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Kaushik Mukherjee,1 Vance L Albaugh,2 Justin E Richards,3 Kelli A Rumbaugh,4 Addison K May1 1Division of Trauma and Surgical Critical Care, 2Division of General Surgery, 3Department of Anesthesiology, 4Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, TN, USA Abstract: Glucose metabolism in humans is exceedingly complex. At baseline, it is controlled by elaborate signaling mechanisms, and these mechanisms are profoundly altered by the surge of catecholamines and cytokines associated with acute postsurgical and post-traumatic stress. These alterations in signaling mechanisms result in hyperglycemia; although this hyperglycemia can start very rapidly after the traumatic or surgical insult, it can persist during the entire period of critical illness and even afterward. Numerous randomized clinical trials have been conducted to determine if hyperglycemia is associated with increased mortality in surgical patients. These studies have had different conclusions that are difficult to interpret in light of differences in study methodology, but there is certainly ample evidence that inadequately controlled hyperglycemia causes harm due to increased infectious morbidity, and possibly increased mortality. As we have become more proficient in controlling hyperglycemia, the concept of insulin resistance, determined as the amount of insulin required to achieve hyperglycemia, has come to the fore. Insulin resistance is not a static concept, and may change before significant events such as infection. Patients with elevated and persistent insulin resistance have been demonstrated to suffer increased infectious morbidity and mortality, albeit in nonrandomized studies. Along with insulin resistance, the concept of glycemic variability, the amount of variation in serum blood glucose over time, has also become relevant; increased variability has been associated with hypoglycemia and mortality. Both of these risks can result from aggressive insulin therapy, and glycemic control protocols must be appropriately planned and implemented to avoid hypoglycemia and excessive externally induced variability. Computer-assisted protocols may be of significant benefit in optimizing glycemic control. The most recent recommendations available are to keep serum blood glucose levels below 150 mg/dL and to avoid hypoglycemia. Keywords: insulin resistance, hypoglycemia, insulin signaling, hyperglycemia, critical illness, glycemic variability

Background:The Acute Respiratory Distress Syndrome (ARDS) is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung epithelial injury than indirect ARDS (e.g. non-pulmonary sepsis); however, this hypothesis has not been well-studied in humans. Methods:We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single center study of 100 patients with ARDS and severe sepsis, and in a secondary analysis of 853 ARDS patients drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts. Results:In both studies, direct ARDS patients had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein-D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2), compared with indirect ARDS patients. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, direct ARDS patients also had lower levels of von Willebrand factor antigen and interleukins 6 and 8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS. Conclusions:Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct or indirect ARDS, respectively.The Acute Respiratory Distress Syndrome (ARDS) is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung epithelial injury than indirect ARDS (e.g. non-pulmonary sepsis); however, this hypothesis has not been well-studied in humans.We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single center study of 100 patients with ARDS and severe sepsis, and in a secondary analysis of 853 ARDS patients drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts.In both studies, direct ARDS patients had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein-D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2), compared with indirect ARDS patients. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, direct ARDS patients also had lower levels of von Willebrand factor antigen and interleukins 6 and 8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS.Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct or indirect ARDS, respectively.

ازداد في الآونة الأخيرة الاتجاه نحو استخدام اللعاب كبديل عن المصل في تشخيص العديد من الحالات في طب الأسنان , وكذلك الاهتمام بالأنزيمات والبحث عن وجود علاقة بين مستويات الأنزيمات والمعالجات المختلفة.وباعتبار الفوسفات القلوي من المحددات الأساسية لإعادة تشكيل العظام توجهالاهتمام بالبحث عن علاقة لاختلاف تركيز اللعاب لهذا الانزيم وربطها بالحركة السنية التقويمية . هدف الدراسة: تقييم مستويات أنزيم الأكالين فوسفات(Alp) في اللعاب عند المرضى المعالجون بأجهزة تقويمية ثابتة في مرحلة رصف وتسوية الأسنان. المواد والطرق: تضمنت عينة الدراسة( 9) مرضى من مراجعين قسم تقويم الأسنان والفكين وهم بحاجة لمعالجة بجهاز تقويمي ثابت، تم أخذ عينة من اللعاب من خلال محقنة بلاستيكية نبوذة( 3مل ) قبل العمل وبعد تركيب الجهاز وبعد عدة فترات أخرى ومعايرة اللعاب ضمن جهاز مقياس الطيف الضوئي . النتائج: كان هناك ارتفاع بمستوى الأنزيم بعد 7 أيام من العمل و بعد 14 يوم وكان هذا الارتفاع هام احصائيا.في حين لم يكن هناك أي تغيرات خلال الساعة الأولى و اليوم الأول. الاستنتاجات: يمكن استخدام الألكالين فوسفات (Alp)كمؤشر حيوي في اللعاب.

Objectives: Acute Care Surgery (ACS) admissions and procedures are substantially increasing. ACS disproportionally accounts for a majority of morbidity and mortality among surgical patients. Minimally invasive techniques are associated with improved outcomes and shorter hospital length of stay within the ACS population. While laparoscopy is widespread, ACS surgeons have been slower to adopt the use of robotics. We aimed to evaluate the feasibility of incorporating robotic surgery within ACS practice., Methods: Robotic General Surgery operations performed by 8 Acute Care Surgeons from 5 local facilities within a large integrated healthcare system were queried over a 15 month period. Patients who underwent emergent, urgent, sub-acute, and elective robotic operations by ACS staff were identified. Demographics collected included age, gender, BMI, and ASA score. Outcomes recorded included procedure classification, total supply and implant charges (TSI), conversion to open, hospital length of stay (LOS), 30 day readmission, and 30 day mortality., Results: Of 200 operations, the most common were Cholecystectomy (43.5%), Inguinal hernia repair (26.0%), Ventral hernia repair (18.0%), Appendectomy (5.0%), and Sigmoid Colectomy (3.5%). The median (± std dev) age was 48 ± 16.66 years and BMI was 29.9 ± 8.79 kg/m 2 . 46% of cases were sub-acute (n = 92), 33.5% were elective (n = 67), 14% were emergent (n = 28), and 6.5% were urgent (n = 13). Most patients were ASA 2 (107, 46.1%) or ASA 3 (71, 45.9%). The median (IQR) TSI and LOS were $1,770 (889.50) USD and 0.1 (0.9) days. Forty-one inpatient procedures were performed. Median LOS was 3 days and expected LOS was 3.1 days (O:E = 0.96). Five patients were readmitted within 30 days, and there were no deaths within 30 days., Conclusion: Robotic techniques may be safely implemented by ACS surgeons, potentially benefitting both patient and surgeon. LOS was similar between laparoscopic and robotic cases and only two cases required conversion to an open procedure. Next steps include a multi-center prospective trial comparing robotic to laparoscopic cases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Individuals with high environmental sensitivity have nervous systems that are disproportionately receptive to both the protective and imperilling aspects of the environment, suggesting their mental health is strongly context-dependent. However, there have been few consolidated attempts to examine putative markers of sensitivity, across different levels of analysis, within a single cohort of individuals with high-priority mental health needs. Here, we examine psychological (self-report), physiological (hair hormones) and genetic (polygenic scores) markers of sensitivity in a large cohort of 1591 Syrian refugee children across two waves of data. Child-caregiver dyads were recruited from informal tented settlements in Lebanon, and completed a battery of psychological instruments at baseline and follow-up (12 months apart). Univariate and multivariate Bayesian linear mixed models were used to examine a) the interrelationships between markers of sensitivity and b) the ability of sensitivity markers to predict anxiety, depression, post-traumatic stress disorder, and externalising behaviour. Self-reported sensitivity (using the Highly Sensitive Child Scale) significantly predicted a higher burden of all forms of mental illness across both waves, however, there were no significant cross-lagged pathways. Physiological and genetic markers were not stably predictive of self-reported sensitivity, and failed to similarly predict mental health outcomes. The measurement of environmental sensitivity may have significant implications for identifying and treating mental illness, especially amongst vulnerable populations, but clinical utility is currently limited to self-report assessment., (© 2024. The Author(s).)

For numerous issues of convenience and acceptability, hair hormone data have been increasingly incorporated in the field of war trauma and forced displacement, allowing retrospective examination of several biological metrics thought to covary with refugees' mental health. As a relatively new research method, however, there remain several complexities and uncertainties surrounding the use of hair hormones, from initial hair sampling to final statistical analysis, many of which are underappreciated in the extant literature, and restrict the potential utility of hair hormones. To promote awareness, we provide a narrative overview of our experiences collecting and analyzing hair hormone data in a large cohort of Syrian refugee children ( n  = 1594), across two sampling waves spaced 12 months apart. We highlight both the challenges faced, and the promising results obtained thus far, and draw comparisons to other prominent studies in this field. Recommendations are provided to future researchers, with emphasis on longitudinal study designs, thorough collection and reporting of hair-related variables, and careful adherence to current laboratory guidelines and practices., Competing Interests: No conflict of interest., (© 2024 The Authors.)

Refugee children are often exposed to substantial trauma, placing them at increased risk for mental illness. However, this risk can be mitigated by a capacity for resilience, conferred from multiple ecological systems (e.g., family, community), including at an individual biological level. We examined the ability of hair cortisol concentrations and polygenic scores for mental health to predict risk and resilience in a sample of Syrian refugee children ( n = 1359). Children were categorized as either at-risk or resilient depending on clinical thresholds for posttraumatic stress disorder, depression, and externalizing behavior problems. Logistic regression was used to examine main and interacting effects while controlling for covariates. Elevated hair cortisol concentrations were significantly associated with reduced resilience (odds ratio (OR)=0.58, 95%CI [0.40, 0.83]) while controlling for levels of war exposure. Polygenic scores for depression, self-harm, and neuroticism were not found to have any significant main effects. However, a significant interaction emerged between hair cortisol and polygenic scores for depression (OR=0.04, 95%CI [0.003 0.47]), suggesting that children predisposed to depression were more at risk for mental health problems when hair cortisol concentrations were high. Our results suggest that biomarkers (separately and in combination) might support early identification of refugee children at risk for mental health problems.

Surgical site infections remain a significant cause of morbidity and mortality. High-quality evidence supports several measures to prevent surgical site infections that should be applied with high compliance, although effective application remains suboptimal. Recognizing high-risk patients and avoiding potential pitfalls in the diagnosis of surgical site infections is paramount in preventing progression to sepsis, particularly in emergency surgical patients with physiologic derangement. A high index of suspicion postoperatively is critical to identify patients with surgical site infections and to prevent failure to rescue., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Human microbiota demonstrate diversity and balance that is adaptive for the host and supports maintaining homeostasis. Although acute illness or injury may derange microbiota diversity and the proportion of potentially pathogenic microbes, that derangement may be further exacerbated by commonly deployed intensive care unit (ICU) therapeutic and practices. These include antibiotic administration, delayed luminal nutrition, acid suppression, and vasopressor infusion. Furthermore, the local ICU microbial ecology, regardless of disinfection practices, shapes the patient's microbiota, especially with the acquisition of multi-drug-resistant pathogens. Current approaches to protect a normal microbiome, or restore a deranged one, are part of a multifaceted approach that may include antibiotic stewardship and infection control practices as microbiome-directed therapeutics emerge.

Background: Emergency general surgery (EGS) patients presenting at tertiary care hospitals may bypass local hospitals with adequate resources. However, many tertiary care hospitals frequently operate at capacity. We hypothesized that understanding patient geographic origin could identify opportunities for enhanced system triage and optimization and be an important first step for EGS regionalization and care coordination that could potentially lead to improved utilization of resources., Methods: We analyzed patient zip code and categorized EGS patients who were cared for at our tertiary care hospital as potentially divertible if the southern region hospital was geographically closer to their home, regional hospital admission (RHA) patients, or local admission (LA) patients if the tertiary care facility was closer. Baseline characteristics and outcomes were compared for RHA and LA patients., Results: Of 14 714 EGS patients presenting to the tertiary care hospital, 30.2% were categorized as RHA patients. Overall, 1526 (10.4%) patients required an operation including 527 (34.5%) patients who were potentially divertible. Appendectomy and cholecystectomy comprised 66% of the operations for potentially divertible patients. Length of stay was not significantly different ( P = .06) for RHA patients, but they did have lower measured short-term and long-term mortality when compared to their LA counterparts ( P < .05)., Conclusions: EGS diagnoses and patient geocode analysis can identify opportunities to optimize regional operating room and bed utilization. Understanding where EGS patients are cared for and factors that influenced care facility will be critical for next steps in developing EGS regionalization within our system.

Interactions between the MAOA uVNTR and rearing environment are suggested to influence the developmental manifestations of childhood internalizing and externalizing behavior. However, few studies in the MAOA literature have included continental African children, or focused on non-clinical samples. We explored the main and interactive effects of the MAOA uVNTR (high and low activity alleles) in Black South African male ( n  = 478) and female ( n  = 540) children who were part of the longitudinal Birth to Twenty Plus cohort. Historical data on birth weight, gestational age at delivery, socioeconomic status, and maternal education were combined with genotypic information and analyzed using regression modeling. We found no significant main effects for the MAOA uVNTR on childhood behavior in either sex. A significant interaction ( p = .04) was identified between MAOA and maternal education, suggesting that externalizing behavior in boys carrying a low activity MAOA allele varied in direct proportion to the education levels of their mothers. However, the model fit failed to reach significance, possibly due to our inclusion of only non-clinical pre-pubertal males. No significant interactions were detected for female children. Our findings lend tentative credibility to the Environmental Sensitivity metaframework, which suggests that MAOA is an important plasticity factor in childhood development.

Background: The aim of this study was to evaluate the impact of the COVID-19 pandemic on volume and outcomes of Acute Care Surgery patients, and we hypothesized that inpatient mortality would increase due to COVID+ and resource constraints., Methods: An American College of Surgeons verified Level I Trauma Center's trauma and operative emergency general surgery (EGS) registries were queried for all patients from Jan. 2019 to Dec. 2020. April 1st, 2020, was the demarcation date for pre- and during COVID pandemic. Primary outcome was inpatient mortality., Results: There were 14,460 trauma and 3091 EGS patients, and month-over-month volumes of both remained similar (p > 0.05). Blunt trauma decreased by 7.4% and penetrating increased by 31%, with a concomitant 25% increase in initial operative management (p < 0.001). Despite this, trauma (3.7%) and EGS (2.9-3.0%) mortality rates remained stable which was confirmed on multivariate analysis; p > 0.05. COVID + mortality was 8.8% and 3.7% in trauma and EGS patients, respectively., Conclusion: Acute Care Surgeons provided high quality care to trauma and EGS patients during the pandemic without allowing excess mortality despite many hardships and resource constraints., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: The 2016 National Academies of Science, Engineering and Medicine report included a proposal to establish a National Trauma Research Action Plan. In response, the Department of Defense funded the Coalition for National Trauma Research to generate a comprehensive research agenda spanning the continuum of trauma and burn care from prehospital care to rehabilitation as part of an overall strategy to achieve zero preventable deaths and disability after injury. The Postadmission Critical Care Research panel was 1 of 11 panels constituted to develop this research agenda., Methods: We recruited interdisciplinary experts in surgical critical care and recruited them to identify current gaps in clinical critical care research, generate research questions, and establish the priority of these questions using a consensus-driven Delphi survey approach. The first of four survey rounds asked participants to generate key research questions. On subsequent rounds, we asked survey participants to rank the priority of each research question on a 9-point Likert scale, categorized to represent low-, medium-, and high-priority items. Consensus was defined as ≥60% of panelists agreeing on the priority category., Results: Twenty-five subject matter experts generated 595 questions. By Round 3, 249 questions reached ≥60% consensus. Of these, 22 questions were high, 185 were medium, and 42 were low priority. The clinical states of hypovolemic shock and delirium were most represented in the high-priority questions. Traumatic brain injury was the only specific injury pattern with a high-priority question., Conclusion: The National Trauma Research Action Plan critical care research panel identified 22 high-priority research questions, which, if answered, would reduce preventable death and disability after injury., Level of Evidence: Diagnostic Tests or Criteria; Level IV., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Recent antibiotic exposure has previously been associated with poor outcomes following elective surgery. The purpose of this study is to evaluate the impact of prior recent antibiotic exposure in a multicenter cohort of Veterans Affairs patients undergoing elective non-colorectal surgery., Methods: This is a retrospective cohort study of the Veterans Affairs Surgical Quality Improvement Program, including elective, non-cardiovascular, non-colorectal surgery from 2013 to 2017. Outpatient antibiotic exposure within 90 days prior to surgery was identified from the Veterans Affairs outpatient pharmacy database and matched with each case. Primary outcomes included serious complication, any complication, any infection, or surgical site infection. Secondary outcomes included 30-day mortality, length of stay, and Clostridioides difficile infection., Results: Of 21,112 eligible patients, 2885 (13.7%) were exposed to antibiotics within 90 days prior to surgery with a duration of 7 (IQR: 5-10) days and prescribed 42 (IQR: 21-64) days prior to surgical intervention. Compared to non-exposed patients, exposed patients had higher unadjusted complication rates, increased length of stay, and rates of return to the operating. Exposure was independently associated with return to the operating room (OR: 1.39; 99% CI: 1.05-1.84)., Conclusions: Among Veterans, recent antibiotic exposure within 90 days of elective surgery was associated with a 39% increase in the odds of return to the operating room. Further work is needed to evaluate the effects of antibiotic exposure and dysbiosis on surgical outcomes.

Host genetic factors are known to modify the susceptibility, severity, and outcomes of COVID-19 and vary across populations. However, continental Africans are yet to be adequately represented in such studies despite the importance of genetic factors in understanding Africa's response to the pandemic. We describe the development of a research resource for coronavirus host genomics studies in South Africa known as COVIGen-SA-a multicollaborator strategic partnership designed to provide harmonised demographic, clinical, and genetic information specific to Black South Africans with COVID-19. Over 2,000 participants have been recruited to date. Preliminary results on 1,354 SARS-CoV-2 positive participants from four participating studies showed that 64.7% were female, 333 had severe disease, and 329 were people living with HIV. Through this resource, we aim to provide insights into host genetic factors relevant to African-ancestry populations, using both genome-wide association testing and targeted sequencing of important genomic loci. This project will promote and enhance partnerships, build skills, and develop resources needed to address the COVID-19 burden and associated risk factors in South African communities., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Andrew K. May et al.)

Background: Emergency general surgery (EGS) patients have increased mortality risk compared with elective counterparts. Recent studies on risk factors have largely used national data sets limited to administrative data. Our aim was to examine risk factors in an integrated regional health system EGS database, including clinical and administrative data, hypothesizing that this novel process would identify clinical variables as important risk factors for mortality., Methods: Our nine-hospital health system's billing data were queried for EGS International Classification of Disease codes between 2013 and 2018. Codes were grouped by diagnosis, and urgent or emergent encounters were included and merged with electronic medical record clinical data. Outcomes assessed were inpatient and 1-year mortality. Standard and multivariable statistics evaluated factors associated with mortality., Results: There were 253,331 EGS admissions with 3.6% inpatient mortality rate. Patients who suffered inpatient and 1-year mortality were older, more likely to be underweight, and have neutropenia or elevated lactate. On multivariable analysis for inpatient mortality: age (odds ratio [OR], 1.7-6.7), underweight body mass index (OR, 1.6), transfer admission (OR, 1.8), leukopenia (OR, 2.0), elevated lactate (OR, 1.8), and ventilator requirement (OR, 7.1) remained associated with increased risk. Adjusted analysis for 1-year mortality demonstrated similar findings, with highest risk associated with older age (OR, 2.8-14.6), underweight body mass index (OR, 2.3), neutropenia (OR, 2.0), and tachycardia (OR, 1.7)., Conclusion: After controlling for patient and disease characteristics available in administrative databases, clinical variables remained significantly associated with mortality. This novel yet simple process allows for easy identification of clinical data points imperative to the study of EGS diagnoses that are critical in understanding factors that impact mortality., Level of Evidence: Prognostic and Epidemiologic; Level III., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The aim of this study was to evaluate the use of laparoscopic surgery for common emergency general surgery (EGS) procedures within an integrated Acute Care Surgery (ACS) network. We hypothesized that laparoscopy would be associated with improved outcomes., Methods: Our integrated health care system's EGS registry created from AAST EGS ICD-9 codes was queried from January 2013 to October 2015. Procedures were grouped as laparoscopic or open. Standard descriptive and univariate tests were performed, and a multivariable logistic regression controlling for open status, age, BMI, Charlson Comorbidity Index (CCI), trauma tier, and resuscitation diagnosis was performed. Laparoscopic procedures converted to open were identified and analyzed using concurrent procedure billing codes across episodes of care., Results: Of 60,604 EGS patients identified over the 33-month period, 7280 (12.0%) had an operation and 6914 (11.4%) included AAST-defined EGS procedures. There were 4813 (69.6%) surgeries performed laparoscopically. Patients undergoing a laparoscopic procedure tended to be younger (45.7 ± 18.0 years vs. 57.2 ± 17.6, p < 0.001) with similar BMI (29.7 ± 9.0 kg/m 2 vs. 28.8 ± 8.3, p < 0.001). Patients in the laparoscopic group had lower mean CCI score (1.6 ± 2.3 vs. 3.4 ± 3.2, p ≤ 0.0001). On multivariable analysis, open surgery had the highest association with inpatient mortality (OR 8.67, 4.23-17.75, p < 0.0001) and at all time points (30-, 90-day, 1-, 3-year). At all time points, conversion to open was found to be a statistically significant protective factor., Conclusion: Use of laparoscopy in EGS is common and associated with a decreased risk of all-cause mortality at all time points compared to open procedures. Conversion to open was protective at all time points compared to open procedures., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Operative management of emergency general surgery (EGS) diagnoses involves a range of procedures which can carry high morbidity and mortality. Little is known about the impact of obesity on patient outcomes. The aim of this study was to examine the association between body mass index (BMI) >30 kg/m 2 and mortality for EGS patients. We hypothesized that obese patients would have increased mortality rates., Methods: A regional integrated health system EGS registry derived from The American Association for the Surgery of Trauma EGS ICD-9 codes was analyzed from January 2013 to October 2015. Patients were stratified into BMI categories based on WHO classifications. The primary outcome was 30-day mortality. Longer-term mortality with linkage to the Social Security Death Index was also examined. Univariate and multivariable analyses were performed., Results: A total of 60 604 encounters were identified and 7183 (11.9%) underwent operative intervention. Patient characteristics include 53% women, mean age 58.2 ± 18.7 years, 64.2% >BMI 30 kg/m 2 , 30.2% with chronic obstructive pulmonary disease, 19% with congestive heart failure, and 31.1% with diabetes. The most common procedure was laparoscopic cholecystectomy (36.4%). Overall, 90-day mortality was 10.9%. In multivariable analysis, all classes of obesity were protective against mortality compared to normal BMI. Underweight patients had increased risk of inpatient (OR = 1.9, CI = 1.7-2.3), 30-day (OR = 1.9, CI = 1.7-2.1), 90-day (OR = 1.8, CI 1.6-2.0), 1-year (OR = 1.8, CI = 1.7-2.0), and 3-year mortality (OR = 1.7, CI = 1.6-1.9)., Conclusions: When stratified by BMI, underweight EGS patients have the highest odds of death. Paradoxically, obesity appears protective against death, even when controlling for potentially confounding factors. Increased rates of nonoperative management in the obese population may impact these findings.

Background: Data on duration of antibiotics in patients managed with an open abdomen (OA) due to intra-abdominal infection (IAI) are scarce. We hypothesized that patients with IAI managed with OA rather than closed abdomen (CA) would have higher rates of secondary infections (SIs) independent of the duration of the antibiotic treatment., Methods: This was an observational, prospective, multicenter, international study of patients with IAI requiring laparotomy for source control. Demographic and antibiotic duration values were collected. Primary outcomes were SI (surgical site, bloodstream, pneumonia, urinary tract) and mortality. Statistical analysis included ANOVA, chi-square/Fisher's exact test, and logistic regression., Results: Twenty-one centers contributed 752 patients. The average age was 59.6 years, 43.6% were women, and 43.9% were managed with OA. Overall mortality was 16.1%, with higher rates among OA patients (31.6% vs 4.4%, p < 0.001). OA patients had higher Sequential Organ Failure Assessment (4.7 vs 1.8, p < 0.001), American Society of Anesthesiologists Physical Status (3.6 vs 2.7, p < 0.001), and APACHE II scores (16.1 vs 9.4, p < 0.001). The mean duration of antibiotics was 6.5 days (8.0 OA vs 5.4 CA, p < 0.001). A total of 179 (23.8%) patients developed SI (33.1% OA vs 16.8% CA, p < 0.001). Longer antibiotic duration was associated with increased rates of SI: 1 to 2 days, 15.8%; 3 to 5 days, 20.4%; 6 to 14 days, 26.6%; and more than 14 days, 46.8% (p < 0.001)., Conclusions: Patients with IAI managed with OA had higher rates of SI and increased mortality compared with CA. A prolonged duration of antibiotics was associated with increased rates of SI. Increased antibiotic duration is not associated with improved outcomes in patients with IAI and OA., (Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Resistance-based blood flow restriction training (BFRT) improves skeletal muscle strength and size. Unlike heavy-load resistance training (HLRT), there is debate as to whether strength adaptations following BFRT interventions can be primarily attributed to concurrent muscle hypertrophy, as the magnitude of hypertrophy is often minor. The present study aimed to investigate the effect of 7 weeks of BFRT and HLRT on muscle strength and hypertrophy. The expression of protein growth markers from muscle biopsy samples was also measured. Male participants were allocated to moderately heavy-load training (HL; n  = 9), low-load BFRT (LL + BFR; n  = 8), or a control (CON; n  = 9) group to control for the effect of time. HL and LL + BFR completed 21 training sessions (3 d.week -1 ) comprising bilateral knee extension and knee flexion exercises (HL = 70% one-repetition maximum (1-RM), LL + BFR = 20% 1-RM + blood flow restriction). Bilateral knee extension and flexion 1-RM strength were assessed, and leg muscle CSA was measured via peripheral quantitative computed tomography. Protein growth markers were measured in vastus lateralis biopsy samples taken pre- and post the first and last training sessions. Biopsy samples were also taken from CON at the same time intervals as HL and LL + BFR. Knee extension 1-RM strength increased in HL (19%) and LL + BFR (19%) but not CON (2%; p  < 0.05). Knee flexion 1-RM strength increased similarly between all groups, as did muscle CSA (50% femur length; HL = 2.2%, LL + BFR = 3.0%, CON = 2.1%; TIME main effects). 4E-BP1 (Thr37/46) phosphorylation was lower in HL and LL + BFR immediately post-exercise compared with CON in both sessions ( p  < 0.05). Expression of other growth markers was similar between groups ( p  > 0.05). Overall, BFRT and HLRT improved muscle strength and size similarly, with comparable changes in intramuscular protein growth marker expression, both acutely and chronically, suggesting the activation of similar anabolic pathways. However, the low magnitude of muscle hypertrophy was not significantly different to the non-training control suggesting that strength adaptation following 7 weeks of BFRT is not driven by hypertrophy, but rather neurological adaptation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 May, Russell, Della Gatta and Warmington.)

Background: Interstitial lung disease is a debilitating condition associated with significant dyspnoea, fatigue, and poor exercise tolerance. Pulmonary rehabilitation is an effective and key intervention in people with interstitial lung disease. However, despite the best efforts of patients and clinicians, many of those who participate are not achieving clinically meaningful benefits. This assessor-blinded, multi-centre, randomised controlled trial aims to compare the clinical benefits of high intensity interval exercise training versus the standard pulmonary rehabilitation method of continuous training at moderate intensity in people with fibrotic interstitial lung disease., Methods: Eligible participants will be randomised to either a standard pulmonary rehabilitation group using moderate intensity continuous exercise training or high intensity interval exercise training. Participants in both groups will undertake an 8-week pulmonary rehabilitation program of twice-weekly supervised exercise training including aerobic (cycling) and strengthening exercises. In addition, participants in both groups will be prescribed a home exercise program. Outcomes will be assessed at baseline, upon completion of the intervention and at six months following the intervention by a blinded assessor. The primary outcome is endurance time on a constant work rate test. Secondary outcomes are functional capacity (6-min walk distance), health-related quality of life (Chronic Respiratory Disease Questionnaire (CRQ), St George's Respiratory Questionnaire idiopathic pulmonary fibrosis specific version (SGRQ-I), breathlessness (Dyspnoea 12, Modified Medical Research Council Dyspnoea Scale), fatigue (fatigue severity scale), anxiety (Hospital Anxiety and Depression Scale), physical activity level (GeneActiv), skeletal muscle changes (ultrasonography) and completion and adherence to pulmonary rehabilitation., Discussion: The standard exercise training strategies used in pulmonary rehabilitation may not provide an optimal exercise training stimulus for people with interstitial lung disease. This study will determine whether high intensity interval training can produce equivalent or even superior changes in exercise performance and symptoms. If high intensity interval training proves effective, it will provide an exercise training strategy that can readily be implemented into clinical practice for people with interstitial lung disease. Trial registration ClinicalTrials.gov Registry (NCT03800914). Registered 11 January 2019, https://clinicaltrials.gov/ct2/show/NCT03800914 Australian New Zealand Clinical Trials Registry ACTRN12619000019101. Registered 9 January 2019, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376050&isReview=true., (© 2021. The Author(s).)

Background: Diagnostic criterion for pneumonia includes clinical data and bronchoalveolar lavage cultures (BALCx) to identify pathogens. Although ~60% of BALCx are negative, there may be reluctance to discontinue antibiotics, leading to prolonged antibiotic use (PAU). Objective: The purpose of this study is to compare outcomes of subjects with negative BALCx with PAU versus without prolonged antibiotic use (nPAU). Methods: A retrospective cohort study was conducted including subjects admitted to the intensive care unit (ICU), with suspected pneumonia, and negative BALCx. Data were compared based on length of exposure to antibiotics, PAU (antibiotics >4 days) versus nPAU (antibiotics <4 days). Results: A total of 128 subjects were included, 57 in the PAU group and 71 in the nPAU group. Baseline demographics were similar between groups. Severity of illness measured by multiple organ dysfunction scores at time of bronchoalveolar lavage (BAL) collection to final result showed a statistically significant decrease in the PAU group but not in the nPAU group. No differences were found in ICU days, ventilator-free days, or mortality; however, length of stay was longer for PAU (23 vs. 17, p = .04). In the PAU group, there were fewer BALCx results of "no growth" (23% vs. 45%, p = .04), more positive gram stains (83% vs. 60%, p = .01) and more positive non-BALCx (40% vs. 14%, p = .01). In a multivariate analysis, factors associated with PAU were positive BAL gram stains (adjusted odds ratio [aOR] 3.1, p = .037) and positive non-BALCx (aOR 4.7, p = .002). Conclusion: For subjects with suspected pneumonia and negative BALCx, positive non-BALCx and positive BALCx gram stain influenced the length of exposure of antibiotics., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Ventilator-associated pneumonia is poorly understood in trauma. Ventilated trauma patients can develop bacterial burden without symptoms; the factors that influence this are unknown., Methods: Injured adults ventilated for > 2 days were enrolled. Mini-bronchoalveolar lavage was performed for 14 days or until extubation. Semi-quantitative cultures were blinded from clinicians. All cultures with > 104 colony forming units (CFU) were assessed for antibiotic exposure (ABXE) and spectrum of coverage. mBAL CFU was assessed daily., Results: 60 patients were ventilated for 9 days (median). There were 75 with > 104 CFU. 46 had > 104 CFU and no ABXE on the sample day. 74% had clearance or a decrease (CoD) in CFU without ABXE. 29 had > 104 CFU and ABXE on the sample day. 19 had ABXE with pathogen coverage. 84% had CoD in CFU. 10 had ABXE with no spectrum of coverage. 1/10 had increased CFU and the remaining 9/10 CoD in CFU. The three groups were not statistically different on chi-squared analysis., Conclusion: Clearance of pathogens on surveillance cultures was unaffected by ABXE.

Background: Necrotizing soft tissue infections (NSTIs) are an acute surgical condition with high morbidity and mortality. Timely identification, resuscitation, and aggressive surgical management have significantly decreased inpatient mortality. However, reduced inpatient mortality has shifted the burden of disease to long-term mortality associated with persistent organ dysfunction., Methods: We performed a combined analysis of NSTI patients from the AB103 Clinical Composite Endpoint Study in Necrotizing Soft Tissue Infections randomized-controlled interventional trial (ATB-202) and comprehensive administrative database (ATB-204) to determine the association of persistent organ dysfunction on inpatient and long-term outcomes. Persistent organ dysfunction was defined as a modified Sequential Organ Failure Assessment (mSOFA) score of 2 or greater at Day 14 (D14) after NSTI diagnosis, and resolution of organ dysfunction defined as mSOFA score of 1 or less., Results: The analysis included 506 hospitalized NSTI patients requiring surgical debridement, including 247 from ATB-202, and 259 from ATB-204. In both study cohorts, age and comorbidity burden were higher in the D14 mSOFA ≥2 group. Patients with D14 mSOFA score of 1 or less had significantly lower 90-day mortality than those with mSOFA score of 2 or higher in both ATB-202 (2.4% vs. 21.5%; p < 0.001) and ATB-204 (6% vs. 16%: p = 0.008) studies. In addition, in an adjusted covariate analysis of the combined study data sets D14 mSOFA score of 1 or lesss was an independent predictor of lower 90-day mortality (odds ratio, 0.26; 95% confidence interval, 0.13-0.53; p = 0.001). In both studies, D14 mSOFA score of 1 or less was associated with more favorable discharge status and decreased resource utilization., Conclusion: For patients with NSTI undergoing surgical management, persistent organ dysfunction at 14 days, strongly predicts higher resource utilization, poor discharge disposition, and higher long-term mortality. Promoting the resolution of acute organ dysfunction after NSTI should be considered as a target for investigational therapies to improve long-term outcomes after NSTI., Level of Evidence: Prognostic/epidemiology study, level III., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Previous estimates of the incidence of necrotizing soft tissue infections (NSTI) in the United States have substantial limitations and underestimate its occurrence. Improvements in hospital mortality after NSTI have increased the number of survivors at risk for long-term sequelae. This study estimates the incidence of NSTI and the burden of re-admission and associated healthcare spending in patients who survived admission for NSTI. Methods: Index admissions for NSTI were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes combined with either Current Procedural Technology (CPT) or diagnosis-related group codes to increase specificity. Two separate datasets were used to provide primary and secondary estimates of the annual incidence of NSTIs in the United States: the National Inpatient Sample (NIS) for the years 2012-2016 and the Watson Health dataset for 2009-2013, respectively, and extrapolated to estimate the incidence for 2018. The Nationwide Readmissions Database (NRD) from 2013-2015 was used to estimate of the risk for re-admission, cost of re-admissions, and to compare 90-day re-admission rates for NSTI to common medical conditions. Results: National Inpatient Sample and Watson Health datasets demonstrated an increasing annual incidence and estimated 33,600 and 28,500 cases in 2018, respectively. The estimated annual incidences in the United States in 2018 were 10.3 and 8.7 per 100,000 persons, respectively. Risk of 90-day re-admission ranged from 24%-29% over the 3 years, 89% of which were unplanned. Of those re-admitted, 90% had one or more comorbidities, the most common diagnoses associated with re-admission were infection in 65%, acute kidney injury in 22%, and shock in 10%. The median re-admission length of stay was seven days (interquartile range [IQR]: 4-13 days) with a median cost of re-admission of $13,590 (IQR: $7186-$27440). Conclusion: The incidence of NSTI is more common than generally reported. Re-admission within 90 days is common, occurring in more than one in four survivors resulting in high healthcare costs.

Background: The Emergency General Surgery (EGS) population is particularly at high risk for readmission. Currently, no system exists to predict which EGS patients are most at risk. We hypothesized that a subset of EGS patients could be identified with increased 30-day unplanned readmission. We also hypothesized that a majority of readmissions occur sooner than the conventional 2-week follow-up period., Methods: National Surgical Quality Improvement Program (NSQIP) nonelective general surgery patients were analyzed. Multivariable logistic regression identified factors with increased odds of unplanned readmission. AAST EGS Diagnosis Categories were used to categorize postop ICD-9 codes, and the top 10 CPT codes in each group were analyzed. Readmission rate, the reason for unplanned readmission, and time to readmission were analyzed., Results: A total of 383,726 patients were identified with a readmission rate of 8.1% within 30 d of their primary procedure. The top 50 CPT codes accounted for 84% of EGS readmissions. Increased readmission risk was demonstrated for underweight patients (OR = 1.15, P < 0.05). High-risk hospital characteristics were LOS >2 d, any inpatient pulmonary complications, and discharge to any facility or rehab (all P < 0.05). Surgical site infections cause nearly 25% of readmissions. Intestinal procedures are most frequently readmitted (22% of EGS readmissions), with colorectal procedures having the higher odds of readmission. Most readmissions occur <10 d after discharge., Conclusions: A high-risk subpopulation exists within EGS, and most readmissions occur sooner than a typical 2-week follow-up. Early interventions for high-risk EGS subpopulations may allow for early intervention and reduction of unnecessary healthcare utilization., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Emergency surgical services often encounter patients with generalized peritonitis. Difficult perioperative decisions impact morbidity, mortality, cost, and utilization of hospital resources. The ability to preoperatively predict patient nonsurvival despite surgical intervention using clinical physiologic indicators was the aim of this study and would be helpful in counseling patients/families., Methods: A retrospective cohort from an institutional database was queried for nontrauma patients with peritonitis undergoing emergency laparotomy from 2012 to 2016. Time to mortality after surgery was compared: early (≤72 hours) versus late (>72 hours) and no death., Results: After 534 emergency laparotomies, there were 74 (13.9%) mortalities. Of these, death occurred early (≤72 hours) after surgery in 28 (37.8%) patients and late (>72 hours) in 46 (62.2%). Early death patients had a significantly more deranged physiology, as evidenced by higher Acute Physiology and Chronic Health Evaluation II scores (mean 28.1 ± 8.4 vs 22.9 ± 8.7, P = .01), worse acute kidney injury (preoperative creatinine 3.7 ± 3.2 vs 1.9 ± 1.4, P = .001), and greater level of acidosis (pH 7.19 ± 0.12 vs 7.27 ± 0.13, P = .017). Additionally, preoperative lactate was significantly increased in patients with early mortality (6.8 ± 4.1 vs 5.1 ± 4.0, P = .045). Using logarithmic regression, a nomogram was constructed using age, Glasgow Coma Scale, lactate, creatinine, and pH. This nomogram had an area under the curve of 0.908 on receiver operator curve analysis. A score of 13 equates to greater than 50% risk of early mortality after surgery., Conclusion: Early mortality (≤72 hours after emergency laparotomy) is associated with decreased pH, elevated creatinine, and elevated lactate. These factors combined into the nomogram constructed may assist surgical teams with patient and family discussions to prevent futile surgical interventions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Objective: Reltecimod, a CD 28 T-lymphocyte receptor mimetic, inhibits T-cell stimulation by an array of bacterial pathogens. A previous phase 2 trial demonstrated improved resolution of organ dysfunction after NSTI. We hypothesized that early administration of reltecimod would improve outcome in severe NSTI., Methods: Randomized, double-blind, placebo-controlled trial of single dose reltecimod (0.5 mg/kg) administered within 6 hours of NSTI diagnosis at 65 of 93 study sites. Inclusion: surgical confirmation of NSTI and organ dysfunction [modified Sequential Organ Failure Assessment Score (mSOFA) score ≥3]. Primary analysis was modified Intent-to-Treat (mITT), responder analysis using a previously validated composite endpoint, necrotizing infection clinical composite endpoint, defined as: alive at day 28, ≤3 debridements, no amputation beyond first operation, and day 14 mSOFA ≤1 with ≥3 point reduction (organ dysfunction resolution). A prespecified, per protocol (PP) analysis excluded 17 patients with major protocol violations before unblinding., Results: Two hundred ninety patients were enrolled, mITT (Reltecimod 142, Placebo 148): mean age 55 ± 15 years, 60% male, 42.4% diabetic, 28.6% perineal infection, screening mSOFA mean 5.5 ± 2.4. Twenty-eight-day mortality was 15% in both groups. mITT necrotizing infection clinical composite endpoint success was 48.6% reltecimod versus 39.9% placebo, P = 0.135 and PP was 54.3% reltecimod versus 40.3% placebo, P = 0.021. Resolution of organ dysfunction was 65.1% reltecimod versus 52.6% placebo, P = 0.041, mITT and 70.9% versus 53.4%, P = 0.005, PP., Conclusion: Early administration of reltecimod in severe NSTI resulted in a significant improvement in the primary composite endpoint in the PP population but not in the mITT population. Reltecimod was associated with improved resolution of organ dysfunction and hospital discharge status., Competing Interests: The authors have no other conflicts of interests to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Blood flow restriction exercise has increasingly broad applications among healthy and clinical populations. Ensuring the technique is applied in a safe, controlled, and beneficial way for target populations is essential. Individualized cuff pressures are a favored method for achieving this. However, there remains marked inconsistency in how individualized cuff pressures are applied., Objectives: To quantify the cuff pressures used in the broader blood flow restriction exercise literature, and determine whether there is clear justification for the choice of pressure prescribed., Methods: Studies were included in this review from database searches if they employed an experimental design using original data, involved either acute or chronic exercise using blood flow restriction, and they assessed limb or arterial occlusion pressure to determine an individualized cuff pressure. Methodologies of the studies were evaluated using a bespoke quality assessment tool., Results: Fifty-one studies met the inclusion criteria. Individualized cuff pressures ranged from 30% to 100% arterial occlusion pressure. Only 7 out of 52 studies attempted to justify the individualized cuff pressure applied during exercise. The mean quality rating for all studies was 11.1 ± 1.2 out of 13., Conclusions: The broader blood flow restriction exercise literature uses markedly heterogeneous prescription variables despite using individualized cuff pressures. This is problematic in the absence of any clear justification for the individualized cuff pressures selected. Systematically measuring and reporting all relevant acute responses and training adaptations to the full spectrum of BFR pressures alongside increased clarity around the methodology used during blood flow restriction exercise is paramount., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

New Findings: What is the central question of this study? Do elevated levels of the stress-response protein NDRG2 protect against fasting and chronic disease in mouse skeletal muscle? What is the main finding and its importance? NDRG2 levels increased in the tibialis anterior muscle in response to fasting and the effects of motor neurone disease. No alleviation of the stress-related and proteasomal pathways, mitochondrial dysfunction or muscle mass loss was observed even with the addition of exogenous NDRG2 indicating that the increase in NDRG2 is a normal adaptive response., Abstract: Skeletal muscle mass loss and dysfunction can arise from stress, which leads to enhanced protein degradation and metabolic impairment. The expression of N-myc downstream-regulated gene 2 (NDRG2) is induced in response to different stressors and is protective against the effects of stress in some tissues and cell types. Here, we investigated the endogenous NDRG2 response to the stress of fasting and chronic disease in mice and whether exogenous NDRG2 overexpression through adeno-associated viral (AAV) treatment ameliorated the response of skeletal muscle to these conditions. Endogenous levels of NDRG2 increased in the tibialis anterior muscle in response to 24 h fasting and with the development of the motor neurone disease, amyotrophic lateral sclerosis, in SOD1 G93A transgenic mice. Despite AAV-induced overexpression and increased expression with fasting, NDRG2 was unable to protect against the activation of proteasomal and stress pathways in response to fasting. Furthermore, NDRG2 was unable to reduce muscle mass loss, mitochondrial dysfunction and elevated oxidative and endoplasmic reticulum stress levels in SOD1 G93A mice. Conversely, elevated NDRG2 levels did not exacerbate these stress responses. Overall, increasing NDRG2 levels might not be a useful therapeutic strategy to alleviate stress-related disease pathologies in skeletal muscle., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

The novel coronavirus (COVID-19) was first diagnosed in Wuhan, China in December 2019 and has now spread throughout the world, being verified by the World Health Organization as a pandemic on March 11. This had led to the calling of a national emergency on March 13 in the US. Many hospitals, healthcare networks, and specifically, departments of surgery, are asking the same questions about how to cope and plan for surge capacity, personnel attrition, novel infrastructure utilization, and resource exhaustion. Herein, we present a tiered plan for surgical department planning based on incident command levels. This includes acute care surgeon deployment (given their critical care training and vertically integrated position in the hospital), recommended infrastructure and transfer utilization, triage principles, and faculty, resident, and advanced care practitioner deployment., (Copyright © 2020 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-associated viral infection (coronavirus disease 2019, COVID-19) is a virulent, contagious viral pandemic that is affecting populations worldwide. As with any airborne viral respiratory infection, surgical and non-surgical patients may be affected. Methods: Review and synthesis of pertinent English-language literature pertaining to COVID-19 infection among adult patients. Results: COVID-19 disease that requires hospitalization results in critical illness approximately 25% of the time and requires mechanical ventilation with positive airway pressure. Acute kidney injury, a marked hypercoagulable state, and sometimes myocarditis can be features of COVID-19 in addition to the characteristic severe acute lung injury. Even if not among the most seriously afflicted, older patients with medical comorbidities are both predisposed to infection and risk increased morbidity and mortality, however, all persons presenting for surgical intervention should be suspected of infection (and thus transmissibility) even if asymptomatic. Although most elective surgery has been curtailed by administrative or governmental fiat, patients will still need urgent or emergency operative intervention for time-sensitive disease processes such as malignant neoplasia or for true emergencies such as perforated viscus or traumatic injury. It is possible to provide safe surgical care for SARS-CoV-2-positive patients and minimize nosocomial transmission to healthcare workers. Conclusions: This guidance will facilitate appropriate protection of patients and staff, and maintenance of infection control measures to assist surgical personnel and facilities to prepare for COVID-19-infected adult patients requiring urgent or emergent operative intervention and to provide optimal patient care.

Background: Surgical research is potentially invasive, high-risk, and costly. Research that advances medical dogma must justify both its ends and its means. Although ethical questions do not always have simple answers, it is critically important for the clinician, researcher, and patient to approach these dilemmas and surgical research in a thoughtful, conscientious manner. Methods: We present four ethical issues in surgical research and discuss the opposing viewpoints. These topics were presented and discussed at the 39th Annual Meeting of the Surgical Infection Society as pro-con debates. The presenters of each opinion developed a succinct summary of their respective reviews for this publication. Results: The key subjects for these pro-con debates were: (1) Should patients be enrolled for time-sensitive surgical infection research using an opt-out or an opt-in strategy? (2) Should patients who are being enrolled in a randomized controlled trial (RCT) comparing surgery with a non-operative intervention pay the costs of their treatment arm? (3) Should the scientific community embrace open access journals as the future of scientific publishing? (4) Should the majority of funding go to clinical or basic science research? Important points were illustrated in each of the pro-con presentations and illustrated the difficulties that are facing the performance and payment of infection research in the future. Conclusions: Surgical research is ethically complex, with conflicting demands between individual patients, society, and healthcare economics. At present, there are no clear answers to these and the many other ethical issues facing research in the future. Answers will only come from continued robust dialogue among all stakeholders in surgical research.

Background: Nutrients, such as glutamine (GLN), have been shown to effect levels of a family of protective proteins termed heat shock proteins (HSPs) in experimental and clinical critical illness. HSPs are believed to serve as extracellular inflammatory messengers and intracellular cytoprotective molecules. Extracellular HSP70 (eHSP70) has been termed a chaperokine due to ability to modulate the immune response. Altered levels of eHSP70 are associated with various disease states. Larger clinical trial data on GLN effect on eHSP expression and eHSP70's association with inflammatory mediators and clinical outcomes in critical illness are limited., Objective: Explore effect of longitudinal change in serum eHSP70, eHSP27 and inflammatory cytokine levels on clinical outcomes such as pneumonia and mortality in adult surgical intensive care unit (SICU) patients. Further, evaluate effect of parenteral nutrition (PN) supplemented with GLN (GLN-PN) versus GLN-free, standard PN (STD-PN) on serum eHSP70 and eHSP27 concentrations., Methods: Secondary observational analysis of a multicenter clinical trial in 150 adults after cardiac, vascular, or gastrointestinal surgery requiring PN support and SICU care conducted at five academic medical centers. Patients received isocaloric, isonitrogenous PN, with or without GLN dipeptide. Serum eHSP70 and eHSP27, interleukin-6 (IL-6), and 8 (IL-8) concentrations were analyzed in patient serum at baseline (prior to study PN) and over 28 days of follow up., Results: eHSP70 declined over time in survivors during 28 days follow-up, but non-survivors had significantly higher eHSP70 concentrations compared to survivors. In patients developing pneumonia, eHSP70, eHSP27, IL-8, and IL-6 were significantly elevated. Adjusted relative risk for hospital mortality was reduced 75% (RR = 0.25, p = 0.001) for SICU patients with a faster decline in eHSP70. The area under the receiver operating characteristic curve was 0.85 (95% CI: 0.76 to 0.94) for the final model suggesting excellent discrimination between SICU survivors and non-survivors. GLN-PN did not alter eHSP70 or eHSP27 serum concentrations over time compared to STD-PN., Conclusion: Our results suggest that serum HSP70 concentration may be an important marker for severity of illness and likelihood of recovery in the SICU. GLN-supplemented-PN did not increase eHSP70., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Creatine is a metabolite important for cellular energy homeostasis as it provides spatio-temporal adenosine triphosphate (ATP) buffering for cells with fluctuating energy demands. Here, we examined whether placental creatine metabolism was altered in cases of early-onset pre-eclampsia (PE), a condition known to cause placental metabolic dysfunction. We studied third trimester human placentae collected between 27-40 weeks' gestation from women with early-onset PE ( n = 20) and gestation-matched normotensive control pregnancies ( n = 20). Placental total creatine and creatine precursor guanidinoacetate (GAA) content were measured. mRNA expression of the creatine synthesizing enzymes arginine:glycine aminotransferase ( GATM ) and guanidinoacetate methyltransferase ( GAMT ), the creatine transporter ( SLC6A8 ), and the creatine kinases (mitochondrial CKMT1A & cytosolic BBCK ) was assessed. Placental protein levels of arginine:glycine aminotransferase (AGAT), GAMT, CKMT1A and BBCK were also determined. Key findings; total creatine content of PE placentae was 38% higher than controls ( p < 0.01). mRNA expression of GATM (p < 0.001), GAMT (p < 0.001), SLC6A8 (p = 0.021) and BBCK (p < 0.001) was also elevated in PE placentae. No differences in GAA content, nor protein levels of AGAT, GAMT, BBCK or CKMT1A were observed between cohorts. Advancing gestation and birth weight were associated with a down-regulation in placental GATM mRNA expression, and a reduction in GAA content, in control placentae. These relationships were absent in PE cases. Our results suggest PE placentae may have an ongoing reliance on the creatine kinase circuit for maintenance of cellular energetics with increased total creatine content and transcriptional changes to creatine synthesizing enzymes and the creatine transporter. Understanding the functional consequences of these changes warrants further investigation., Competing Interests: The authors declare no conflict of interest.

Objectives: To identify exercise tests that are suitable for home-based or remote administration in people with chronic lung disease., Methods: Rapid review of studies that reported home-based or remote administration of an exercise test in people with chronic lung disease, and studies reporting their clinimetric (measurement) properties., Results: 84 studies were included. Tests used at home were the 6-minute walk test (6MWT, two studies), sit-to-stand tests (STS, five studies), Timed Up and Go (TUG, 4 studies) and step tests (two studies). Exercise tests administered remotely were the 6MWT (two studies) and step test (one study). Compared to centre-based testing the 6MWT distance was similar when performed outdoors but shorter when performed at home (two studies). The STS, TUG and step tests were feasible, reliable (intra-class correlation coefficients >0.80), valid (concurrent and known groups validity) and moderately responsive to pulmonary rehabilitation (medium effect sizes). These tests elicited less desaturation than the 6MWT, and validated methods to prescribe exercise were not reported., Discussion: The STS, step and TUG tests can be performed at home, but do not accurately document desaturation with walking or allow exercise prescription. Patients at risk of desaturation should be prioritised for centre-based exercise testing when this is available.

The optical limiting (OL) properties of a 3,5-di- p -benzyloxystyrylBODIPY dye with an p -acetamidophenyl moiety at the meso -position have been investigated by using the open-aperture Z-scan technique at 532 nm with 10 ns laser pulses. There is a ca. 140 nm red shift of the main spectral band to 644 nm relative to the corresponding BODIPY core dye, due to the incorporation of p -benzyloxystyryl groups at the 3,5-positions. As a result, there is relatively weak absorbance across most of the visible region under ambient light conditions. Analysis of the observed reverse saturable absorbance (RSA) profiles demonstrates that the dye is potentially suitable for use in optical limiting applications as has been reported previously for other 3,5-distyrylBODIPY dyes. Time-resolved transient absorption spectroscopy and kinetic studies with femtosecond and nanosecond scale laser pulses provide the first direct spectral evidence that excited state absorption (ESA) from the S 1 state is responsible for the observed OL properties., (Copyright © 2019 Ngoy, May, Mack and Nyokong.)

Purpose: No current guidelines or recommendations exist informing the selection of restriction pressure during blood flow restriction exercise (BFRE). Moreover, the effects of specific relative restriction pressures on the acute muscle, metabolic and cardiopulmonary responses to BFRE are unclear. The purpose of this study was to characterize these acute responses at different levels of restriction pressure., Methods: Participants ( n = 10) completed rhythmic isometric knee extension exercise across five experimental trials in a balanced randomized order. Three were BFRE trials {B-40 [restriction pressure set to 40% LOP (total limb occlusion pressure)]; B-60 (60% LOP); and B-80 (80% LOP)} with a workload equivalent to 20% maximal voluntary force (MVC), one was non-BFRE at 20% MVC (LL) and one was non-BFRE at 80% MVC (HL). Measurements recorded were torque, muscle activity via electromyography (EMG), tissue oxygenation via near infrared spectroscopy, whole body oxygen consumption, blood lactate and heart rate., Results: For the LL and B-40 trials, most measures remained constant. However, for the B-60 and B-80 trials, significant fatigue was demonstrated by a reduction in MVC torque across the trial ( p < 0.05). Blood lactate increased from baseline in HL, B-60, and B-80 ( p < 0.05). Submaximal EMG was greater in B-60 and B-80 than LL, but lower compared with HL ( p < 0.05). Tissue oxygenation decreased in HL, B-40, B-60, and B-80 ( p < 0.05), which was lower in the B-80 trial compared to all other trials ( p < 0.01). Whole body oxygen consumption was not different between the BFRE trials ( p > 0.05)., Conclusion: We demonstrate graded/progressive acute responses with increasing applied pressure during BFRE, from which we speculate that an effective minimum "threshold" around 60% LOP may be necessary for BFRE to be effective with training. While these data provide some insight on the possible mechanisms by which BFRE develops skeletal muscle size and strength when undertaken chronically across a training program, the outcomes of chronic training programs using different levels of applied restriction pressures remain to be tested. Overall, the present study recommends 60-80% LOP as a suitable "minimum" BFRE pressure.

Creatine is a metabolite involved in cellular energy homeostasis. In this study, we examined placental creatine content, and expression of the enzymes required for creatine synthesis, transport and the creatine kinase reaction, in pregnancies complicated by low birthweight. We studied first trimester chorionic villus biopsies (CVBs) of small for gestational age (SGA) and appropriately grown infants (AGA), along with third trimester placental samples from fetal growth restricted (FGR) and healthy gestation-matched controls. Placental creatine and creatine precursor (guanidinoacetate-GAA) levels were measured. Maternal and cord serum from control and FGR pregnancies were also analyzed for creatine concentration. mRNA expression of the creatine transporter (SLC6A8); synthesizing enzymes arginine:glycine aminotransferase (GATM) and guanidinoacetate methyltransferase (GAMT); mitochondrial (mtCK) and cytosolic (BBCK) creatine kinases; and amino acid transporters (SLC7A1 & SLC7A2) was assessed in both CVBs and placental samples. Protein levels of AGAT (arginine:glycine aminotransferase), GAMT, mtCK and BBCK were also measured in placental samples. Key findings; total creatine content of the third trimester FGR placentae was 43% higher than controls. The increased creatine content of placental tissue was not reflected in maternal or fetal serum from FGR pregnancies. Tissue concentrations of GAA were lower in the third trimester FGR placentae compared to controls, with lower GATM and GAMT mRNA expression also observed. No differences in the mRNA expression of GATM, GAMT or SLC6A8 were observed between CVBs from SGA and AGA pregnancies. These results suggest placental creatine metabolism in FGR pregnancies is altered in late gestation. The relevance of these changes on placental bioenergetics should be the focus of future investigations., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A methodological survey of density functional theory (DFT) methods for the prediction of UV-visible (vis)-near-infrared (NIR) spectra of phthalocyanines is reported. Four methods, namely, full time-dependent (TD)-DFT and its Tamm-Dancoff approximation (TDA), together with their simplified modifications (sTD-DFT and sTDA, respectively), were tested by using the examples of unsubstituted and alkoxy-substituted metal-free ligands and zinc complexes. The theoretical results were compared with experimental data derived from UV-visible absorption and magnetic circular dichroism spectroscopy. Seven popular exchange-correlation functionals (BP86, B3LYP, TPSSh, M06, CAM-B3LYP, LC-BLYP, and ωB97X) were tested within these four approaches starting at a relatively modest level using 6-31G(d) basis sets and gas-phase BP86/def2-SVP optimized geometries. A gradual augmentation of the computational levels was used to identify the influence of starting geometry, solvation effects, and basis sets on the results of TD-DFT and sTD-DFT calculations. It was found that although these factors do influence the predicted energies of the vertical excitations, they do not affect the trends predicted in the spectral properties across series of structurally related substituted free bases and metallophthalocyanines. The best accuracy for the gas-phase vertical excitations was observed in the lower-energy Q-band region for calculations that made use of range-separated hybrids for both full and simplified TD-DFT approaches. The CAM-B3LYP functional provided particularly accurate results in the context of the sTD-DFT approach. The description of the higher-energy B-band region is considerably less accurate, and this demonstrates the need for further advances in the accuracy of theoretical calculations. Together with a general increase in accuracy, the application of simplified TD-DFT methods affords a 2-3 orders of magnitude speedup of the calculations in comparison to the full TD-DFT approach. It is anticipated that this approach will be widely used on desktop computers during the interpretation of UV-vis-NIR spectra of phthalocyanines and related macrocycles in the years ahead., Competing Interests: The authors declare no competing financial interest.

Despite evidence supporting the effectiveness of best practices of infection prevention and management, many surgeons worldwide fail to implement them. Evidence-based practices tend to be underused in routine practice. Surgeons with knowledge in surgical infections should provide feedback to prescribers and integrate best practices among surgeons and implement changes within their team. Identifying a local opinion leader to serve as a champion within the surgical department may be important. The "surgeon champion" can integrate best clinical practices of infection prevention and management, drive behavior change in their colleagues, and interact with both infection control teams in promoting antimicrobial stewardship., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.