Current and novel therapies for management of Acinetobacter baumannii-associated pneumonia.

Acinetobacter baumannii is a common pathogen associated with hospital-acquired pneumonia showing increased resistance to carbapenem and colistin antibiotics nowadays. Infections with A. baumannii cause high patient fatalities due to their capability to evade current antimicrobial therapies, emphasizing the urgency of developing viable therapeutics to treat A. baumannii-associated pneumonia. In this review, we explore current and novel therapeutic options for overcoming therapeutic failure when dealing with A. baumannii-associated pneumonia. Among them, antibiotic combination therapy administering several drugs simultaneously or alternately, is one promising approach for optimizing therapeutic success. However, it has been associated with inconsistent and inconclusive therapeutic outcomes across different studies. Therefore, it is critical to undertake additional clinical trials to ascertain the clinical effectiveness of different antibiotic combinations. We also discuss the prospective roles of novel antimicrobial therapies including antimicrobial peptides, bacteriophage-based therapy, repurposed drugs, naturally-occurring compounds, nanoparticle-based therapy, anti-virulence strategies, immunotherapy, photodynamic and sonodynamic therapy, for utilizing them as additional alternative therapy while tackling A. baumannii-associated pneumonia. Importantly, these innovative therapies further require pharmacokinetic and pharmacodynamic evaluation for safety, stability, immunogenicity, toxicity, and tolerability before they can be clinically approved as an alternative rescue therapy for A. baumannii-associated pulmonary infections.

Novel insights into patient's thoughts about their body image in abdominal wall hernia.

BACKGROUND: Abdominal wall hernias (AWH) are frequently large and deforming. Despite this, little is known about how AWH impact upon body image. This study is the first study to qualitatively examine patients' subjective lived experiences of how AWH affects their body image. METHODS: Fifteen patients were interviewed from a purposive sample of AWH patients awaiting surgery until no new narrative themes emerged. Interviews explored patient thoughts and experiences of AWH and body image. Data were examined using interpretative phenomenological analysis (IPA). RESULTS: Two key themes pertaining to body image were identified: "Changes to perceptions of self" and "Fears concerning other's perceptions of them". Both themes were often interrelated and displayed detrimental effects AWH had on patients' body image. CONCLUSIONS: Our findings illustrate that AWH detrimentally affected patients' body image. This aspect of patient care can be treated and managed through better pre-operative information, including on body image as part of a holistic needs assessment (HNA), and ensuring the results are addressed in a patient care package. These development suggestions may positively affect the AWH patient's experience and outcomes in terms of Quality of Life (QoL) by preparing patients better for realistic results regarding what can be achieved in terms of form, function thus making a more holistic recovery from surgery.

Abdominal wall hernia and mental health: patients lived experiences and implications for patient care.

BACKGROUND: Abdominal wall hernia (AWH) affects mental health and mental health questions are frequently included within Patient-Reported Outcome Measures (PROMS) for this patient population. However, these questions have not been informed by the subjective lived experiences of mental health in AWH patients. This study is the first to qualitatively examine how AWH affects patients' mental health. METHODS: Fifteen patients were interviewed from a purposive sample of AWH patients until no new themes emerged. Interviews explored patient thoughts and experiences of AWH and mental health. Data were examined using Interpretative Phenomenological Analysis (IPA). RESULTS: Three key themes pertaining to mental health were identified: "psychological and emotional distress", "identity disruption" and "coping mechanisms and support systems". CONCLUSION: Our findings illustrate that AWH is a pathology that can have a significant detrimental impact on people's mental health. This impact has implications for patient care and can be treated and managed through better psychological support. This support may positively affect AWH patient's experience and outcomes in terms of quality of life. This paper provides recommendations for improved AWH patient care in regard to mental health.

Evaluation of in ovo feeding of low or high mixtures of cysteine and lysine on performance, intestinal morphology and physiological responses of thermal-challenged broiler embryos.

The objective of this study was to evaluate the effect of in ovo feeding cysteine, lysine or their combinations on the perinatal and post-hatch physiological responses of broiler embryos exposed to heat stress during incubation. A total of two thousand fertile eggs of broiler breeders (Ross 308) flock (at 38 weeks of age) were used for this study. In the first 10 days, the eggs were incubated using the conventional protocol of relative humidity and temperature of 55% and 37.8°C respectively. From day ten onward, the temperature was increased to 39.6°C for 6 h per day. On day 17.5, 1,500 eggs with the evidence of living embryos were randomly selected and assigned to 6 treatments having five replicates of 50 eggs each. The treatments were: un-injected eggs (UI), eggs injected with only 0.5 ml distilled water (DW), 3.5 mg/egg cysteine (CY), 2mg/egg lysine (LY), 3.4 mg cysteine+2 mg lysine (CLH) and 1.7 mg cysteine+1 mg lysine (CLL). On day 21, the hatchability, anatomical characteristics, chick quality and the antioxidant status of the chicks were evaluated. During the post-hatch phase, data were collected on the haematology, biochemical parameters, growth performance and intestinal morphology of the birds. The results revealed that the hatchability of CY chicks was higher (p < 0.05) than in the other treatments, while the lowest values were recorded in CLH. The hatching muscle of the chicks of CLL was similar to those of CY but higher (p < 0.05) than the others. The MDA of DW and UI chickens was similar and higher than birds in the other treatment groups. The serum SOD of CLL birds was comparable to that of CY but higher than the values recorded in the other treatments. The final weights of CLL chickens were similar to those of LY but significantly higher (p < 0.05) than those of the other treatments. The duodenal villus heights of the birds of CLL were higher than those of the other treatment groups, whereas the villus height of the birds of CLH was higher than those of UI, DW and CY. Overall, in ovo feeding of cysteine alone improved the hatchability of thermally-challenged broiler embryos. In contrast, a low-dose mixture of cysteine plus lysine improved the post-hatch growth performance.

Health-related quality of life in abdominal wall hernia: let's ask patients what matters to them?

INTRODUCTION: Quality of Life (QoL) is an important consideration in patients with abdominal wall hernia (AWH). What matters to patients and their everyday experience living with AWH may depend on a variety of personal, psychological, social and environmental factors. At present, no study has addressed what is important to this particular group of patients by asking the patients themselves. This study aims to determine QoL from the patient's perspective by examining the lived experience in this patient population. METHODS: We interviewed 15 patients with AWH until thematic saturation. The patients were purposively sampled from AWH clinic between February 2020 and June 2020 using topic guides and interview schedules. Verbatim interview transcripts were coded and analysed using NVivo12 software and Interpretative Phenomenological Analysis (IPA). We adhered to consolidated criteria for reporting qualitative research (COREQ). RESULTS: Fifteen participants (8 men and 7 women) of age range 36-85 years, median 65 years, covering all Ventral Hernia Working Group (VHWG) grades. Five superordinate themes were identified each with several subordinate themes, as follows: (1) body image (subthemes-'changes to perceptions of self' and 'fears concerning perceptions of others'). (2) Mental health (subthemes-'emotional responses', 'disruptions to previously solid aspects of identity', 'developing coping strategies'). (3) Symptoms (subthemes-'managing pain', 'freedom of movement', 'restriction and adaptation of function'). (4) Interpersonal relationships (subthemes-'difficulties socially connecting' and 'changes in sexual relations'). (5) Employment (subthemes-'financial pressure', 'return to work issues' and 'costs to family'). CONCLUSION: This is the first phenomenological qualitative study in the field of AWH and presents a rich account of what is important to these patients in terms of QoL. Developed from the patients' own words, the themes are interrelated and should shape our understanding of patients with AWH. This study provides qualitative examples of each theme. This study has identified new themes (body image, interpersonal relationships and employment) that are not incorporated in existing AWH-specific QoL instruments. This is important for surgeons because the study suggests that we are currently not capturing all data relevant to QoL in this specific patient group with current tools. The wider impact of this would be to help counsel patients and support them more holistically through the disease process and it's management. Further research is needed to generate a standardised AWH QoL instrument which incorporates bio-psycho-emotional-social themes important to patients, as identified by patients.

The Development of a National Paediatric Psycho-Oncology Service.

Aims To investigate the psychological care provided to children and young adolescents with cancer and their families within the National Children's Cancer Service (NCCS), Ireland, in respect of the national and international standards of care. Methods A retrospective audit of 316 referrals made over 32 months by the NCCS to the psychology service in malignant haematology and oncology was performed. Results The audit revealed that out of 316 patients, a yearly average of 189 (50%) of urgently referred patients received psychological support within the NCCS between January 2013 and August 2016. Furthermore only 20 (22%) undergoing haematopoietic stem cell transplantation (HSCT), 14 (22%) referred to the paediatric palliative care team, and 84 (62%) of teenage patients received psychological input during this timeframe. Conclusion The audit revealed that the current psychology service provision is failing to meet the international standards of care. Due to the data provided by this audit, in conjunction with a clinical risk assessment of the service, funds for the post of principal psychologist have been secured. Further psychology posts (HSCT, late-effects and neuropsychology), and development of the psycho-oncology model of care are required to ensure equality of access and evidence-based psychological care for all children with cancer.

Adolescents and young adults (AYA) with cancer: a position paper from the AYA Working Group of the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE).

It is well recognised that adolescents and young adults (AYA) with cancer have inequitable access to oncology services that provide expert cancer care and consider their unique needs. Subsequently, survival gains in this patient population have improved only modestly compared with older adults and children with cancer. In 2015, the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE) established the joint Cancer in AYA Working Group in order to increase awareness among adult and paediatric oncology communities, enhance knowledge on specific issues in AYA and ultimately improve the standard of care for AYA with cancer across Europe. This manuscript reflects the position of this working group regarding current AYA cancer care, the challenges to be addressed and possible solutions. Key challenges include the lack of specific biological understanding of AYA cancers, the lack of access to specialised centres with age-appropriate multidisciplinary care and the lack of available clinical trials with novel therapeutics. Key recommendations include diversifying interprofessional cooperation in AYA care and specific measures to improve trial accrual, including centralising care where that is the best means to achieve trial accrual. This defines a common vision that can lead to improved outcomes for AYA with cancer in Europe.

A structured pathway for developing your complex abdominal hernia service: our York pathway.

PURPOSE: Clinical pathways are widely prevalent in health care and may be associated with increased clinical efficacy, improved patient care, streamlining of services, while providing clarity on patient management. Such pathways are well established in several branches of healthcare services but, to the authors' knowledge, not in complex abdominal wall reconstruction (CAWR). A stepwise, structured and comprehensive approach to managing complex abdominal wall hernia (CAWH) patients, which has been successfully implemented in our practice, is presented. METHODS: A literature search of common databases including Embase® and MEDLINE® for CAWH pathways identified no comprehensive pathway. We therefore undertook a reiterative process to develop the York Abdominal Wall Unit (YAWU) through examination of current evidence and logic to produce a pragmatic redesign of our own pathway. Having introduced our pathway, we then performed a retrospective analysis of the complexity and number of abdominal wall cases performed in our trust over time. RESULTS: We describe our pathway and demonstrate that the percentage of cases and their complexity, as defined by the VHWG classification, have increased over time in York Abdominal Wall Unit. CONCLUSION: A structured pathway for complex abdominal wall hernia service is one way to improve patient experience and streamline services. The relevance of pathways for the hernia surgeon is discussed alongside this pathway. This may provide a useful guide to those wishing to establish similar personalised pathways within their own units and allow them to expand their service.

A multistage process leading to the development of a structured consent form and patient information leaflet for complex abdominal wall reconstruction (CAWR).

PURPOSE: Informed consent is vital in surgery. The General Medical Council, UK and Royal College of Surgeons of England provide clear guidance on what constitutes the process of informed patient consent. Despite this, evidence suggests that the consent process may not be performed well in surgery. We utilised a staged patient-centred approach and rigorous methodology to develop a standardised patient information leaflet (PIL) and pre-written structured consent form for complex abdominal wall reconstruction (CAWR). METHODS: We utilised the principles of Deming's Plan-Do-Study-Act (PDSA) cycles to approach the process. Buzan's mind maps were used to identify the stakeholders and deficiencies in the consent process ('Plan' phase). The content of the PIL and pre-written consent form was then developed in collaboration with stakeholders ('Do' phase). Multidisciplinary and multidepartmental feedback was obtained on the proposed content and amendments were made ('Study' and 'Act' phases). RESULTS: We successfully produced a clear, focused PIL and structured consent form, in Plain English, presenting accurate, relevant and detailed information in a highly understandable way. The PIL had a Flesch Reading Ease score of > 80, demonstrating a high level of readability and comprehensibility, with positive implications for informed patient decision making and preparedness for surgery. CONCLUSION: Through sharing the process that we undertook, we aim to support other abdominal wall units who wish to develop and improve their own consent process.

Evaluation of light colour manipulation on physiological response and growth performance of broiler chickens.

Artificial illumination, including light quality, is crucial in modern broiler management. The aim of this study was to examine the effect of a switch in light colour on the performance of broiler chickens in tropical environments. A total of 280 1-day-old Arbor acre male chicks were used for this study and were weighed and assigned to different light environments viz. white (WH), green (GR), blue (BL), GR switched to BL at 14 days (GB), BL switched to GR at 14 days (BG), BL switched to GR at 28 days (BGG) and GR switched to BL at 28 days (GBB) having four replicates of ten birds each. Body weight, weight gain, feed intake and feed conversion ratio were recorded weekly. Blood samples were collected from 2 birds per replicate weekly for the determination of plasma triiodothyronine (T3), haematology and serum biochemical parameters. The experiment was laid out in a completely randomised design. Results showed that the final body weights of the birds in GBB and GB were comparable but higher than those of the other treatment groups. Feed intake of the chickens in WH was similar to that of BG but higher than those of the other treatment groups, while FCR of the birds in WH was higher (P < 0.05) than the other treatment groups. Plasma T3 of the birds in GR was comparable to that of birds in BL but significantly higher than those of the birds in WH and a similar trend was also observed at weeks 1 and 2. Heterophil/lymphocyte ratio (H/L) of the birds in WH was significantly higher than those of BL and GR whose values were similar to those in GB and BG. Heterophil/lymphocytes of the birds in WH was higher than those of BG, GR, BGG, GB and GBB but similar to those of BL. The breast muscle of the birds in GBB and GB was similar to those of BGG and GR and significantly higher than those of WH, BL and BG. Based on the results obtained in this study, it was concluded that the use of green light up to 28 days in combination with blue light stimulated the growth of broiler chickens and manipulation of light colours can be used to improve the welfare and performance of chickens.

Burkitt Lymphoma/Leukaemia in Children & Young Adolescents.

Aims Burkitt Lymphoma (BL) accounts for approximately 40% of childhood non-Hodgkin Lymphoma (NHL) in the developed world. Survival rates have improved dramatically in recent years, a success attributed to better use of poly-chemotherapy and targeted immunotherapy. Nevertheless, relapse is unpredictable and carries a dismal prognosis. We report on event-free survival (EFS) and overall survival (OS) rates in the Republic of Ireland (ROI) during 2000-2017, and evaluate novel predictors of outcome. Methods Data was collected by retrospective review of patient medical records. Results Thirty-three patients were identified (twenty-five [76%] males, eight [24%] females), fourteen [42%] having stage III disease at presentation. Six [18%] had stage IV disease. Five [15%] had refractory disease; one salvaged with allogeneic stem cell transplantation. Of the four [12%] who died; two [50%] had weights >99th centile, one [25%] >90th centile. One died during induction from refractory lactic acidosis, one from early relapse. Discussion EFS and OS was 85% and 89% respectively; in keeping with the best international standards. Obesity appears to be a poor predictor of outcome in our cohort.

Cascading failures in networks of heterogeneous node behavior.

Variability in the dynamical function of nodes comprising a complex network impacts upon cascading failures that can compromise the network's ability to operate. Node types correspond to sources, sinks, or passive conduits of a current flow, applicable to renewable electrical power microgrids containing a variable number of intermittently operating generators and consumers of power. The resilience to cascading failures of ensembles of synthetic networks with different topology is examined as a function of the edge current carrying capacity and mix of node types, together with exemplar real-world networks. While a network with a homogeneous composition of node types can be resilient to failure, onewith an identical topology but with heterogeneous nodes can be strongly susceptible to failure. For networks with similar numbers of sources, sinks, and passive nodes the mean resilience decreases as networks become more disordered. Nevertheless all network topologies have enhanced regions of resilience, accessible by the manipulation of node composition and functionality.

Living donor liver transplantation in South Africa: the donor experience.

BACKGROUND: Living donor liver transplantation (LDLT) plays a crucial role in liver transplant programmes, particularly in regions with a scarcity of deceased donor organs and especially for paediatric recipients. LDLT is a complex and demanding procedure which places a healthy living donor in harm's way. Donor safety is therefore the overriding concern. This study aimed to report our standardised approach to the evaluation, technical aspects and outcomes of LDLT donor hepatectomy at Wits Donald Gordon Medical Centre. METHOD: The study population consisted of all patients undergoing LDLT donor hepatectomy since the inception of the programme in March 2013 until 2018. Sixty five living donor hepatectomies were performed. Primary outcome measures included donor demographics, operative time, peak bilirubin, aspartate and alanine transaminase levels postoperatively, length of hospital stay and postoperative complications using the Clavien-Dindo classification. RESULTS: The majority of the donors were female, most were parents with mothers being the donor almost 85% of the time. The median operative time was 374 minutes with a downward trend over time as experience was gained. The median length of hospital stay was 7 days. There was no mortality and the complication rate was 30% with the majority being minor (Grade 1). CONCLUSION: Living donor liver transplant from adult-to-child has been successfully initiated in South Africa. Living donor hepatectomy can be safely performed with acceptable outcomes for the donor. Wait-list mortality however remains unacceptably high. Expansion of LDLT as well as real change in deceased donor policy is required to address this issue.

Postprandial Amino Acid Kinetics of Milk Protein Mixtures are Affected by Composition, But Not Denaturation, in Neonatal Piglets.

BACKGROUND: Multiple studies have indicated that formula-fed infants show a different growth trajectory compared with breastfed infants. The observed growth rates are suggested to be linked to higher postprandial levels of branched chain amino acids (BCAAs) and insulin related to differences in protein quality. OBJECTIVE: We evaluated the effects of milk protein denaturation and milk protein composition on postprandial plasma and hormone concentrations. METHODS: Neonatal piglets were bolus-fed randomly, in an incomplete crossover design, 2 of 3 milk protein solutions: native whey protein isolate (NWPI), denatured whey protein isolate (DWPI), or protein base ingredient, comprising whey and casein (PBI). Postprandial plasma amino acids (AAs), insulin, glucagon-like peptide 1, glucose, and paracetamol concentrations were assayed. Plasma responses were fitted with a model of first-order absorption with linear elimination. RESULTS: DWPI (91% denatured protein) compared with NWPI (91% native protein) showed lower essential amino acids (EAAs) (∼10%) and BCAA (13-19%) concentrations in the first 30-60 min. However, total amino acid (TAA) concentration per time-point and area under the curve (AUC), as well as EAA and BCAA AUC were not different. PBI induced a ∼30% lower postprandial insulin spike than NWPI, yet plasma TAA concentration at several time-points and AUC was higher in PBI than in NWPI. The TAA rate constant for absorption (k a) was twofold higher in PBI than in NWPI. Plasma BCAA levels from 60 to 180 min and AUC were higher in PBI than in NWPI. Plasma EAA concentrations and AUCs in PBI and NWPI were not different. CONCLUSIONS: Denaturation of WPI had a minimal effect on postprandial plasma AA concentration. The differences between PBI and NWPI were partly explained by the difference in AA composition, but more likely differences in protein digestion and absorption kinetics. We conclude that modifying protein composition, but not denaturation, of milk protein solutions impacts the postprandial amino acid availability in neonatal piglets.

The furosemide stress test for prediction of worsening acute kidney injury in critically ill patients: A multicenter, prospective, observational study.

PURPOSE: To validate the furosemide stress test (FST) for predicting the progression of acute kidney injury (AKI). MATERIALS AND METHODS: We performed a multicenter, prospective, observational study in patients with stage I or II AKI. The FST (1 mg/kg for loop diuretic naïve patients and 1.5 mg/kg in patients previously exposed to loop diuretics) was administered. Subsequent urinary flow rate (UFR) recorded and predictive ability of urinary output was measured by the area under the curve receiver operatic characteristics (AuROC). Primary outcome was progression to Stage III AKI. Secondary outcomes included in-hospital mortality and adverse events. RESULTS: We studied 92 critically ill patients. 23 patients progressed to stage III AKI and had significantly lower UFR (p < 0.0001). The UFR during the first 2 h was most predictive of progression to stage III AKI (AuROC = 0.87), with an ideal cut-off of less than 200mls, with a sensitivity of 73.9% and specificity of 90.0%. CONCLUSION: In ICU patients without severe CKD with mild AKI, a UFR of less than 200mls in the first 2 h after an FST is predictive of progression to stage III AKI. Future studies should focus on incorporating a FST as part of a clinical decision tool for further management of critically ill patients with AKI.

Development of the central nervous system in equine twin fetuses derived by somatic cell nuclear transfer.

Because of the growing importance of horses in leisure and several sports, somatic cell nuclear transfer (SCNT) is being used more frequently for cloning animals for performance and reproductive purposes. However, because of the need to perforate the zona pellucida during microsurgical reconstruction of the oocyte, it is possible that SCNT-derived embryos undergo premature hatching, resulting in embryo bisection and twinning. Therefore, because equine twin pregnancies often lead to abnormal embryo development and pregnancy failure, we performed a detailed comparative assessment of equine twin fetuses derived by SCNT with particular attention on the development of the central nervous system at 40 and 60 days gestation. The results of this study indicate that although cloned twin embryos show small differences in size, they do not exhibit apparent macro- or microscopic developmental discrepancies in the central nervous system, suggesting that the twining phenomenon resulting from SCNT does not affect fetal differentiation.

Food for thought. Malnutrition risk associated with increased risk of healthcare-associated infection.

BACKGROUND: Infection and malnutrition are interconnected. UK and Irish guidelines recommend the Malnutrition Universal Screening Tool (MUST) for nutritional risk screening. Patients with a MUST score of ≥2 are considered at high risk of malnutrition and referral for nutritional assessment is recommended. AIM: To explore the association between healthcare-associated infection (HCAI) and the MUST score categories of patients. METHODS: This was a cross-sectional study in May 2017 on ten representative wards in our institution. Patient demographics, MUST score, presence of medical devices, HCAI and antimicrobial use were collected. FINDINGS: Of 240 patients, the HCAI prevalence was 10.4% (N = 25) and 26% (N = 63) were at high risk of malnutrition (MUST score ≥2). Patients with HCAI were more likely to have had surgery (odds ratio (OR): 5.5; confidence interval (CI): 2.1-14.3; P < 0.001), a central vascular catheter (OR: 10.0; CI: 3.6-27.2; P < 0.001), or a urinary catheter in situ (OR: 7.5; CI: 2.8-20.0; P < 0.001), and to have a high risk of malnutrition (OR: 4.3; CI: 1.7-11.2; P < 0.001). A higher MUST score remained a significant predictor of a patient having HCAI on multivariate regression analysis (CI: 0.2-0.6; P < 0.001). CONCLUSION: Patients at risk of malnutrition when assessed with the MUST were more likely to have HCAI. However, prospective studies are required to investigate the temporal association between MUST and HCAI and which interventions best address malnutrition risk and HCAI reduction in different settings.

A novel protein C-factor VII chimera provides new insights into the structural requirements for cytoprotective protease-activated receptor 1 signaling.

Essentials The basis of cytoprotective protease-activated receptor 1 (PAR1) signaling is not fully understood. Activated protein C chimera (APCFVII-82 ) was used to identify requirements for PAR1 signaling. APCFVII-82 did not initiate PAR1 signaling, but conferred monocyte anti-inflammatory activity. APC-specific light chain residues are required for cytoprotective PAR1 signaling. SUMMARY: Background Activated protein C (APC) cell signaling is largely reliant upon its ability to mediate protease-activated receptor (PAR) 1 proteolysis when bound to the endothelial cell (EC) protein C (PC) receptor (EPCR). Furthermore, EPCR-bound PC modulates PAR1 signaling by thrombin to induce APC-like EC cytoprotection. Objective The molecular determinants of EPCR-dependent cytoprotective PAR1 signaling remain poorly defined. To address this, a PC-factor VII chimera (PCFVII-82 ) possessing FVII N-terminal domains and conserved EPCR binding was characterized. Methods Activated PC-FVII chimera (APCFVII-82 ) anticoagulant activity was measured with calibrated automated thrombography and activated FV degradation assays. APCFVII-82 signaling activity was characterized by the use of reporter assays of PAR1 proteolysis and EC barrier integrity. APCFVII-82 anti-inflammatory activity was assessed according to its inhibition of nuclear factor-κB (NF-κB) activation and cytokine secretion from monocytes. Results PCFVII-82 was activated normally by thrombin on ECs, but was unable to inhibit plasma thrombin generation. Surprisingly, APCFVII-82 did not mediate EPCR-dependent PAR1 proteolysis, confer PAR1-dependent protection of thrombin-induced EC barrier disruption, or limit PAR1-dependent attenuation of interleukin-6 release from lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, EPCR occupation by active site-blocked APCFVII-82 was, like FVII, unable to mimic EC barrier stabilization induced by PC upon PAR1 proteolysis by thrombin. APCFVII-82 did, however, diminish LPS-induced NF-κB activation and tumor necrosis factor-α release from monocytes in an apolipoprotein E receptor 2-dependent manner, with similar efficacy as wild-type APC. Conclusions These findings identify a novel role for APC light chain amino acid residues outside the EPCR-binding site in enabling cytoprotective PAR1 signaling.