Diffuse large B-cell lymphoma with contemporary involvement of central and peripheral nervous system: A case report and literature review.

Introduction: Simultaneous involvement of the peripheral nervous system (PNS) and central nervous system (CNS) during the same period in diffuse large B-cell lymphoma (DLBCL) is rarely documented. In this particular case, the diagnosis of diffuse large B-cell lymphoma was pathologically confirmed, with invasion into the basal ganglia, diencephalon, and several peripheral nerves. The initial clinical manifestations were dyspnoea and hyperventilation. Case presentation: The patient presented to the hospital with fatigue, dyspnoea, and limb pain for over 7 months, accompanied by progressive breathlessness and unconsciousness in the last 6 days. Initial treatment with glucocorticoids for Guillain-Barre syndrome (GBS) proved ineffective in controlling the severe shortness of breath and hyperventilation, necessitating the use of ventilator-assisted ventilation. 18-Fluorodeoxyglucose positron emission tomography/computed tomography (18FDG PET/CT) showed that the basal ganglia, brainstem, and multiple peripheral nerves were thickened and metabolically active. There were atypical cells in the cerebrospinal fluid; the pathology indicated invasive B-cell lymphoma, demonstrating a propensity toward diffuse large B-cell lymphoma (DLBCL). After receiving chemotherapy, the patient regained consciousness and was successfully weaned off ventilator assistance but died of severe pneumonia. Discussion: The early clinical manifestations of DLBCL lack specificity, and multifocal DLBCL complicates the diagnostic process. When a single primary disease cannot explain multiple symptoms, the possibility of DLBCL should be considered, and nervous system invasion should be considered when nervous system symptoms are present. Once nervous system involvement occurs in DLBCL, whether the central or peripheral nervous system, it indicates a poor prognosis.

Intestinal recruitment of CCR6-expressing Th17 cells by suppressing miR-681 alleviates endotoxemia-induced intestinal injury and reduces mortality.

INTRODUCTION: Sepsis or endotoxemia can induce intestinal dysfunction in the epithelial and immune barrier. Th17 cells, a distinct subset of CD4+ T-helper cells, act as "border patrol" in the intestine under pathological condition and in the previous studies, Th17 cells exhibited an ambiguous function in intestinal inflammation. Our study will explore a specific role of Th17 cells and its relevant mechanism in endotoxemia-induced intestinal injury. MATERIALS AND METHODS: Lipopolysaccharide was used to establish mouse model of endotoxemia. miR-681 was analyzed by RT-PCR and northern blot analysis and its regulation by HIF-1α was determined by chromatin immunoprecipitation and luciferase reporter assay. Intestinal Th17 cells isolated from endotoxemic mice were quantitatively evaluated by flow cytometry and its recruitment to the intestine controlled by miR-681/CCR6 pathway was assessed by using anti-miRNA treatment and CCR6 knockout mice. Intestinal histopathology, villus length, intestinal inflammation, intestinal permeability, bacterial translocation and survival were investigated, by histology and TUNEL analysis, ELISA, measurement of diamine oxidase, bacterial culture, with or without anti-miR-681 treatment in endotoxemic wild-type and (or) CCR6 knockout mice. RESULTS: In this study, we found that miR-681 was significantly promoted in intestinal Th17 cells during endotoxemia, which was dependent on hypoxia-inducible factor-1α (HIF-1α). Interestingly, miR-681 could directly suppress CCR6, which was a critical modulator for Th17 cell recruitment to the intestines. In vivo, anti-miR-681 enhanced survival, increased number of intestinal Th17 cells, reduced crypt and villi apoptosis, decreased intestinal inflammation and bacterial translocation, resulting in protection against endotoxemia-induced intestinal injury in mice. However, CCR6 deficiency could neutralize the beneficial effect of anti-miR-681 on the intestine during endotoxemia, suggesting that the increment of intestinal Th17 cells caused by anti-miR-681 relies on CCR6 expression. CONCLUSION: The results of the study indicate that control of intestinal Th17 cells by regulating novel miR-681/CCR6 signaling attenuates endotoxemia-induced intestinal injury.

The Effectiveness of Student-Led Ward Round Training on Knowledge Acquisition, Critical Thinking Ability, and Self-Confidence of Acute Upper Gastrointestinal Bleeding for Nursing Students.

Introduction: Nursing knowledge, critical thinking ability, and self-perceived confidence are imperative to nursing skills in professional nursing practice. Therefore, nurse educators are required to use teaching strategies that will help promote their knowledge, critical thinking, and self-confidence in complex contents such as the nursing of acute upper gastrointestinal bleeding (AUGIB). Purpose: This study compares the effect of student-led and instructor-led ward-round training methods on knowledge acquisition, critical thinking ability, and self-perceived confidence during AUGIB sessions. Methods: Forty nursing students in the first year of the Emergency Nursing Residency Program were randomly divided into a student-led ward round training group (SG) and an instructor-led ward round training group (IG) with a ratio of 1:1. A knowledge quiz, critical thinking ability test, and self-perceived confidence questionnaire were performed before and after the ward round training to assess both groups of students for their knowledge acquisition, critical thinking ability, and self-perceived confidence improvement. Feedback questionnaires were conducted after the training to evaluate students' perspectives and interests concerning the teaching module. Results: The scores of the post-training quiz were significantly higher than that of the pre-training quiz in both the SG (44.10±2.92 vs 31.10±4.27, p<0.001) and IG (32.35±2.21 vs 30.55±2.24, p=0.01). In the post-training quiz, scores achieved by the students from the SG (44.10±2.92) were significantly higher than those achieved by the students from the IG (32.35±2.21, p< 0.001). The level of self-perceived confidence improved significantly after ward round training in the SG (p< 0.001). However, there was no statistically significant difference in the IG with respect to the change from pre- to post-training (p=0.43).The students' critical thinking ability improved significantly in the SG (14.95±2.58 vs 7.10±1.79, p<0.001), while no significant improvement was found in the IG (7.91±2.28 vs 6.52±2.21, p=0.07) after ward round training. Conclusion: The teaching method of SWRT improves nursing students' knowledge acquisition, critical thinking ability, and self-perceived confidence in AUGIB.

High-Fidelity Patient Simulation Incorporated Into a Flipped Classroom Improves Students' Long-Term Knowledge Retention of Acute Organophosphorus Pesticide Poisoning.

INTRODUCTION: The flipped classroom (FC) approach and high-fidelity patient simulation (HFPS) training have shown promising effects in short-term acquisition or long-term retention of knowledge in medical education. In this study, we aimed to explore the incorporation of HFPS into the FC and the impact on the long-term (3 months after classes) knowledge retention of medical undergraduate students learning about acute organophosphorus pesticide poisoning (AOPP). METHODS: Eighty-two fifth-year medical students were randomly divided into an HFPS group (HG, n = 40) and an FC group (FG, n = 42). A postclass quiz and preinternship quiz were performed to assess the short-term knowledge acquisition and long-term (3 months after classes) knowledge retention of both groups of students. Feedback questionnaires were administered immediately after the class and before the internship to assess the students' self-perceived competency. RESULTS: In the postclass quiz, the scores achieved by the students from the HG and FG were 15.58 ± 2.69 and 14.62 ± 2.19, respectively. No significant difference was found between the 2 groups (P = 0.19). In the preinternship quiz, the scores achieved by the students from the HG (14.50 ± 2.16) were significantly higher than those achieved by the students from the FG (11.40 ± 2.07, P < 0.001). There was no significant difference between the postclass quiz and preinternship quiz scores achieved by the HG students (P = 0.05). However, scores in the preinternship quiz showed a significant decline compared with the postclass quiz for the FG students (P < 0.001). Students in the HG gave significantly higher scores for self-perceived confidence in dealing with AOPP patients in the forthcoming internship on the postclass and preinternship questionnaires. CONCLUSIONS: The incorporation of HFPS into the FC approach could improve students' long-term knowledge retention of AOPP and enhance their confidence in caring for these patients in their internship.

Flipped Classroom Approach Used in the Training of Mass Casualty Triage for Medical Undergraduate Students.

OBJECTIVE: The aim of this study was to explore the application of the flipped classroom approach in the training of Mass Casualty Triage (MCT) to medical undergraduate students. METHODS: In this study, 103 fourth-year medical students were randomly divided into a Flipped Classroom (FC) group (n = 51) and a Traditional Lecture-based Classroom (TLC) group (n = 52). A post-class quiz, simulated field triage (SFT) and feedback questionnaires were performed to assess both groups of students for their learning of the course. RESULTS: In the post-quiz, the median (IQR) scores achieved by students from the FC and TLC groups were 42(5) and 39(5.5), respectively. Significant differences were found between the two groups. In the SFT, overall triage accuracy was 67.06% for FC, and 64.23% for TLC students. Over-triage and under-triage errors occurred in 18.43% and 14.50% of the FC group, respectively. The TLC group had a similar pattern of 20.77% over-triage and 15.0% under-triage errors. No significant differences were found regarding overall triage accuracy or triage errors between the two groups. CONCLUSIONS: The FC approach could enhance course grades reflected in the post-quiz and improve students' satisfaction with the class. However, there was no significant difference of competency between the two groups demonstrated in the SFT exercise.

Reduced Number and Activity of Circulating Endothelial Progenitor Cells in Acute Aortic Dissection and Its Relationship With IL-6 and IL-17.

This study investigates the alteration in function and number of circulating endothelial progenitor cells (EPCs) in patients with aortic dissection (AD), compared with hypertensive patients, and its possible mechanism. Thirty-four patients with acute aortic dissection (AAD) and 20 patients with primary hypertension were involved. Flow cytometry analysis was performed to detect the number of CD34+/KDR+ cells, and acetylated low density lipoprotein (ac-LDL) and lectin fluorescent staining method was applied to test the number of cultured EPCs. In addition, EPC migration and proliferation were measured, and plasma interleukin 6 (IL-6) and interleukin 17 (IL-17) levels were investigated. The number of circulating EPCs in the AAD group was lower than that in the non-AD group, and the proliferation and migration of circulating EPCs in the AAD group were lower than that in the non-AD group. In addition, the number, proliferation, and migration of circulating EPCs were significantly inversely correlated with the aortic dissection detection risk score (ADD-RS). More importantly, increased plasma IL-6 and IL-17 level was found in the AAD group, and the two inflammatory factors were inversely associated with the function and number of circulating EPCs in the AAD group. We first demonstrated that the number and function of circulating EPCs are reduced in the AAD group, which may be partly related to upregulated plasma IL-6 and IL-17. Our study provides novel insight on the underlying mechanism and potential therapeutic target of AAD.

Impaired activity of circulating EPCs and endothelial function are associated with increased Syntax score in patients with coronary artery disease.

It has previously been shown that the number of endothelial progenitor cells (EPCs) is negatively correlated with Syntax score in patients with coronary artery disease (CAD). However, the association between alterations in EPC function and Syntax score is still unknown. The present study evaluated the association between the activity of EPCs as well as endothelial function and Syntax score in patients with CAD and investigated the underlying mechanisms. A total of 60 patients with CAD were enrolled in 3 groups according to Syntax score, and 20 healthy subjects were recruited as the control group. The number and migratory, proliferative and adhesive activities of circulating EPCs were studied. The endothelial function was measured by flow­mediated dilatation (FMD) and the levels of nitric oxide (NO) in plasma or secreted by EPCs were detected. The number and activity of circulating EPCs were lower in patients with a high Syntax score, which was similar to the alteration in FMD. The level of NO in plasma or secreted by EPCs also decreased as Syntax score increased. There was a negative association between FMD or circulating EPCs and Syntax score. A similar association was observed between the levels of NO in plasma or secreted by EPCs and Syntax score. Patients with CAD who had a higher Syntax score exhibited lower EPC numbers or activity and weaker endothelial function, which may be associated with attenuated NO production. These findings provide novel surrogate parameters for evaluation of the severity and complexity of CAD.

Mapping the Multi-Organ miRNA-mRNA Regulatory Network in LPS-Mediated Endotoxemic Mice: Exploring the Shared Underlying Key Genes and Mechanisms.

BACKGROUND: To this day, the molecular mechanism of endotoxin-induced multi-organ failure has not been completely clarified. This study aimed to construct an miRNA-mRNA regulatory network and identify main pathways and key genes in multi-organ of LPS-mediated endotoxemic mice. METHODS: Public datasets from six mRNA and three miRNA microarray datasets were downloaded from the GEO website to screen final differentially expressed genes (FDEGs) and hub genes in the heart, lung, liver, and kidney of LPS-mediated endotoxemic mice. Functional and pathway enrichment analysis of FDEGs was used to identify the main pathways in multi-organ damage of LPS-treated mice. Finally, hub genes of each organ were intersected to obtain the key genes of multi-organ. RESULTS: Firstly, 158, 358, 299, and 91 FDEGs were identified in the heart, lung, liver, and kidney, respectively. The pathway enrichment analysis of the FDEGs then showed that the TNF signaling pathway, Toll-like receptor signaling pathway, and some viral-infection-related pathways (influenza A, measles, and herpes simplex) were the main pathways in multi-organ damage of LPS-mediated endotoxemic mice. Moreover, miRNA-mRNA or PPI regulatory networks were constructed based on FDEGs. According to these networks, 31, 34, 34, and 31 hub genes were identified in the heart, lung, liver, and kidney, respectively. Among them, nine key genes (Cd274, Cxcl1, Cxcl9, Icam1, Ifit2, Isg15, Stat1, Tlr2, and Usp18) were enriched in Toll-like receptor signaling pathway and chemokine signaling pathway. Finally, seven potential drugs were predicted based on these key genes. CONCLUSION: The shared underlying molecular pathways in endotoxin-induced multi-organ damage that have been identified include Toll-like receptor signaling pathway and TNF signaling pathway. Besides, nine key genes (Cd274, Cxcl1, Cxcl9, Icam1, Ifit2, Isg15, Stat1, Tlr2, and Usp18) and seven potential drugs were identified. Our data provide a new sight and potential target for future therapy in endotoxemia-induced multi-organ failure.

Out-of-Hospital Cardiac Arrest due to Drowning in North America: Comparison of Patient Characteristics between Survival and Mortality Groups.

Out-of-hospital cardiac arrest (OHCA) due to drowning carries high morbidity and mortality. There are a few studies on drowning-related out-of-hospital cardiac arrest (OHCA), in which patients are followed from the scene to hospital discharge. This study aims to compare patient characteristics between the survival group and mortality group of OHCA due to drowning. OHCA due to drowning cases were selected from the North America Termination of Resuscitation Association database between 2011 and 2015. The retrospective analysis of epidemiological characteristics and clinical features of all OHCA patients were performed. Of the 17,094 OHCA cases in the registry, 54 cases of OHCA due to drowning were included in this study. Among the 54 OHCAs due to drowning, 7 (13.0%) survived, while 47 (87.0%) died. Compared to the mortality group, the survival group had a higher bystander witness rate (57.1% versus 17.0%, p < 0.05), higher asystole rate (42.9% versus 78.7%, p < 0.05), and higher mild therapeutic hypothermia rate (28.6% versus 2.1%, p < 0.05). In addition, a large proportion of survivors were children (71.4%) and males (71.4%). Survival among OHCA's due to drowning was found to be improved with a higher bystander rate, higher asystole rate, and higher mild hypothermia rate. In addition, children and males comprised the majority of survivors.

Admission IL-32 concentration predicts severity and mortality of severe community-acquired pneumonia independently of etiology.

BACKGROUND: Severe community-acquired pneumonia (SCAP) is a critical disorder with high morbidity and mortality, usually manifested as acute respiratory failure and septic shock generally caused by exaggerated systemic inflammation. Interleukin-32 (IL-32), a pro-inflammatory cytokine, has been reported involved in various infectious diseases. We investigated the efficacy of the plasma IL-32 as a biomarker for evaluating the severity and clinical outcomes in SCAP patients. METHODS: A total of 124 adult immunocompetent SCAP patients and 87 healthy controls were enrolled in this observational, prospective cohort study. RESULTS: We found that PBMCs IL-32 mRNA and plasma IL-32 concentrations on admission of SCAP patients were significantly higher than healthy controls. Plasma IL-32 concentrations closely correlated with increasing severity scores, the need for vasopressor support or invasive mechanical ventilation but not with the etiology. The area under the curve (AUC) for predicting 30-day mortality using IL-32 was 0.812, is superior to WBCs and CRP. Incorporation of IL-32 with the severity scores were shown to improve the prognostic accuracy considerably. Furthermore, the 30-day cumulative survival rate in high IL-32 concentration group was significantly lower than that in the low concentration group. In a multivariate Cox regression analysis, higher IL-32 concentration and higher PSI score were recognized as the independent risk factors for survival, and the relative risks were 2.568 and 3.362, respectively. CONCLUSIONS: Admission IL-32 concentration closely related to the severity and mortality of SCAP, and it may be served as a potential biomarker to help clinical judgment and management.

Elevated GTP Cyclohydrolase I Pathway in Endothelial Progenitor Cells of Overweight Premenopausal Women.

Background/Aims. Sexual differences exist in endothelial progenitor cells (EPCs), and various cardiovascular risk factors are associated with the preservation of endothelial function in premenopausal women. However, it is unclear whether differences in endothelial function and circulating EPCs exist between overweight premenopausal women and age-matched men. Methods. We compared EPC counting and functions in normal-weight and overweight premenopausal women and men, evaluated endothelial function in each group, and detected the expression of the guanosine triphosphate cyclohydrolase I (GTPCH I) pathway. Results. The number of EPCs was lower in the male group than in the female group, regardless of normal-weight or overweight status, and there was no significant difference between the different weight groups among females or males. Endothelial function and EPC migration and proliferation were preserved in overweight premenopausal women compared with overweight men as were nitric oxide (NO) levels in plasma and secreted by EPCs. Endothelial function, the circulating EPC population, and NO levels were not different between normal-weight and overweight premenopausal women. Flow-mediated dilatation was significantly correlated with EPC function, plasma NO levels, and EPC-secreted NO. Conclusions. This investigation provides the first evidence for sex-based differences in EPC activity and endothelial function in overweight middle-aged individuals; these differences are associated with alterations in NO production and may partly occur through downregulation of the GTPCH I pathway. The present results provide new insights into the mechanism underlying the preserved endothelial function in overweight premenopausal women and may uncover a potential therapeutic target for endothelial repair in overweight population.

Conversion from Nonshockable to Shockable Rhythms and Out-of-Hospital Cardiac Arrest Outcomes by Initial Heart Rhythm and Rhythm Conversion Time.

BACKGROUND: The conversion from a nonshockable rhythm (asystole or pulseless electrical activity (PEA)) to a shockable rhythm (pulseless ventricular tachycardia or ventricular fibrillation) may be associated with better out-of-hospital cardiac arrest (OHCA) outcomes. There are insufficient data on the prognostic significance of such conversions by initial heart rhythm and different rhythm conversion time. METHODS: Among 24,849 adult OHCA patients of presumed cardiac etiology with initial asystole or PEA in the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry (version 3, 2011-2015), we examined the association of shockable rhythm conversion with prehospital return of spontaneous circulation (ROSC), survival, and favorable functional outcome (modified Rankin Scale score ≤3) at hospital discharge by initial rhythm and rhythm conversion time (time from cardiopulmonary resuscitation (CPR) initiation by emergency medical providers to first shock delivery), using logistic regression adjusting for key clinical characteristics. RESULTS: Of 16,516 patients with initial asystole and 8,333 patients with initial PEA, 16% and 20% underwent shockable rhythm conversions; the median rhythm conversion time was 12.0 (IQR: 6.7-18.7) and 13.2 (IQR: 7.0-20.5) min, respectively. No difference was found in odds of prehospital ROSC across rhythm conversion time, regardless of initial heart rhythm. Shockable rhythm conversion was associated with survival and favorable functional outcome at hospital discharge only when occurred during the first 15 min of CPR, for those with initial asystole, or the first 10 min of CPR, for those with initial PEA. The associations between shockable rhythm conversion and outcomes were stronger among those with initial asystole compared with those with initial PEA. CONCLUSIONS: The conversion from a nonshockable rhythm to a shockable rhythm was associated with better outcomes only when occurred early in initial nonshockable rhythm OHCA, and it has greater prognostic significance when the initial rhythm was asystole.

Intravenous versus intraosseous adrenaline administration in out-of-hospital cardiac arrest: A retrospective cohort study.

BACKGROUND: Adrenaline is an important component in the resuscitation of individuals experiencing out-of-hospital cardiac arrest (OHCA). The 2018 Advanced Cardiac Life Support (ACLS) algorithm gives the option of either intravenous (IV) or intraosseous (IO) routes for adrenaline administration during cardiac arrest. However, the optimal route during prehospital resuscitation remains controversial. This study aims to investigate whether IV and IO routes lead to different outcomes in OHCA patients who received prehospital adrenaline. METHODS: This retrospective analysis included adult patients with OHCA of presumed cardiac origin who had Emergency Medical Services (EMS) CPR, received adrenaline, and were enrolled in the Resuscitation Outcomes Consortium (ROC) Cardiac Epistry version 3 database between 2011 and 2015. We divided the study population into IV and IO groups based on the administration route. Logistic regression analysis was performed to evaluate the association between adrenaline delivery routes and prehospital return of spontaneous circulation (ROSC), survival to hospital discharge, and favorable neurological outcome. RESULTS: Of the 35,733 patients included, 27,758 (77.7%) had adrenaline administered via IV access and 7975 (22.3%) via IO access. With the IO group as a reference in the logistic regression model, the adjusted odds ratios of the IV group for prehospital ROSC, survival and favorable neurological outcome were 1.367 (95%CI, 1.276-1.464), 1.468 (95%CI, 1.264-1.705) and 1.849 (95%CI, 1.526-2.240), respectively. Similar results were found in the propensity score matched population and subgroup analysis. CONCLUSION: Compared with the IO approach, the IV approach appears to be the optimal route for adrenaline administration in advanced life support for OHCA during prehospital resuscitation.

Prolonged versus Intermittent Infusion of Antibiotics in Acute and Severe Infections: A Meta-analysis.

BACKGROUND: Acute and severe infections are an absolute indication for the use of intravenous broad-spectrum antibiotics. However, previous studies have found inconsistent clinical advantages of prolonged (extended [≥3-hour infusion] or continuous [24-hour fixed rate infusion]) over intermittent (6, or 8, or 12 interval hours infusion) infusion. The clinical superiority between prolonged and intermittent infusion in treating acute and severe infections thus continues to be elusive. We conducted a meta-analysis to summarize all published randomized controlled trials (RCTs), prospective and retrospective observational studies to determine whether prolonged infusion, compared to intermittent infusion, is correlated with lower mortality and better clinical outcome. METHODS: We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to August 31, 2018) and EMBASE (January 1, 1980 to August 31, 2018) with no restrictions to collect RCTs and observational studies comparing prolonged infusion with intermittent infusion of the same intravenous administered antibiotics among adult hospitalized patients. A total of 43 studies including 30 RCTs, 5 prospective observational studies and 8 retrospective observational studies were identified. RESULTS: In comparison with intermittent infusion, prolonged infusion of antibiotics was associated with a reduction in all-cause mortality (pooled relative risk [RR] = 0.77, 95% confidence interval [CI] = 0.66-0.89) and improvement in clinical cure (RR = 1.11, 95% CI = 1.04-1.19), which was also observed in subgroups such as non-RCTs (mortality, RR = 0.63, 95% CI = 0.48-0.81; clinical cure RR = 1.33, 95% CI = 1.13-1.57) or studies with patients and APACHE II scores 15 (mortality, RR = 0.74, 95% CI 0.63-0.89; clinical cure RR = 1.19, 95% CI = 1.07-1.32). Moreover, in RCTs, mortality (RR = 0.86, 95% CI 0.72-1.03) between the two dosing strategies was not remarkably changed but clinical cure (RR = 1.07, 95% CI = 1.01-1.13) showed a significant advantage for prolonged infusion. Additionally, no significant differences in mortality between the two dosing strategies was found (RR = 0.87, 95% CI = 0.70-1.09) but a distinct improvement in clinical cure was observed (RR = 1.14, 95% CI = 1.02-1.28) in the prolonged infusion group for septic patients. Among two infusion modes, statistically significant severe adverse events were not reported (RR=0.83, 95% CI = 0.62-1.13). CONCLUSION: Better outcomes in hospitalized patients, especially in those who were critical ill, were reported in prolonged infusion of intravenous antibiotics compared with traditional intermittent infusion.

PERK is essential for proliferation of intestinal stem cells in mice.

Protein kinase RNA-like Endoplasmic Reticulum Kinase (PERK) is an endoplasmic reticulum stress sensor that possesses pro-survival capability and contributes to cell homeostasis and survival. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) has been recognized as a stem cell marker in intestinal epithelial cells. To determine whether PERK modulates the proliferation of intestinal stem cells, we investigated the effects of PERK knock-down on intestinal Lgr5-positive stem cells in mice. Lgr5-EGFP knock-in mice were fed with lentivirus-PERK shRNA twice a day for three days. Isolated intestinal Lgr5-positive stem cells were treated with lentivirus-PERK shRNA. The number of Lgr5-positive cells, the proliferation and apoptotic indices, several biomarkers for proliferation and differentiation, and Akt expression in intestinal stem cells were detected in vivo, in vitro and in two intestinal epithelial injury models caused by radiotherapy and sepsis. PERK knock-down could significantly diminish the number and proliferation of Lgr5-positive cells, induce the low expression of several proliferation markers and the high expression of several differentiation markers in Lgr5-positive cells, enhance the apoptotic Lgr5-positive cells, and reduce the Akt expression in intestinal Lgr5-positive stem cells. Similar results were observed in radiotherapy- and sepsis-induced intestinal injuries. Moreover, PERK inhibition markedly decreased the survival of mice in response to radiation and sepsis. These results suggest a critical role for PERK in the proliferation and survival of intestinal stem cells in mice.

Downregulated GTCPH I/BH4 Pathway and Decreased Function of Circulating Endothelial Progenitor Cells and Their Relationship with Endothelial Dysfunction in Overweight Postmenopausal Women.

Endothelial progenitor cells (EPCs) have endogenous endothelium-reparative potential, but obesity impairs EPCs. Overweight premenopausal women have a normal number of circulating EPCs with functional activity, but whether EPCs in overweight postmenopausal women can repair obesity-related endothelial damage requires further investigation. For this purpose, we examined the function and number of circulating EPCs, evaluated vascular endothelial function, and explored the underlying mechanism. Compared with normal weight or overweight age-matched men, postmenopausal women (overweight or normal weight) had a diminished number of circulating EPCs and impaired vascular endothelial function, as detected by flow-mediated dilatation. Moreover, GTCPH I expression and the nitric oxide level in overweight postmenopausal women and men were significantly decreased. Together, our findings demonstrate that the number or function of circulating EPCs and endothelial function, which is partially regulated by the GTCPH I/BH4 signaling pathway, is not preserved in overweight postmenopausal women. The GTCPH I/BH4 pathway in circulating EPCs may be a potential therapeutic target for endothelial injury in overweight postmenopausal women.

Out-of-hospital cardiac arrest with Do-Not-Resuscitate orders signed in hospital: Who are the survivors?

BACKGROUND: Signing Do-Not-Resuscitate orders is an important element contributing to a worse prognosis for out-of-hospital cardiac arrest (OHCA). However, our data showed that some of those OHCA patients with Do-Not-Resuscitate orders signed in hospital survived to hospital discharge, and even recovered with favorable neurological function. In this study, we described their clinical features and identified those factors that were associated with better outcomes. METHODS: A retrospective, observational analysis was performed on all adult non-traumatic OHCA who were enrolled in the Resuscitation Outcomes Consortium (ROC) PRIMED study but signed Do-Not-Resuscitate orders in hospital after admission. We reported their demographics, characteristics, interventions and outcomes of all enrolled cases. Patients surviving and not surviving to hospital discharge, as well as those who did and did not obtain favorable neurological recovery, were compared. Logistic regression models assessed those factors which might be prognostic to survival and favorable neurological outcomes at discharge. RESULTS: Of 2289 admitted patients with Do-Not-Resuscitate order signed in hospital, 132(5.8%) survived to hospital discharge and 28(1.2%) achieved favorable neurological recovery. Those factors, including witnessed arrest, prehospital shock delivered, Return of Spontaneous Circulation (ROSC) obtained in the field, cardiovascular interventions or procedures applied, and no prehospital adrenaline administered, were independently associated with better outcomes. CONCLUSIONS: We suggest that some factors should be taken into considerations before Do-Not-Resuscitate decisions are made in hospital for those admitted OHCA patients.

The efficacy of initial ventilation strategy for adult immunocompromised patients with severe acute hypoxemic respiratory failure: study protocol for a multicentre randomized controlled trial (VENIM).

BACKGROUND: Acute respiratory failure (ARF) is still one of the most severe complications in immunocompromised patients. Our previous systematic review showed noninvasive mechanical ventilation (NIV) reduced mortality, length of hospitalization and ICU stay in AIDS/hematological malignancy patients with relatively less severe ARF, compared to invasive mechanical ventilation (IMV). However, this systematic review was based on 13 observational studies and the quality of evidence was low to moderate. The efficacy of NIV in more severe ARF and in patients with other causes of immunodeficiency is still unclear. We aim to determine the efficacy of the initial ventilation strategy in managing ARF in immunocompromised patients stratified by different disease severity and causes of immunodeficiency, and explore predictors for failure of NIV. METHODS AND ANALYSIS: The VENIM is a multicentre randomized controlled trial (RCT) comparing the effects of NIV compared with IMV in adult immunocompromised patients with severe hypoxemic ARF. Patients who meet the indications for both forms of ventilatory support will be included. Primary outcome will be 30-day all-cause mortality. Secondary outcomes will include in-hospital mortality, length of stay in hospital, improvement of oxygenation, nosocomial infections, seven-day organ failure, adverse events of intervention, et al. Subgroups with different disease severity and causes of immunodeficiency will also be analyzed. DISCUSSION: VENIM is the first randomized controlled trial aiming at assessing the efficacy of initial ventilation strategy in treating moderate and severe acute respiratory failure in immunocompromised patients. The result of this RCT may help doctors with their ventilation decisions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02983851 . Registered 2 September 2016.

Conversion to shockable rhythms is associated with better outcomes in out-of-hospital cardiac arrest patients with initial asystole but not in those with pulseless electrical activity.

BACKGROUND: The prognostic implication of conversion from initially non-shockable to shockable rhythms in patients with out-of-hospital cardiac arrest (OHCA) remains unclear. Our objective is to determine whether the conversion to shockable rhythms is a reliable predictor of short- and long-term outcomes both in patients who initially presented with pulseless electrical activity (PEA) and in those with asystole. METHODS: A secondary analysis was performed on non-traumatic OHCA cases ≥18 years old with PEA or asystole as initial rhythms, who were treated in the field and enrolled in the Resuscitation Outcomes Consortium (ROC) PRIMED study (clinicaltrials.gov/ct2/show/NCT00394706). We reported the characteristics and outcomes for those patients with or without shocks delivered in the field. Logistic regression analysis assessed the association of shock delivery with pre-hospital return of spontaneous circulation (ROSC), survival to hospital discharge and favorable neurological outcome as well. RESULTS: Of the 9902 included cases, 3415 (34.5%) were initially in PEA and 6487 (65.5%) were in asystole. 744 (21.8%) PEA and 1134 (17.5%) asystolic patients underwent rhythm conversions and received subsequent shocks. For asystolic patients, the adjusted odds ratios (ORs) of shock delivery for pre-hospital ROSC, survival to discharge and favorable neurological outcome were 1.862 (95%CI 1.590-2.180), 3.778 (95%CI 2.374-6.014) and 4.154 (95%CI 2.192-7.871) respectively, while for PEA patients they were 0.951 (95%CI 0.796-1.137), 1.115 (95%CI 0.720-1.726) and 1.373 (95%CI 0.790-2.385) respectively. CONCLUSIONS: Conversion to shockable rhythms was associated with better outcomes in initially asystolic OHCA patients, whereas such associations were not observed in patients initially in PEA.