Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial.

BACKGROUND: Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. METHODS: We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. RESULTS: Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference - 0.40 [95% CI - 0.71 to - 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference - 1.6% [95% CI - 4.3% to 1.2%]; P = 0.42) between groups. CONCLUSIONS: In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. TRIAL REGISTRATION: ISRCTN, ISRCTN12233792 . Registered November 20th, 2017.

Lower vitamin D levels and VDR FokI variants are associated with susceptibility to sepsis: a hospital-based case-control study.

Background: Vitamin D deficiency has been associated with increased sepsis incidence and mortality in various populations. Vitamin D exerts its effect through vitamin receptor (VDR), and various single nucleotide polymorphisms have been reported to affects the expression and structure of the VDR. In the present study, we investigated the possible role of vitamin D deficiency and VDR polymorphisms in susceptibility to sepsis.Methods: 576 sepsis patients and 421 healthy controls were enrolled in the present study. Plasma vitamin D levels in patients and healthy controls were quantified by ELISA. Genetic variants in the VDR (FokI, TaqI, BsmI, and ApaI) were genotyped by TaqMan assay.Results: Reduced serum Vitamin D level was observed in subjects with sepsis compared to healthy controls (p ≤ 0.0001). Further, subjects with septic shock had diminished 25(OH) vitamin D compared to severe sepsis cases (p ≤ 0.0001). FokI variants and minor alleles were more prevalent in sepsis patients compared to healthy controls (Ff: p ≤ 0.0001, χ2 =17.39; ff: p=0.001, χ2 =10.79; f: p ≤ 0.0001, χ2 =23.51). Furthermore, combined plasma levels of 25(OH) vitamin D and FokI polymorphism revealed a significant role in a predisposition to sepsis and septic shock. However, the prevalence of other VDR polymorphisms (TaqI, BsmI and ApaI) were comparable among different clinical categories.Conclusions: Low 25(OH) vitamin D levels and FokI mutants are associated with an increased risk of sepsis and septic shock in a Chinese cohort.Clinical significanceLower levels of 25-OH vitamin D are highly prevalent in Sepsis patients.Subjects harbouring VDR FokI variants are predisposed to susceptibility to sepsis in the studied cohort.

Metformin ameliorates brain damage caused by cardiopulmonary resuscitation via targeting endoplasmic reticulum stress-related proteins GRP78 and XBP1.

Cerebral damage after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is a primary cause of death. Endoplasmic reticulum stress (ERS) is very important during these situations. This study aimed to explore the role of metformin in protecting brain endoplasmic reticulum post CA/CPR. Male SD rats (n = 132) were treated with 6-min CA-posted asphyxia and sham surgery. Before CA/CPR, metformin (200 mg/kg/day) or a vehicle (0.9% saline) were administered randomly for two weeks. The neurological deficit scores were assessed 24 h, 48 h, 72 h, and 7 days after CA/CPR, and the rat brains were analyzed by Western blotting and qRT-PCR. Apoptosis was detected by the TUNEL assay according to the mitochondrial membrane potential (MMP). Oxidative stress and ERS-related protein expression were also investigated. The Western blotting and qRT-PCR results revealed that the resuscitated animals had time-dependent elevated GRP78 and XBP1 levels compared with the sham operative rats. Moreover, our results showed that the rats treated with metformin had increased neurological deficit scores (NDS), an improved seven-day survival rate, decreased cell apoptosis within the hippocampus CA1 area, and less oxidative stress compared with the CA/CPR group. Furthermore, metformin inhibited the mRNA and protein expressions of glucose-regulated protein 78 (GRP78) and X-box binding protein 1 (XBP1) in the CA/CPR rat model. We confirmed that CA/CPR can induce ERS-related apoptosis and oxidative stress in the brain; moreover, inhibiting ERS-related proteins GRP78 and XBP1 with metformin might attenuate cerebral injury post CA/CPR.

Notoginsenoside R1 Suppresses Inflammatory Signaling and Rescues Renal Ischemia-Reperfusion Injury in Experimental Rats.

BACKGROUND Notoginsenoside R1 (NR) is a major dynamic constituent of Panax notoginseng found to possess anti-inflammatory activity against various inflammatory diseases. However, its protective effects against renal ischemia-reperfusion (I/R) injury have not been elucidated. In male Wistar rats, we induced I/R under general anesthesia by occluding the renal artery for 60 min, followed by reperfusion and right nephrectomy. MATERIAL AND METHODS Rats were randomized to 4 groups: a sham group, an I/R group, an NR-pretreated (50 mg/kg) before I/R induction group, and an NR control group. All animals were killed at 72 h after I/R induction. Blood and renal tissues were collected, and histological and basic renal function parameters were assessed. In addition, levels of various kidney markers and proinflammatory cytokines were measured using RT-PCR, ELISA, and immunohistochemistry analysis. RESULTS After I/R induction, the onset of renal dysfunction was shown by the elevated levels of serum urea, creatinine levels, and histological evaluation, showing a 2-fold increase in the renal failure markers kim-1 and NGAL compared to control rats. Rats pretreated with NR before I/R induction had significantly better renal functions, with attenuated levels of oxidative markers, restored levels of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), tumor growth factor-ß1 (TGF-ß1), INF-γ, and IL-6, and increased anti-inflammatory cytokine levels (IL-10) compared to I/R-induced rats. CONCLUSIONS NR suppressed I/R-induced inflammatory cytokines production by suppressing oxidative stress and kidney markers, suggesting that NR is a promising drug candidate for prevention, progression, and treatment of renal dysfunction.

Construction of Anti-CD20 Single-Chain Antibody-CD28-CD137-TCRζ Recombinant Genetic Modified T Cells and its Treatment Effect on B Cell Lymphoma.

BACKGROUND: Immunotherapy has been explored as a new therapy for B cell lymphoma, which is a non-Hodgkin's lymphoma. Because CD20 is a B lymphocyte-specific marker, anti-CD20 single chain-tagged T lymphocytes have already begun to be experimentally used in B cell lymphoma treatment, but its use is still limited because of its unspecific targeting. T cells transfected with CD28 and CD137 can significantly improve the ability of cytokines secretion and anti-tumor effect, as well as extending T cell survival time and improving their proliferation ability. MATERIAL AND METHODS: Genes containing anti-CD20-CD28-CD137-TCRζ were constructed. After cloning and sequencing, the plasmid was constructed and packaged by lentivirus. It was transfected to the peripheral blood T lymphocyte after identification transfection to induce the fusion protein expression. The cells were incubated with Raji cells and the LDH test was performed to detect the cytotoxic effect of CAR-T cells; the tumor volume and survival rate were measured to observe its inhibitory effect on B cell lymphoma in nude mice. RESULTS: Gene with anti-CD20-CD28-CD137-TCRζ was successfully constructed and transfected to the T cell surface. LDH assay revealed that CAR-T cells can kill the Raji cells with a killing rate of 32.89±6.26%. It can significantly inhibit B cell lymphoma growth in nude mice. CONCLUSIONS: T lymphocytes transfected with anti-CD20-CD28-CD137-TCRζ fusion gene can kill B cell lymphoma, which could provide a new strategy for tumor treatment.