ECRG4 regulates neutrophil recruitment and CD44 expression during the inflammatory response to injury.

The complex molecular microenvironment of the wound bed regulates the duration and degree of inflammation in the wound repair process, while its dysregulation leads to impaired healing. Understanding factors controlling this response provides therapeutic targets for inflammatory disease. Esophageal cancer-related gene 4 (ECRG4) is a candidate chemokine that is highly expressed on leukocytes. We used ECRG4 knockout (KO) mice to establish that the absence of ECRG4 leads to defective neutrophil recruitment with a delay in wound healing. An in vitro human promyelocyte model identified an ECRG4-mediated suppression of the hyaluronic acid receptor, CD44, a key receptor mediating inflammation resolution. In ECRG4 KO mouse leukocytes, there was an increase in CD44 expression, consistent with a model in which ECRG4 negatively regulates CD44 levels. Therefore, we propose a previously unidentified mechanism in which ECRG4 regulates early neutrophil recruitment and subsequent CD44-mediated resolution of inflammation

Uniquely human CHRFAM7A gene increases the hematopoietic stem cell reservoir in mice and amplifies their inflammatory response.

A subset of genes in the human genome are uniquely human and not found in other species. One example is CHRFAM7A, a dominant-negative inhibitor of the antiinflammatory α7 nicotinic acetylcholine receptor (α7nAChR/CHRNA7) that is also a neurotransmitter receptor linked to cognitive function, mental health, and neurodegenerative disease. Here we show that CHRFAM7A blocks ligand binding to both mouse and human α7nAChR, and hypothesized that CHRFAM7A-transgenic mice would allow us to study its biological significance in a tractable animal model of human inflammatory disease, namely SIRS, the systemic inflammatory response syndrome that accompanies severe injury and sepsis. We found that CHRFAM7A increased the hematopoietic stem cell (HSC) reservoir in bone marrow and biased HSC differentiation to the monocyte lineage in vitro. We also observed that while the HSC reservoir was depleted in SIRS, HSCs were spared in CHRFAM7A-transgenic mice and that these mice also had increased immune cell mobilization, myeloid cell differentiation, and a shift to inflammatory monocytes from granulocytes in their inflamed lungs. Together, the findings point to a pathophysiological inflammatory consequence to the emergence of CHRFAM7A in the human genome. To this end, it is interesting to speculate that human genes like CHRFAM7A can account for discrepancies between the effectiveness of drugs like α7nAChR agonists in animal models and human clinical trials for inflammatory and neurodegenerative disease. The findings also support the hypothesis that uniquely human genes may be contributing to underrecognized human-specific differences in resiliency/susceptibility to complications of injury, infection, and inflammation, not to mention the onset of neurodegenerative disease

A Novel Fluid Resuscitation Strategy Modulates Pulmonary Transcription Factor Activation in a Murine Model of Hemorrhagic Shock

INTRODUCTION: Combining the hemodynamic and immune benefits of hypertonic saline with the anti-inflammatory effects of the phosphodiesterase inhibitor pentoxifylline (HSPTX) as a hemorrhagic shock resuscitation strategy reduces lung injury when compared with the effects of Ringer's lactate (RL). We hypothesized that HSPTX exerts its anti-inflammatory effects by interfering with nuclear factor kappa B/cAMP response element-binding protein (NF-κB-CREB) competition for the coactivator CREB-binding protein (CBP) in lung tissue, thus affecting pro-inflammatory mediator production. METHODS: Male Sprague-Dawley rats underwent 60 minutes of hemorrhagic shock to reach a mean arterial blood pressure of 35 mmHg followed by resuscitation with either RL or HSPTX (7.5% HS + 25 mg/kg PTX). After four hours, lung samples were collected. NF-κB activation was assessed by measuring the levels of phosphorylated cytoplasmic inhibitor of kappa B (I-κB) and nuclear NF-κB p65 by western blot. NF-κB and CREB DNA-binding activity were measured by electrophoretic mobility shift assay (EMSA). Competition between NF-κB and CREB for the coactivator CBP was determined by immunoprecipitation. Interleukin-8 (IL-8) levels in the lung were measured by ELISA. RESULTS: RL resuscitation produced significantly higher levels of lung IL-8 levels, I-κB phosphorylation, p65 phosphorylation, and NF-κB DNA binding compared with HSPTX. NF-κB-CBP-binding activity was similar in both groups, whereas CREB-CBP-binding activity was significantly increased with HSPTX. CREB-DNA binding-activity increased to a greater level with HSPTX compared with RL. DISCUSSION: HSPTX decreases lung inflammation following hemorrhagic shock compared with conventional resuscitation using RL through attenuation of NF-κB signaling and increased CREB-DNA binding activity. HSPTX may have therapeutic potential in the attenuation of ischemia-reperfusion injury observed after severe hemorrhagic shock

Abdominal damage control surgery and reconstruction: world society of emergency surgery position paper

Abstract Damage control laparotomy was first described by Dr. Harlan Stone in 1983 when he suggested that patients with severe trauma should have their primary procedures abbreviated when coagulopathy was encountered. He recommended temporizing patients with abdominal packing and temporary closure to allow restoration of normal physiology prior to returning to the operating room for definitive repair. The term damage control in the trauma setting was coined by Rotondo et al., in 1993. Studies in subsequent years have validated this technique by demonstrating decreased mortality and immediate post-operative complications. The indications for damage control laparotomy have evolved to encompass abdominal compartment syndrome, abdominal sepsis, vascular and acute care surgery cases. The perioperative critical care provided to these patients, including sedation, paralysis, nutrition, and fluid management strategies may improve closure rates and recovery. In the rare cases of inability to primarily close the abdomen, there are a number of reconstructive strategies that may be used in the acute and chronic phases of abdominal closure

Esophageal cancer-related gene 4 at the interface of injury, inflammation, infection, and malignancy

In humans, esophageal cancer-related gene 4 (ECRG4) is encoded by four exons in the c2orf40 locus of chromosome 2. Translation of ECRG4 messenger ribonucleic acid produces a 148 amino acid-secreted 17 KDa protein that is then processed to 14, ten, eight, six, four, and two KDa peptides, depending on the cell in which the gene is expressed. As hypermethylation at the c2orf40 locus inhibits ECRG4 gene expression in many epithelial cancers, several investigators have speculated that ECRG4 is a candidate tumor suppressor. Indeed, overexpression of ECRG4 inhibits cell proliferation in vitro, but it also has a wide range of effects in vivo beyond its antitumor activity. ECRG4 overexpression affects apoptosis, senescence, cell migration, inflammation, injury, and infection responsiveness. ECRG4 activities also depend on its cellular localization, secretion, and post-translational processing. These cytokine/chemokine-like characteristics argue that ECRG4 is not a traditional candidate tumor suppressor gene, as originally predicted by its downregulation in cancer. We review how insights into the regulation of ECRG4 gene expression, knowledge of its primary structure, and the study of its emerging physiological functions come together to support a much more complex role for ECRG4 at the interface of inflammation, infection, and malignancy

Hospital-based specialist palliative care compared with usual care for adults with advanced illness and their caregivers: a systematic review

Background Most deaths still take place in hospital; cost-effective commissioning of end-of-life resources is a priority. This review provides clarity on the effectiveness of hospital-based specialist palliative care. Objectives The objectives were to assess the effectiveness and cost-effectiveness of hospital-based specialist palliative care. Population Adult patients with advanced illnesses and their unpaid caregivers. Intervention Hospital-based specialist palliative care. Comparators Inpatient or outpatient hospital care without specialist palliative care input at the point of entry to the study, or community care or hospice care provided outside the hospital setting (usual care). Primary outcomes Patient health-related quality of life and symptom burden. Data sources Six databases (The Cochrane Library, MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO and CareSearch), clinical trial registers, reference lists and systematic reviews were searched to August 2019. Review methods Two independent reviewers screened, data extracted and assessed methodological quality. Meta-analysis was carried out using RevMan (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark), with separate synthesis of qualitative data. Results Forty-two randomised controlled trials involving 7779 participants (6678 patients and 1101 unpaid caregivers) were included. Diagnoses of participants were as follows: cancer, 21 studies; non-cancer, 14 studies; and mixed cancer and non-cancer, seven studies. Hospital-based specialist palliative care was offered in the following models: ward based (one study), inpatient consult (10 studies), outpatient (six studies), hospital at home or hospital outreach (five studies) and multiple settings that included hospital (20 studies). Meta-analyses demonstrated significant improvement favouring hospital-based specialist palliative care over usual care in patient health-related quality of life (10 studies, standardised mean difference 0.26, 95% confidence interval 0.15 to 0.37; I 2 = 3%) and patient satisfaction with care (two studies, standardised mean difference 0.36, 95% confidence interval 0.14 to 0.57; I 2 = 0%), a significant reduction in patient symptom burden (six studies, standardised mean difference –0.26, 95% confidence interval –0.41 to –0.12; I 2 = 0%) and patient depression (eight studies, standardised mean difference –0.22, 95% confidence interval –0.34 to –0.10; I 2 = 0%), and a significant increase in the chances of patients dying in their preferred place (measured by number of patients with home death) (seven studies, odds ratio 1.63, 95% confidence interval 1.23 to 2.16; I 2 = 0%). There were non-significant improvements in pain (four studies, standardised mean difference –0.16, 95% confidence interval –0.33 to 0.01; I 2 = 0%) and patient anxiety (five studies, mean difference –0.63, 95% confidence interval –2.22 to 0.96; I 2 = 76%). Hospital-based specialist palliative care showed no evidence of causing serious harm. The evidence on mortality/survival and cost-effectiveness was inconclusive. Qualitative studies (10 studies, 322 participants) suggested that hospital-based specialist palliative care was beneficial as it ensured personalised and holistic care for patients and their families, while also fostering open communication, shared decision-making and respectful and compassionate care. Limitation In almost half of the included randomised controlled trials, there was palliative care involvement in the control group. Conclusions Hospital-based specialist palliative care may offer benefits for person-centred outcomes including health-related quality of life, symptom burden, patient depression and satisfaction with care, while also increasing the chances of patients dying in their preferred place (measured by home death) with little evidence of harm. Future work More studies are needed of populations with non-malignant diseases, different models of hospital-based specialist palliative care, and cost-effectiveness. Study registration This study is registered as PROSPERO CRD42017083205. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 12. See the NIHR Journals Library website for further project information

The effectiveness and cost-effectiveness of hospital-based specialist palliative care for adults with advanced illness and their caregivers

BackgroundSerious illness is often characterised by physical/psychological problems, family support needs, and high healthcare resource use. Hospital‐based specialist palliative care (HSPC) has developed to assist in better meeting the needs of patients and their families and potentially reducing hospital care expenditure. There is a need for clarity on the effectiveness and optimal models of HSPC, given that most people still die in hospital and also to allocate scarce resources judiciously.ObjectivesTo assess the effectiveness and cost‐effectiveness of HSPC compared to usual care for adults with advanced illness (hereafter patients) and their unpaid caregivers/families.Search methodsWe searched CENTRAL, CDSR, DARE and HTA database via the Cochrane Library; MEDLINE; Embase; CINAHL; PsycINFO; CareSearch; National Health Service Economic Evaluation Database (NHS EED) and two trial registers to August 2019, together with checking of reference lists and relevant systematic reviews, citation searching and contact with experts to identify additional studies.Selection criteriaWe included randomised controlled trials (RCTs) evaluating the impact of HSPC on outcomes for patients or their unpaid caregivers/families, or both. HSPC was defined as specialist palliative care delivered by a palliative care team that is based in a hospital providing holistic care, co‐ordination by a multidisciplinary team, and collaboration between HSPC providers and generalists. HSPC was provided to patients while they were admitted as inpatients to acute care hospitals, outpatients or patients receiving care from hospital outreach teams at home. The comparator was usual care, defined as inpatient or outpatient hospital care without specialist palliative care input at the point of entry into the study, community care or hospice care provided outside of the hospital setting.Data collection and analysisWe used standard methodological procedures expected by Cochrane. We assessed risk of bias and extracted data. To account for use of different scales across studies, we calculated standardised mean differences (SMDs) with 95% confidence intervals (CIs) for continuous data. We used an inverse variance random‐effects model. For binary data, we calculated odds ratio (ORs) with 95% CIs. We assessed the evidence using GRADE and created a 'Summary of findings' table.Our primary outcomes were patient health‐related quality of life (HRQoL) and symptom burden (a collection of two or more symptoms). Key secondary outcomes were pain, depression, satisfaction with care, achieving preferred place of death, mortality/survival, unpaid caregiver burden, and cost‐effectiveness. Qualitative data was analysed where available.Main resultsWe identified 42 RCTs involving 7779 participants (6678 patients and 1101 caregivers/family members). Twenty‐one studies were with cancer populations, 14 were with non‐cancer populations (of which six were with heart failure patients), and seven with mixed cancer and non‐cancer populations (mixed diagnoses).HSPC was offered in different ways and included the following models: ward‐based, inpatient consult, outpatient, hospital‐at‐home or hospital outreach, and service provision across multiple settings which included hospital. For our main analyses, we pooled data from studies reporting adjusted endpoint values. Forty studies had a high risk of bias in at least one domain.Compared with usual care, HSPC improved patient HRQoL with a small effect size of 0.26 SMD over usual care (95% CI 0.15 to 0.37; I2 = 3%, 10 studies, 1344 participants, low‐quality evidence, higher scores indicate better patient HRQoL). HSPC also improved other person‐centred outcomes. It reduced patient symptom burden with a small effect size of ‐0.26 SMD over usual care (95% CI ‐0.41 to ‐0.12; I2 = 0%, 6 studies, 761 participants, very low‐quality evidence, lower scores indicate lower symptom burden). HSPC improved patient satisfaction with care with a small effect size of 0.36 SMD over usual care (95% CI 0.41 to 0.57; I2 = 0%, 2 studies, 337 participants, low‐quality evidence, higher scores indicate better patient satisfaction with care). Using home death as a proxy measure for achieving patient's preferred place of death, patients were more likely to die at home with HSPC compared to usual care (OR 1.63, 95% CI 1.23 to 2.16; I2 = 0%, 7 studies, 861 participants, low‐quality evidence). Data on pain (4 studies, 525 participants) showed no evidence of a difference between HSPC and usual care (SMD ‐0.16, 95% CI ‐0.33 to 0.01; I2 = 0%, very low‐quality evidence). Eight studies (N = 1252 participants) reported on adverse events and very low‐quality evidence did not demonstrate an effect of HSPC on serious harms. Two studies (170 participants) presented data on caregiver burden and both found no evidence of effect of HSPC (very low‐quality evidence). We included 13 economic studies (2103 participants). Overall, the evidence on cost‐effectiveness of HSPC compared to usual care was inconsistent among the four full economic studies. Other studies that used only partial economic analysis and those that presented more limited resource use and cost information also had inconsistent results (very low‐quality evidence).Quality of the evidenceThe quality of the evidence assessed using GRADE was very low to low, downgraded due to a high risk of bias, inconsistency and imprecision.Authors' conclusionsVery low‐ to low‐quality evidence suggests that when compared to usual care, HSPC may offer small benefits for several person‐centred outcomes including patient HRQoL, symptom burden and patient satisfaction with care, while also increasing the chances of patients dying in their preferred place (measured by home death). While we found no evidence that HSPC causes serious harms, the evidence was insufficient to draw strong conclusions. Although these are only small effect sizes, they may be clinically relevant at an advanced stage of disease with limited prognosis, and are person‐centred outcomes important to many patients and families. More well conducted studies are needed to study populations with non‐malignant diseases and mixed diagnoses, ward‐based models of HSPC, 24 hours access (out‐of‐hours care) as part of HSPC, pain, achieving patient preferred place of care, patient satisfaction with care, caregiver outcomes (satisfaction with care, burden, depression, anxiety, grief, quality of life), and cost‐effectiveness of HSPC. In addition, research is needed to provide validated person‐centred outcomes to be used across studies and populations

A Platform to Study the Effects of Electrical Stimulation on Immune Cell Activation During Wound Healing.

Wound healing is a complex process involving diverse changes in multiple cell types where the application of electric fields has been shown to accelerate wound closure. To define the efficacy of therapies based on electric fields, it would be valuable to have a platform to systematically study the effects of electrical stimulation (ES) upon the inflammation phase and the activation of signaling mediators. Here, an in vivo ES model in which flexible electrodes are applied to an animal model for monitoring inflammation in a wound is reported on. Subcutaneous implants of polyvinyl alcohol sponges elicit inflammation response as defined by the infiltration of leukocytes. The wound site is subjected to electric fields using two types of additively fabricated flexible electrode arrays. The sponges are then harvested for flow cytometry analysis to identify changes in the phosphorylation state of intracellular targets. This platform enables studies of molecular mechanisms, as it shows that an application of low-frequency ES ≤0.5 Hz increases phosphorylation of Erk proteins in recruited leukocytes, identifying a signaling pathway that is activated during the healing process

Outcomes in patients with gunshot wounds to the brain.

Introduction:Gunshot wounds to the brain (GSWB) confer high lethality and uncertain recovery. It is unclear which patients benefit from aggressive resuscitation, and furthermore whether patients with GSWB undergoing cardiopulmonary resuscitation (CPR) have potential for survival or organ donation. Therefore, we sought to determine the rates of survival and organ donation, as well as identify factors associated with both outcomes in patients with GSWB undergoing CPR. Methods:We performed a retrospective, multicenter study at 25 US trauma centers including dates between June 1, 2011 and December 31, 2017. Patients were included if they suffered isolated GSWB and required CPR at a referring hospital, in the field, or in the trauma resuscitation room. Patients were excluded for significant torso or extremity injuries, or if pregnant. Binomial regression models were used to determine predictors of survival/organ donation. Results:825 patients met study criteria; the majority were male (87.6%) with a mean age of 36.5 years. Most (67%) underwent CPR in the field and 2.1% (n=17) survived to discharge. Of the non-survivors, 17.5% (n=141) were considered eligible donors, with a donation rate of 58.9% (n=83) in this group. Regression models found several predictors of survival. Hormone replacement was predictive of both survival and organ donation. Conclusion:We found that GSWB requiring CPR during trauma resuscitation was associated with a 2.1% survival rate and overall organ donation rate of 10.3%. Several factors appear to be favorably associated with survival, although predictions are uncertain due to the low number of survivors in this patient population. Hormone replacement was predictive of both survival and organ donation. These results are a starting point for determining appropriate treatment algorithms for this devastating clinical condition. Level of evidence:Level II