Optimal fluid resuscitation targets in septic patients with acutely decompensated heart failure.

BACKGROUND: To determine the optimal fluid resuscitation volume in septic patients with acutely decompensated heart failure (ADHF). METHODS: Septic patients with ADHF were identified from a tertiary urban medical center. The generalized additive models were used to explore the association between fluid resuscitation volume and endpoints, and the initial 3 h fluid resuscitation volume was divided into four groups according to this model: < 10 mL/kg group, ≥ 10 to ≤ 15 mL/kg group, > 15 to ≤ 20 mL/kg group, and > 20 mL/kg group. Logistic and Cox regression models were employed to explore the association between resuscitation volume and primary endpoint, in-hospital mortality, as well as secondary endpoints including 30-day mortality, 1-year mortality, invasive ventilation, and ICU admission. RESULTS: A total of 598 septic patients with a well-documented history of HF were enrolled in the study; 405 patients (68.8%) had sepsis-induced hypoperfusion. Patients with NYHA functional class III and IV were 494 (83.9%) and 22 (3.74%), respectively. Resuscitation volumes above 20 mL/kg (OR 3.19, 95% CI 1.31-8.15) or below 10 mL/kg (OR 2.33, 95% CI 1.14-5.20) significantly increased the risk of in-hospital mortality in septic patients, while resuscitation volumes between 15 and 20 mL/kg were not associated with the risk of in-hospital death in septic patients (OR 1.79, 95% CI 0.68-4.81). In the multivariable Cox models, the effect of resuscitation volume on 30-day and 1-year mortality in septic patients was similar to the effect on in-hospital mortality. Resuscitation volume exceeds 15 mL/kg significantly increased the risk of tracheal intubation, while fluid resuscitation volume was not associated with ICU admission in the septic patients. In septic patients with hypoperfusion, these fluid resuscitation volumes have similar effects on patient outcomes. This association was consistent across the three subgroups with worsened cardiac function, as well as in sensitivity analyses. CONCLUSIONS: Our study observed that an initial fluid resuscitation volume of 10-15 mL/kg in the first 3 h was optimal for early resuscitation in septic patients with ADHF, particularly those with worsened cardiac function. These results need to be confirmed in randomized controlled trials with larger sample sizes.

Organotin exposure and DNA methylation in non-syndromic cleft lip and palate: Integrating findings from case-control studies and animal experiments.

Human exposure to organotin is common but little is known about the adverse pregnancy outcomes. This study aimed to explore the association between organotin exposure and the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P) and to explore the underlying mechanism. Placental samples (109 NSCL/P cases and 128 controls) were analyzed for 8 organotin concentrations, and subsequent animal experiments were conducted by administering tributyltin (TBT) during critical developmental periods. DNA methylation BeadChip analysis (12 NSCL/P and 12 controls), bisulfite Sequencing analysis (3 NSCL/P and 3 controls mice), and RNA sequencing were performed to explore epigenetic mechanisms. Logistic regression, LASSO regression, support vector machine, random forest, and mediation effect analysis were utilized to identify key genes related to TBT and NSCL/P. Only tributyltin met the detection criteria for further analysis among 8 compounds. The median levels of TBT in cases (8.93 ng/g) were statistically significantly higher than those in controls (5.33 ng/g). Excessive TBT exposure in maternal placenta was associated with an increased risk of NSCL/P (OR = 6.44, 95 % CI, 2.91-14.25) in humans, showing a dose-response relationship (p for trend <0.05). 288 differentially methylated CpG sites in 129 genes were identified between cases and controls. Tributyltin was associated with FGFR2 and SCD hypomethylation, which were identified as potential key genes associated with NSCL/P. Mediation analysis suggested that DNA methylation of FGFR2 and SCD may mediate the impact of TBT on NSCL/P occurrence. TBT exposure during the critical period in mice (GD8.5-GD15.5) can induce progeny NSCL/P. Altered FGFR2 and SCD hypomethylation and gene expression observed in response to TBT exposure in fetal mice. Excessive TBT exposure was associated with increased risks of human NSCL/P. TBT exposure can induce NSCL/P in fetal mice. FGFR2 and SCD were implicated in NSCL/P pathogenesis, potentially mediated by DNA methylation alterations.

Combining host immune response biomarkers and clinical scores for early prediction of sepsis in infection patients.

BACKGROUND: The performance of host immune responses biomarkers and clinical scores was compared to identify infection patient populations at risk of progression to sepsis, ICU admission and mortality. METHODS: Immune response biomarkers were measured and NEWS, SIRS, and MEWS. Logistic and Cox regression models were employed to evaluate the strength of association. RESULTS: IL-10 and NEWS had the strongest association with sepsis development, whereas IL-6 and CRP had the strongest association with ICU admission and in-hospital mortality. IL-6 [HR (95%CI) = 2.68 (1.61-4.46)] was associated with 28-day mortality. Patient subgroups with high IL-10 (≥ 5.03 pg/ml) and high NEWS (> 5 points) values had significantly higher rates of sepsis development (88.3% vs 61.1%; p < 0.001), in-hospital mortality (35.0% vs. 16.7%; p < 0.001), 28-day mortality (25.0% vs. 5.6%; p < 0.001), and ICU admission (66.7% vs. 38.9%; p < 0.001). CONCLUSIONS: Patients exhibiting low severity signs of infection but high IL-10 levels showed an elevated probability of developing sepsis. Combining IL-10 with the NEWS score provides a reliable tool for predicting the progression from infection to sepsis at an early stage. Utilizing IL-6 in the emergency room can help identify patients with low NEWS or SIRS scores.

Gal-1-mediated cytochrome p450 activation promotes fibroblast into myofibroblast differentiation in pulmonary fibrosis.

Pulmonary fibrosis (PF) results from excessive extracellular matrix (ECM) deposition and tissue remodeling after activation of fibroblasts into myofibroblasts. Abnormally deposited fibrotic ECM, in turn, promotes fibroblast activation and accelerates loss of lung structure and function. However, the molecular mediators and exact mechanisms by which fibrotic ECM promotes fibroblast activation are unclear. In a bleomycin-induced PF mouse model, we found Galectin-1 (Gal-1) expression was significantly increased in lung tissue, and overexpression of Gal-1 plasmid-transfected fibroblasts were activated into myofibroblasts. Using the decellularization technique to prepare decellularized fibrotic ECM and constructing a 3D in vitro co-culture system with fibroblasts, we found that decellularized fibrotic ECM induced a high expression of Gal-1 and promoted the activation of fibroblasts into myofibroblasts. Therefore, Gal-1 has been identified as a pivotal mediator in PF. Further, we found that decellularized fibrotic ECM delivered mechanical signals to cells through the Gal-1-mediated FAK-Src-P130Cas mechanical signalling pathway, while the CYP450 enzymes (mainly involved in CYP1A1, CYP24A1, CYP3A4, and CYP2D6 isoforms) acted as a chemical signalling pathway to receive mechanical signals transmitted from upstream Gal-1, thereby promoting fibroblast activation. The Gal-1 inhibitor OTX008 or the CYP1A1 inhibitor 7-Hydroxyflavone prevented PF in mice and inhibited the role of fibrotic ECM in promoting fibroblast activation into myofibroblasts, preventing PF. These results reveal novel molecular mechanisms of lung fibrosis formation and identify Gal-1 and its downstream CYP1A1 as potential therapeutic targets for PF disease treatmnts.

Environmental exposure patterns to 94 current-use pesticides in women of reproductive age who are preparing for pregnancy.

Current-use pesticides (CUPs), including insecticides, fungicides, and herbicides, are extensively employed in agriculture to manage pests, diseases, and weeds. Nonetheless, their widespread application raises significant concerns regarding potential impacts on human health, particularly with reproductive health. This study focuses on exploring the landscape of CUP exposure among pre-pregnancy women. Based on a cohort study comprising 354 pre-pregnancy women of reproductive age in Beijing, China, we measured the concentrations of 94 CUPs in serum and conducted an in-depth analysis of exposure profiles, health risks, and contributing factors. The results revealed that the serum of pre-pregnancy women was contaminated with CUPs, of which the median concentrations ranged from 0.114 (fenamiphos-sulfone) to 61.2 ng/L (mefenacet). Among the 94 CUPs, 54 exhibited detection rates higher than 50 %, including 26 insecticides, 14 fungicides, and 14 herbicides. The exposure concentration profile highlighted that the insecticides contributed 56 % to the total CUP concentration percentages, with organophosphate insecticides being the primary contributors within this category (63.0 %). The average daily intake (ADI) of CUPs ranged from 2.23 to 16,432.28 ng/kg, while diflubenzuron had the highest ADI. Health risk assessments showed that exposure to a combination of total insecticides or herbicides poses a moderate risk for 15.8 % and 30.2 % of women, with mefenacet being the most significant, which showed moderate hazard in 29.4 % of participants. The overlap analysis showed that methiocarb-sulfone, diflubenzuron, and mefenacet were the dominant pesticides. In addition, maternal age, annual income level, smoking, and vitamin B12 supplementation were associated with serum CUP concentrations. Our study contributes a novel and comprehensive exposure profile of CUPs in pre-pregnancy women in northern China, providing valuable insights for evaluating the potential consequences of pre-pregnancy exposure on reproductive health. SYNOPSIS: We provided a comprehensive exposure landscape, health effects, and influential factors of 94 current-use pesticides among pre-pregnancy women in China.

The Effects of Aflatoxin B1 on Liver Cholestasis and Its Nutritional Regulation in Ducks.

The aim of this study was to investigate the effects of aflatoxin B1 (AFB1) on cholestasis in duck liver and its nutritional regulation. Three hundred sixty 1-day-old ducks were randomly divided into six groups and fed for 4 weeks. The control group was fed a basic diet, while the experimental group diet contained 90 µg/kg of AFB1. Cholestyramine, atorvastatin calcium, taurine, and emodin were added to the diets of four experimental groups. The results show that in the AFB1 group, the growth properties, total bile acid (TBA) serum levels and total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and glutathione (GSH) liver levels decreased, while the malondialdehyde (MDA) and TBA liver levels increased (p < 0.05). Moreover, AFB1 caused cholestasis. Cholestyramine, atorvastatin calcium, taurine, and emodin could reduce the TBA serum and liver levels (p < 0.05), alleviating the symptoms of cholestasis. The qPCR results show that AFB1 upregulated cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and cytochrome P450 family 8 subfamily B member 1 (CYP8B1) gene expression and downregulated ATP binding cassette subfamily B member 11 (BSEP) gene expression in the liver, and taurine and emodin downregulated CYP7A1 and CYP8B1 gene expression (p < 0.05). In summary, AFB1 negatively affects health and alters the expression of genes related to liver bile acid metabolism, leading to cholestasis. Cholestyramine, atorvastatin calcium, taurine, and emodin can alleviate AFB1-induced cholestasis.

Rare MED12L Variants Are Associated with Susceptibility to Guttate Psoriasis in the Han Chinese Population.

INTRODUCTION: According to the common disease/rare variant hypothesis, it is important to study the role of rare variants in complex diseases. The association of rare variants with psoriasis has been demonstrated, but the association between rare variants and specific clinical subtypes of psoriasis has not been investigated. METHODS: Gene-based and gene-level meta-analyses were performed on data extracted from our previous study data sets (2,483 patients with guttate psoriasis and 8,292 patients with non-guttate psoriasis) for genotyping. Then, haplotype analysis was performed for rare loss-of-function variants located in MED12L, and protein function prediction was performed for MED12L. Gene-based analysis at each stage had a moderate significance threshold (p < 0.05). A χ2 test was then conducted on the three potential genes, and the merged gene-based analysis was used to confirm the results. We also conducted association analysis and meta-analysis for functional variants located on the identified gene. RESULTS: Through these gene-level analyses, we determined that MED12L is a guttate psoriasis susceptibility gene (p = 9.99 × 10-5), and the single-nucleotide polymorphism with the strongest association was rs199780529 (p_combine = 1 × 10-3, p_meta = 2 × 10-3). CONCLUSIONS: In our study, a guttate psoriasis-specific subtype-associated susceptibility gene was confirmed in a Chinese Han population. These findings contribute to a better genetic understanding of different subtypes of psoriasis.

Inadvertent antibiotic exposure during pregnancy may increase the risk for neural tube defects in offspring.

BACKGROUND: As emerging environmental contaminants, antibiotics pose potential threats to human health, in particular to pregnant women and infants. However, the potential harm of inadvertent antibiotic exposure (IAE) is often disregarded in light of the focus on intentional antibiotic use during pregnancy. Currently, little is known about the effects of IAE during pregnancy on fetal neural tube development. METHODS: In this case-control study, we used questionnaire data from 855 subjects to investigate the effects of intentional antibiotic use in early pregnancy on neural tube defects (NTDs). Then we tested for placental antibiotics in mothers who had not intentionally used antibiotics, and the compounds were detected in 379 subjects; these were considered IAE cases. We assessed the association between IAE during pregnancy and fetal NTDs using both multivariable logistic and multi-pollutant exposure models. We also analyzed the correlation between maternal dietary habits and placental antibiotics to explore possible sources of IAE. RESULTS: Only 50 of 855 participants (5.8%) intentionally used antibiotics and such use showed no significant association with NTD risk (odds ratio [OR] = 1.92, confidence interval [95%CI] = [0.66, 5.59]). However, 14 of 15 placental antibiotics were detected in 378 of 379 subjects (99.7%) and multivariable logistic analysis indicated that high levels of placental macrolides were significantly associated with increased NTD risk (4.42 [2.01-10.45]). Multi-pollutant exposure analysis suggested an increase in NTD risk with an increase in exposure to a mixture of placental antibiotics, among which macrolides were the most important contributor. In addition, the level of placental macrolides was positively correlated with the intake frequency of milk. Finally, mothers who drank river, well, or pond water had higher levels of placental macrolides than those who drank only tap water. CONCLUSIONS: Intentional antibiotic use during early pregnancy may not be associated with NTDs, while IAE during pregnancy is associated with higher NTD risk in offspring. Macrolides are crucial risk factors. Milk, and river, well, or pond water may be important sources of IAE.

Predicting the risk of pulmonary infection in patients with chronic kidney failure: A-C2GH2S risk score-a retrospective study.

PURPOSE: The objective of this study is to investigate the associated risk factors of pulmonary infection in individuals diagnosed with chronic kidney disease (CKD). The primary goal is to develop a predictive model that can anticipate the likelihood of pulmonary infection during hospitalization among CKD patients. METHODS: This retrospective cohort study was conducted at two prominent tertiary teaching hospitals. Three distinct models were formulated employing three different approaches: (1) the statistics-driven model, (2) the clinical knowledge-driven model, and (3) the decision tree model. The simplest and most efficient model was obtained by comparing their predictive power, stability, and practicability. RESULTS: This study involved a total of 971 patients, with 388 individuals comprising the modeling group and 583 individuals comprising the validation group. Three different models, namely Models A, B, and C, were utilized, resulting in the identification of seven, four, and eleven predictors, respectively. Ultimately, a statistical knowledge-driven model was selected, which exhibited a C-statistic of 0.891 (0.855-0.927) and a Brier score of 0.012. Furthermore, the Hosmer-Lemeshow test indicated that the model demonstrated good calibration. Additionally, Model A displayed a satisfactory C-statistic of 0.883 (0.856-0.911) during external validation. The statistical-driven model, known as the A-C2GH2S risk score (which incorporates factors such as albumin, C2 [previous COPD history, blood calcium], random venous blood glucose, H2 [hemoglobin, high-density lipoprotein], and smoking), was utilized to determine the risk score for the incidence rate of lung infection in patients with CKD. The findings revealed a gradual increase in the occurrence of pulmonary infections, ranging from 1.84% for individuals with an A-C2GH2S Risk Score ≤ 6, to 93.96% for those with an A-C2GH2S Risk Score ≥ 18.5. CONCLUSION: A predictive model comprising seven predictors was developed to forecast pulmonary infection in patients with CKD. This model is characterized by its simplicity, practicality, and it also has good specificity and sensitivity after verification.

Prenatal exposure to poly/perfluoroalkyl substances and risk for congenital heart disease in offspring.

Congenital heart disease (CHD) is the most prevalent congenital malformation worldwide, and the association between per- and polyfluoroalkyl substances (PFASs) exposure and CHD in population has only received limited study. Therefore, we conducted a multicenter case-control study to explore the associations between prenatal exposure to individual PFASs, and also a PFAS mixture, and CHD risk, including 185 CHDs and 247 controls in China from 2016 to 2021. Thirteen PFASs in maternal plasma were quantified using liquid chromatography-tandem mass spectrometry. Logistic regression and two multipollutant models (Bayesian kernel machine regression [BKMR] and quantile g-computation [qgcomp]) were used to assess the potential associations between any individual PFAS, and also a PFAS mixture, and CHD risk. After adjusting for potential confounders, logistic regression indicated significant associations between elevated levels of perfluorononanoic acid (odds ratio [OR]= 1.30, 95% confidence intervals [CI]: 1.07-1.58), perfluorodecanoic acid (OR=2.07, 95%CI: 1.32-3.26), and perfluoroundecanoic acid (OR=2.86, 95%CI:1.45-5.65) and CHD risk. The BKMR model and qgcomp approach identified that a significant positive association between the PFAS mixture and risk for CHD. These findings provide essential evidence that there is indeed a health crisis associated with PFASs and that it is linked to CHD.

Ameliorative Effects of Luteolin and Activated Charcoal on Growth Performance, Immunity Function, and Antioxidant Capacity in Broiler Chickens Exposed to Deoxynivalenol.

Deoxynivalenol (DON, Vomitoxin) is a threatening mycotoxin that mainly produces oxidative stress and leads to hepatotoxicity in poultry. Antioxidant dietary supplements dramatically boost immunity, safeguarding animals from DON poisoning. Luteolin (LUT) is an active plant-derived compound that poses influential antioxidants. This study explored the effectiveness of LUT in combination with activated charcoal (AC) in detoxifying DON in broilers. The 180 one-day broiler chickens were allocated into five different groups having six replicates in each group, provided with ad libitum feed during the trial period (28 days) as follows: in the control group, basal diet (feed with no supplementation of LUT, AC or DON); in group 2, a basal diet added with 10 mg/kg DON from contaminated culture (DON); in group 3, a basal diet augmented by 350 mg/kg LUT and DON 10 mg/kg (DON + LUT); in group 4, a basal diet supplemented by DON 10 mg/kg + AC 200 mg/kg (DON + AC); and in group 5, a basal diet supplemented by 10 mg/kg DON + 350 mg/kg LUT + 200 mg/kg AC (DON + LUT + AC). Concerning the control group, the DON-treated broilers demonstrated a significant decrease in growth performance (p < 0.05) and serum immunoglobulin (p < 0.05) contents, negatively changing the serum biochemical contents and enzymatic activities and an increase in histopathological liver lesions. Furthermore, DON substantially increased (p < 0.05) malondialdehyde (MDA) concentration and decreased total superoxide dismutase (T-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) levels in the serum and liver. The intake of AC and LUT to the DON-contaminated diet decreased DON residue in the liver and potentially reduced the adverse effects of DON. Considering the results, supplementation of LUT with mycotoxin adsorbent has protective effects against mycotoxicosis caused by DON. It could be helpful for the development of novel treatments to combat liver diseases in poultry birds. Our findings may provide important information for applying LUT and AC in poultry production.

Associations among bisphenol A, its analogs, and chlorinated derivatives in placenta and risk for neural tube defects: A case-control study.

Bisphenol A (BPA) and its analogs such as bisphenol Z (BPZ) are widely used in the production of consumer products, but few studies have investigated the associations among BPA, its analogs, and chlorinated derivatives (collectively, BPs) and risk for NTDs. This study investigated the associations between concentrations of BPs in the placenta and risk for NTDs. This was a case-control study including 122 NTDs and 164 controls. BPs in the placenta were determined using liquid chromatography-tandem mass spectrometry. The associations between BPs and NTD risk were evaluated using conventional logistic regression and weighted quantile sum regression (WQS) models. In the logistic regression, exposure to higher levels of BPA and BPZ was associated with increased NTD risk (odds ratio [OR] = 3.17, 95 % confidence interval [CI], 1.22-8.22; OR = 3.11, 95 % CI, 1.20-8.09, respectively). Meanwhile, a significant dose-response relationship was found between BPA and BPZ concentrations and NTD risk. In the WQS model, a quartile increase in WQS index resulted in 4.34 (95 % CI: 1.69, 11.20) higher odds for NTDs, and BPA and BPZ accounted for most of the weight index in the joint effects of BPs. In conclusion, high levels of BPs in the placenta are associated with increased risk for NTDs, of which BPA and BPZ are important risk factors.

Pyroptosis in neurodegenerative diseases: from bench to bedside.

The central nervous system regulates all aspects of physiology to some extent. Neurodegenerative diseases (NDDs) lead to the progressive loss and dysfunction of neurons, which are particularly evident in Alzheimer's disease, Parkinson's disease, and many other conditions. NDDs are multifactorial diseases with complex pathogeneses, and there has been a rapid increase in the prevalence of NDDs. However, none of these diseases can be cured, making the development of novel treatment strategies an urgent necessity. Numerous studies have indicated how pyroptosis induces inflammation and affects many aspects of NDD. Therefore, components related to pyroptosis are potential therapeutic candidates and are attracting increasing attention. Here, we review the role of pyroptosis in the pathogenesis of NDDs and potential treatment options. Additionally, several of the current drugs and relevant inhibitors are discussed. Through this article, we provide theoretical support for exploring new therapeutic targets and updating clinical treatment strategies for NDDs. Notably, pyroptosis, a recently widely studied mode of cell death, is still under-researched compared to other traditional forms of cell death. Moreover, the focus of research has been on the onset and progression of NDDs, and the lack of organ-specific target discovery and drug development is a common problem for many basic studies. This urgent problem requires scientists and companies worldwide to collaborate in order to develop more effective drugs against NDDs.

Dynamic electrostatic assembly of polyelectrolytes and perfluorosurfactants into environmentally Adaptable, freestanding membranes with ultralow surface energy and surface adhesion.

HYPOTHESIS: Integration of ultralow surface energy and surface functionality on one surface coatings is highly desirable in chemical and biomedical applications. However, it is a fundamental challenge to reduce surface energy without cost of surface functionality and vice versa. To address this challenge, the present work made use of the rapid and reversible change of surface orientation conformations of weak polyelectrolyte multilayers to create ionic, perfluorinated surfaces. EXPERIMENTS: Poly(allylamine hydrochloride) (PAH) chains and the micelles of sodium perfluorooctanoate (SPFO) were layer-by-layer (LbL) assembled into (SPFO/PAH)n multilayer films, which readily exfoliated to freestanding membranes. The static and dynamic surface wetting behaviors of the resulting membranes were studied by sessile drop technique and their surface charge behaviors in water by electrokinetic analysis. FINDINGS: As-prepared (SPFO/PAH)n membranes exhibited ultralow surface energy in air; the lowest surface energy is 2.6 ± 0.5 mJ/m2 for PAH-capped surfaces and 7.0 ± 0.9 mJ/m2 for SPFO-capped surfaces. They readily became positively charged in water, which allowed not only effective adsorption of ionic species for further functionalization with subtle change in surface energy, but effective adhesion onto various solid substrates such as glass, stainless steel, and polytetrafluoroethylene to endorse the wide applicability of (SPFO/PAH)n membranes.

Measuring Interprofessional Collaboration's Impact on Healthcare Services Using the Quadruple Aim Framework: A Protocol Paper.

Despite decades of research on the impact of interprofessional collaboration (IPC), we still lack definitive proof that team-based care can lead to a tangible effect on healthcare outcomes. Without return on investment (ROI) evidence, healthcare leaders cannot justifiably throw their weight behind IPC, and the institutional push for healthcare manpower reforms crucial for facilitating IPC will remain variable and fragmentary. The lack of proof for the ROI of IPC is likely due to a lack of a unifying conceptual framework and the over-reliance on the single-method study design. To address the gaps, this paper describes a protocol which uses as a framework the Quadruple Aim which examines the ROI of IPC using four dimensions: patient outcomes, patient experience, provider well-being, and cost of care. A multimethod approach is proposed whereby patient outcomes are measured using quantitative methods, and patient experience and provider well-being are assessed using qualitative methods. Healthcare costs will be calculated using the time-driven activity-based costing methodology. The study is set in a Singapore-based national and regional center that takes care of patients with neurological issues.

Discovery of Macrocycle-Based HPK1 Inhibitors for T-Cell-Based Immunotherapy.

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell activation, and targeting HPK1 is considered a promising strategy for improving responses to antitumor immune therapies. The biggest challenge of HPK1 inhibitor design is to achieve a higher selectivity to GLK, an HPK1 homology protein as a positive regulator of T-cell activation. Herein, we report the design of a series of macrocycle-based HPK1 inhibitors via a conformational constraint strategy. The identified candidate compound 5i exhibited HPK1 inhibition with an IC50 value of 0.8 nM and 101.3-fold selectivity against GLK. Compound 5i also displayed good oral bioavailability (F = 27-49%) in mice and beagles and favorable metabolic stability (T1/2 > 186.4 min) in human liver microsomes. More importantly, compound 5i demonstrated a clear synergistic effect with anti-PD-1 in both MC38 (MSI) and CT26 (MSS) syngeneic tumor mouse models. These results showed that compound 5i has a great potential in immunotherapy.

Viewing interprofessional collaboration through the lens of networked ecological systems theory.

Interprofessional collaboration (IPC) is key to ensuring safe quality care for patients. However, IPC intervention outcomes are variable, leading to calls for systems theories to understand complex interactions in healthcare. Using networked ecological systems theory (NEST), we aimed to uncover facilitators and barriers impacting the interactions between nurses and physicians in a specialty healthcare center. A qualitative study involving 55 non-participant observations and 17 individual semi-structured interviews was conducted at the National Neuroscience Institute of Singapore from April 2019 to March 2021. Template analysis was used to analyze the data. The most important IPC facilitators were exosystemic institutional support and physicians' willingness to engage in IPC in the microsystems that together enabled the establishment of disease-based outpatient programs fostering patient-centered interactions among different healthcare professionals (HCP). We also found that patient-, disease-, and systems-related knowledge played an important role in facilitating IPC. Macrosystemic entrenchments such as intraprofessional composition of ward rounds emerged as a significant barrier. However, microsystemic efforts such as chat groups connecting all HCP involved in the care of the patients in the wards have fostered IPC. Although still preliminary, these findings suggest NEST can be useful to inform systematic interventions to improve IPC.

An artificially designed elastin-like recombinant polypeptide improves aging skin.

BACKGROUND: As a substrate for cell growth, elastin can promote the regeneration and remodeling of the epidermis, which plays an important role in delaying skin aging. However, elastin proteins are more than 700 amino acids long and cannot be absorbed through the skin, which prevents the direct utilization of elastin in the prevention and treatment of aging skin. METHODS: We designed an elastin-like recombinant polypeptide (ELR) which could be absorbed through the skin based on the property of hexapeptide VGVAPG. Thirty healthy Chinese Han female participants which met the criteria were enrolled in this study and all of them completed the tests including elasticity, tightness, and wrinkle detection. The participants used this polypeptide for 4 weeks and were tested in three visits: one day before trial started (D0), and 14 and 28 days after the trial (D14 and D28, respectively). Paired t-tests or Wilcoxon signed-rank tests for non-parametric measures were used to determine the difference between D0 and D14, or D0 and D28. RESULTS: The skin elasticity level in the thirty participants was significantly increased after using ELR for 28 days (P=0.024), and the average value of skin firmness (Uf) declined from 3.313 (D0) to 3.292 (D14) and 3.265 (D28), although there was no statistically significant difference between treatment and pre-treatment. Furthermore, the wrinkle count (D14: P<0.001; D28: P<0.001), wrinkles volume (D14: P<0.001; D28: P=0.008), and wrinkles area (D14: P<0.001; D28: P<0.001) of Crow's feet were significantly improved by using ELR for 14 days or 28 days. CONCLUSION: Continuous use of ELR could significantly improve skin elasticity and reduce wrinkles.

Maternal serum zinc concentration and neural tube defects in offspring: a meta-analysis.

OBJECTIVE: This study was to assess the relationship between maternal serum zinc concentration and NTDs in offspring by conducting a meta-analysis. METHODS: We searched Pubmed, Medline and Web of Science for all English studies about the relationship between maternal serum zinc level and NTDs in offspring (published between 1 January 1975 and 1 January 2020). Pooled effect sizes with corresponding 95% CIs were calculated using a random-effect model by Revman 5.3 and Stata 15.1 software. RESULTS: Eight articles met our selection criteria and a total of 187 cases and 894 controls were included in this meta-analysis. Our results showed that mothers with NTDs infants had lower serum zinc concentration than those with healthy infants (SMD= -0.77, 95%CI [-1.16, -0.37], p = .0001, I2 = 73%). CONCLUSIONS: Compared with mothers with healthy infants, mothers with NTDs infants have lower serum zinc levels, suggesting that low maternal serum zinc level during pregnancy is probably associated with the risk of NTDs in offspring. But the mechanism of the association remains to be ascertained by large-scale cohort studies.

Institutional ethnography - a primer.

This review introduces a qualitative methodology called institutional ethnography (IE) to healthcare professionals interested in studying complex social healthcare systems. We provide the historical context in which IE was developed, and explain the principles and terminology in IE for the novice researcher. Through the use of worked examples, the reader will be able to appreciate how IE can be used to approach research questions in the healthcare system that other methods would be unable to answer. We show how IE and qualitative research methods maintain quality and rigour in research findings. We hope to demonstrate to healthcare professionals and researchers that healthcare systems can be analysed as social organisations, and IE may be used to identify and understand how higher-level processes and policies affect day-to-day clinical work. This understanding may allow the formulation and implementation of actionable improvements to solve problems on the ground.