evident sub-fertile phenotype, characterized by low pregnancy rates on prolonged breeding with wild type female mice, reduced in vitro fertilization efficiency and a reduced percentage of acrosome reactions. We then performed quantitative proteomic analysis of the testes, where we identified 139 proteins to be downregulated in Cmtm4-KO mice, 100 (71.9%) of which were related to sperm motility and acrosome reaction. The same proteomic analysis was performed on sperm, where we identified 3588 proteins with 409 being differentially regulated in Cmtm4-KO mice. Our enrichment analysis showed that upregulated proteins were enriched with nucleosomal DNA binding functions and the downregulated proteins were enriched with actin binding functions. These findings elucidate the roles of CMTM4 in male fertility and demonstrates its potential as a promising molecular candidate for sperm quality assessment and the diagnosis or treatment of male infertility.