Vitamin D Supplementation during Intensive Care Unit Stay Is Associated with Improved Outcomes in Critically Ill Patients with Sepsis: A Cohort Study.

BACKGROUND: Vitamin D, as a common micronutrient, has been widely used in critically ill patients. However, whether supplementation of vitamin D in adult patients with sepsis can improve their prognosis remains controversial. METHODS: Data from the Mart for Intensive Care IV database was used in this retrospective cohort study, and adult patients with sepsis were enrolled. Critically ill patients, admitted to intensive care units (ICUs) between 2008 and 2019 at the Beth Israel Deaconess Medical Center (BIDMC), were divided into the vitamin D supplementation group and non-vitamin D supplementation group. The primary outcomes were defined as all-cause in-hospital, 28-day, and 90-day mortality rates after admission to the ICU. A 1:1 propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and overlap weighting (OW) analyses were used to minimize selection bias and balance the baseline demographic characteristics. Regression and survival analyses were performed to assess the association between vitamin D supplementation and clinical outcomes in patients with sepsis. RESULTS: In total, 3539 patients with sepsis were enrolled as study participants; of these, 315 were supplemented with vitamin D during their ICU stay. In-hospital, 28-day, and 90-day mortality rates were significantly lower in patients with sepsis supplemented with vitamin D. Multivariate regression analysis showed vitamin D supplementation as a potential protective factor for in-hospital mortality with an odds ratio (OR) = 0.70 (0.51-0.96) after adjusting for all confounders. The hazard ratios (HRs) for 28-day and 90-day mortality were 0.65 (0.50-0.85) and 0.70 (0.55-0.90), respectively. The survival analysis showed that the vitamin D supplementation group had a higher survival probability within 28 and 90 days (p-value < 0.05). These results remained relatively stable post PSM, IPTW, and OW. However, we found no evidence that vitamin D supplementation could shorten the length of stay in the ICU or hospital. CONCLUSIONS: Vitamin D supplementation during an ICU stay was associated with improved prognosis in patients with sepsis, as evidenced by lower in-hospital, 28-day, and 90-day mortality rates and lower disease severity-related scores, but showed no influence on the length of stay in the hospital or ICU.

Cthrc1 deficiency aggravates wound healing and promotes cardiac rupture after myocardial infarction via non-canonical WNT5A signaling pathway.

Cardiac fibroblasts are crucial for scar formation and cardiac repair after myocardial infarction (MI). Collagen triple helix repeat containing 1 (CTHRC1), an extracellular matrix protein, is involved in the pathogenesis of vascular remodeling, bone formation, and tumor progression. However, the role and underlying mechanism of CTHRC1 in post-MI wound repair are not fully clear. Bioinformatics analysis demonstrated CTHRC1 up-regulation in cardiac fibroblasts after ischemic cardiac injury. Serum levels of CTHRC1 were increased in MI mice and CTHRC1 expression was up-regulated in cardiac fibroblasts after MI. In vitro results showed that the induction of CTHRC1 expression in cardiac fibroblasts was mediated by canonical TGFß1-Smad2/3 signaling axis. Moreover, CTHRC1 improved wound healing and boosted cardiac fibroblast activation in vitro. Cthrc1 deficiency aggravated cardiac function and reduced collagen deposition as well as increased mortality attributable to cardiac rupture after MI. Consistent with above phenotypes, reduced the levels of myocardial CD31, α-smooth muscle actin, collagen I, and collagen III was observed, whereas myocardial expression of matrix metalloproteinase 2 and matrix metalloproteinase 9 were increased in Cthrc1 knockout mice post-MI. Above effects could be partly reversed by rCTHRC1 protein or rWNT5A protein. Our study indicates that cardiac fibroblast-derived, canonical TGFß1-Smad2/3-dependent CTHRC1 could improve wound repair and prevent cardiac rupture after MI via selectively activating non-canonical WNT5A-PCP signaling pathway.

Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation.

Rationale: Previous studies have suggested that myocardial inflammation plays a critical role after ischemic myocardial infarction (MI); however, the underlying mechanisms still need to be fully elucidated. WW domain-containing ubiquitin E3 ligase 1 (WWP1) is considered as an important therapeutic target for cardiovascular diseases due to its crucial function in non-ischemic cardiomyopathy, though it remains unknown whether targeting WWP1 can alleviate myocardial inflammation and ischemic injury post-MI. Methods: Recombinant adeno-associated virus 9 (rAAV9)-cTnT-mediated WWP1 or Kruppel-like factor 15 (KLF15) gene transfer and a natural WWP1 inhibitor Indole-3-carbinol (I3C) were used to determine the WWP1 function in cardiomyocytes. Cardiac function, tissue injury, myocardial inflammation, and signaling changes in the left ventricular tissues were analyzed after MI. The mechanisms underlying WWP1 regulation of cardiomyocyte phenotypes in vitro were determined using the adenovirus system. Results: We found that WWP1 expression was up-regulated in cardiomyocytes located in the infarct border at the early phase of MI and in hypoxia-treated neonatal rat cardiac myocytes (NRCMs). Cardiomyocyte-specific WWP1 overexpression augmented cardiomyocyte apoptosis, increased infarct size and deteriorated cardiac function. In contrast, inhibition of WWP1 in cardiomyocytes mitigated MI-induced cardiac ischemic injury. Mechanistically, WWP1 triggered excessive cardiomyocyte inflammation after MI by targeting KLF15 to catalyze K48-linked polyubiquitination and degradation. Ultimately, WWP1-mediated degradation of KLF15 contributed to the up-regulation of p65 acetylation, and activated the inflammatory signaling of MAPK in ischemic myocardium and hypoxia-treated cardiomyocytes. Thus, targeting of WWP1 by I3C protected against cardiac dysfunction and remodeling after MI. Conclusions: Our study provides new insights into the previously unrecognized role of WWP1 in cardiomyocyte inflammation and progression of ischemic injury induced by MI. Our findings afford new therapeutic options for patients with ischemic cardiomyopathy.

Cardiac Overexpression of Chil1 Improves Wound Healing to Prevent Cardiac Rupture After Myocardial Infarction.

Timely formation of collagen-rich-scar is of importance to prevent ventricular rupture after myocardial infarction (MI). Chil1 (Chitinase 3-like 1) is a secreted protein associated with tissue remodeling response. However, its function in MI progression remains elusive. Chil1 was downregulated in the injured area overall post-MI. Overexpression of Chil1 markedly reduced cardiac rupture, increased wall thickness, and improved cardiac function post-MI due to collagen-rich-scar formation and extracellular matrix remodeling. In vitro, Chil1 induced the transformation of fibroblasts to myofibroblasts. Mechanistically, a phosphoproteomics study revealed that Chil1 binded to the EGFR enhancing RAF/MEK1/ERK signaling pathway to exert cardiac protection function. The effects of Chil1 on fibroblasts transformation and cardiac protections after MI were partially abolished by co-treated with RAF inhibitor. Together, our findings identify Chil1 as a protection factor in MI progression through binding to EGFR which further activates RAF/MEK1/ERK signaling pathway.

Effects of ondansetron exposure during ICU stay on outcomes of critically ill patients with sepsis: a cohort study.

Background: Sepsis is a life-threatening disease with high morbidity and mortality, characterized by an inadequate systemic immune response to an initial stimulus. Whether the use of ondansetron (OND) during intensive care unit (ICU) stay is associated with the prognosis of sepsis patients remains unclear. Methods: Critically ill patients with sepsis were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Multivariate logistic regression and Cox regression analyses were used to explore the association between OND use and clinical outcomes after adjusting for confounders. Kaplan-Meier survival curve was used for survival analysis. Propensity score matching (PSM) and subgroup analysis were performed to further confirm the results. Results: The OND-medication group showed reduced in-hospital mortality, 28-day and 90-day mortalities. The OR for in-hospital mortality was 0.80 (0.64-0.99) and HRs for 28-day mortality and 90-day mortality were 0.77 (0.64-0.92) and 0.83 (0.70-0.98), respectively. After PSM, the clinical outcomes remained consistent. In-hospital mortality was lower in the OND-medication group (28.1% vs. 35.8%, P= 0.044), as well as 28-day mortality (23.4% vs. 32.1%, P=0.022) and 90-day mortality (27.4% vs. 35.8%, P=0.035). The protective effect of OND in sepsis patients was relatively robust, independent of age, septic shock, vasopressin and mechanical ventilation. Additionally, the OND users had longer lengths of stay in ICU (6.9(3.1-13.2) vs. 5.1(2.5-11.0), P = 0.026) while no statistical differences were found in lengths of stay in hospital (P = 0.333). Conclusion: OND exposure might be associated with lower in-hospital, 28-day, and 90-day mortality rates in critically ill patients with sepsis. This study indicated that OND might help improve the prognosis of patients with sepsis.

Pruritus after continuous administration of epidural morphine for post-cesarean delivery analgesia: a case control study.

BACKGROUND: Pruritus is one of the most common side effects of epidural morphine administered for post-surgery analgesia, and pregnant women tend to be highly susceptible. The relative contributions of morphine concentration, local anesthetics, and level of pain to pruritus after epidural morphine for post-cesarean delivery analgesia remain unclear. Accordingly, the present study aimed to identify risk factors for pruritus after continuous administration of epidural morphine for post-cesarean delivery analgesia. METHODS: This case control study was based on routinely collected clinical data. Participants included women who had undergone cesarean section and adopted a patient-controlled analgesia pump for postoperative analgesia. A series of logistic regression analyses were performed. Interaction terms were added to explore the moderation effects of combined local anesthetics and pain level on associations between morphine concentration and pruritus. Robustness of the results was checked through sensitivity analysis using propensity scores matching approach. RESULTS: Higher morphine concentration, assisted reproductive treatment, and multipara and cesarean section history were significantly more prevalent in the pruritus group than in the control group. The probabilities of pruritus at morphine concentrations of 10, 15, 20, 25, 30 and 40 µg/mL increased sequentially from 0.05, 0.1, 0.2, 0.35, 0.54 to 0.84, respectively. The trend remained steep in the ropivacaine stratum and became flatter when combined with levobupivacaine. At mild pain combined with levobupivacaine, the incidence of pruritus increased from 0.33 (95% confidence interval [CI] 0.1-0.68) in the 10 µg/mL morphine group to 0.48 (95% CI 0.1-0.88) in the 40 µg/mL morphine group. In the stratum of moderate pain combined with levobupivacaine, the incidence increased from 0.4 (95% CI 0.04-0.92) to 0.56 (95% CI 0.03-0.98). The results in the sensitivity analysis were in consistent with above findings. CONCLUSIONS: Higher concentrations of morphine, multipara, and assisted reproductive treatment were factors associated with a higher probability of pruritus. Pain level or combined local anesthetics could moderate the association between morphine concentration and pruritus.

The Survival Benefit and Safety of Splenectomy for Gastric Cancer With Total Gastrectomy: Updated Results.

BACKGROUND: Splenectomy was traditionally performed to dissect the splenic hilar lymph nodes. Considering the important functions of spleen, whether splenectomy would bring beneficial to gastric cancer patients is debatable. This meta-analysis aimed to make an updated evaluation on the effectiveness and safety of splenectomy. METHODS: Literature searches were performed to identify eligible RCTs concerning effectiveness or safety of splenectomy with gastrectomy from PubMed, MEDLINE, CBMdisc, EMBASE, and Cochrane Central Register of Controlled Trials. Two reviewers completed the study selection, data extraction, and quality assessment independently. The meta-analyses were performed by RevMan 5.3. RESULTS: A total of 971 patients from four studies were included (485 in splenectomy group and 486 in spleen preservation group). Splenectomy did not increase 5-year overall survival rate (RR=1.05, 95% CI: 0.96, 1.16) or increase postoperative mortality (RR=1.21, 95% CI: 0.41, 3.54). However, the analysis demonstrated that gastrectomy with splenectomy had significantly higher incidence of postoperative complications (RR=1.80, 95% CI: 1.33, 2.45). No significant differences were found in terms of the number of resected lymph nodes and reoperation rate; however, splenectomy had a tendency to prolong the duration of surgery and hospital stays. Subgroup analyses indicated that splenectomy could not increase overall survival rate for either whole or proximal gastric cancer. Sensitivity analyses also found similar results compared to the primary analyses. CONCLUSIONS: Splenectomy cannot benefit the survival of patients with tumor located at lesser curvature, and it could instead increase postoperative morbidity.

Prognostic significance of inflammation-based indexes in patients with stage III/IV colorectal cancer after adjuvant chemoradiotherapy.

Inflammation-based indexes such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation indexes (SII) have been reported to be associated with prognosis in cancer patients.The aim of this study was to estimate the prognostic significance of inflammation-based indexes such as NLR, PLR, LMR, and SII in stage III/IV colorectal cancer (CRC) patients undertaking adjuvant chemoradiotherapy (CRT).Two hundred twenty stage III/IV CRC patients were enrolled in this study. Inflammatory indexes were defined as follows: NLR = absolute neutrophil counts/absolute lymphocyte counts; PLR = absolute platelet counts/absolute lymphocyte counts; LMR = absolute lymphocyte counts/absolute monocyte counts; SII = absolute neutrophil counts × absolute platelet counts/absolute lymphocyte counts. The correlations between indexes and prognosis were evaluated using the Cox proportional hazard model.The results of univariate analysis demonstrated that NLR, PLR, and SII were significantly associated with progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed that SII (P = .030) was an independent predictor of PFS, and NLR (P = .047) was an independent prognostic factor of OS.Those inflammation-based indexes could provide a convenient and secure method to predict the outcomes of stage III/IV CRC patients receiving adjuvant CRT.