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Drugs that induce reversible slowing of metabolic and physiological processes would have great value for organ preservation, especially for organs with high susceptibility to hypoxia-reperfusion injury, such as the heart. Using whole-organism screening of metabolism, mobility, and development in Xenopus, we identified an existing drug, SNC80, that rapidly and reversibly slows biochemical and metabolic activities while preserving cell and tissue viability. Although SNC80 was developed as a delta opioid receptor activator, we discovered that its ability to slow metabolism is independent of its opioid modulating activity as a novel SNC80 analog (WB3) with almost 1000 times less delta opioid receptor binding activity is equally active. Metabolic suppression was also achieved using SNC80 in microfluidic human organs-on-chips, as well as in explanted whole porcine hearts and limbs, demonstrating the cross-species relevance of this approach and potential clinical relevance for surgical transplantation. Pharmacological induction of physiological slowing in combination with organ perfusion transport systems may offer a new therapeutic approach for tissue and organ preservation for transplantation, trauma management, and enhancing patient survival in remote and low-resource locations.

Abstract Background Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self-perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. A further therapeutic option may be open abdomen (OA) management with negative peritoneal pressure therapy (NPPT) to remove inflammatory ascites and attenuate the systemic damage from SCIAS, although there are definite risks of leaving the abdomen open whenever it might possibly be closed. This potential therapeutic paradigm is the rationale being assessed in the Closed Or Open after Laparotomy (COOL trial) ( https://clinicaltrials.gov/ct2/show/NCT03163095 ). Initially, the COOL trial received Industry sponsorship; however, this funding mandated the use of a specific trademarked and expensive NPPT device in half of the patients allocated to the intervention (open) arm. In August 2022, the 3 M/Acelity Corporation without consultation but within the terms of the contract canceled the financial support of the trial. Although creating financial difficulty, there is now no restriction on specific NPPT devices and removing a cost-prohibitive intervention creates an opportunity to expand the COOL trial to a truly global basis. This document describes the evolution of the COOL trial, with a focus on future opportunities for global growth of the study. Methods The COOL trial is the largest prospective randomized controlled trial examining the random allocation of SCIAS patients intra-operatively to either formal closure of the fascia or the use of the OA with an application of an NPPT dressing. Patients are eligible if they have free uncontained intraperitoneal contamination and physiologic derangements exemplified by septic shock OR severely adverse predicted clinical outcomes. The primary outcome is intended to definitively inform global practice by conclusively evaluating 90-day survival. Initial recruitment has been lower than hoped but satisfactory, and the COOL steering committee and trial investigators intend with increased global support to continue enrollment until recruitment ensures a definitive answer. Discussion OA is mandated in many cases of SCIAS such as the risk of abdominal compartment syndrome associated with closure, or a planned second look as for example part of “damage control”; however, improved source control (locally and systemically) is the most uncertain indication for an OA. The COOL trial seeks to expand potential sites and proceed with the evaluation of NPPT agnostic to device, to properly examine the hypothesis that this treatment attenuates systemic damage and improves survival. This approach will not affect internal validity and should improve the external validity of any observed results of the intervention. Trial registration: National Institutes of Health ( https://clinicaltrials.gov/ct2/show/NCT03163095 ).

Purpose There is debate about the effectiveness and toxicity of pelvic lymph node (PLN) irradiation in addition to prostate bed radiotherapy when used to treat disease recurrence following radical prostatectomy. We compared toxicity from radiation therapy (RT) to the prostate bed and pelvic lymph nodes (PBPLN-RT) with prostatebed only radiation therapy (PBO-RT) following radical prostatectomy. Methods and Materials Patients with prostate cancer who underwent post-prostatectomy RT between 2010 and 2016 were identified by using the National Prostate Cancer Audit (NPCA) database. Follow-up data was available up to December 31, 2018. Validated outcome measures, based on a framework of procedural and diagnostic codes, were used to capture ≥Grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity. An adjusted competing-risks regression analysis estimated subdistribution hazard ratios (sHR). A sHR > 1 indicated a higher incidence of toxicity with PBPLN-RT than with PBO-RT. Results 5-year cumulative incidences in the PBO-RT (n = 5,087) and PBPLNRT (n = 593) groups was 18.2% and 15.9% for GI toxicity, respectively. For GU toxicity it was 19.1% and 20.7%, respectively. There was no evidence of difference in GI or GU toxicity after adjustment between PBO-RT and PBPLN-RT (GI: adjusted sHR, 0.90, 95% CI, 0.67–1.19; P = 0.45); (GU: adjusted sHR, 1.19, 95% CI, 0.99–1.44; P = 0.09). Conclusions This national population-based study found that including PLNs in the radiation field following radical prostatectomy is not associated with a significant increase in rates of ≥Grade 2 GI or GU toxicity at 5 years.

Major extremity hemorrhage is a surgical emergency, and the physical examination is essential to help dictate appropriate clinical decision making. Hard signs that require immediate surgical intervention include ongoing bleeding, expanding hematoma, ischemic limb, as well as partial/complete amputation. Packing, compression, balloon tamponade, and tourniquets are very helpful to temporize major hemorrhage. Mangled extremities are very challenging to manage and require a multidisciplinary approach. Temporary vascular shunts are excellent tools for vascular/orthopedic damage control and for temporary stabilization prior to transport for definitive care.

Abstract Background The five-tiered Cambridge Prognostic Group (CPG) classification is a better predictor of prostate cancer-specific mortality than the traditional three-tiered classification (low, intermediate, and high risk). We investigated radical treatment rates according to CPG in men diagnosed with non-metastatic prostate cancer in England between 2014 and 2017. Methods Patients diagnosed with non-metastatic prostate cancer were identified from the National Prostate Cancer Audit database. Men were risk stratified according to the CPG classification. Risk ratios (RR) were estimated for undergoing radical treatment according to CPG and for receiving radiotherapy for those treated radically. Funnel plots were used to display variation in radical treatment rates across hospitals. Results A total of 61,999 men were included with 10,963 (17.7%) in CPG1 (lowest risk group), 13,588 (21.9%) in CPG2, 9452 (15.2%) in CPG3, 12,831 (20.7%) in CPG4, and 15,165 (24.5%) in CPG5 (highest risk group). The proportion of men receiving radical treatment increased from 11.3% in CPG1 to 78.8% in CGP4, and 73.3% in CPG5. Men in CPG3 were more likely to receive radical treatment than men in CPG2 (66.3% versus 48.4%; adjusted RR 1.44; 95% CI 1.36–1.53; P

Objectives To compare gender diversity between UK surgical specialties, assess trends over time, and estimate when gender parity might be achieved.Design Observational study.Setting National Health Service, UK.Participants NHS Hospital & Community Health Service workforce statistics for 2011 to 2020Main outcome measures Logistic regression was used to compare female representation in 2020 between surgical specialties, and to examine for any significant trends between 2011 and 2020. The method of least squares was used to estimate when female representation of specialty registrars would reach 50% (‘gender parity’) for specialties with 45%) and Vascular Surgery (representation consistently

Abstract Background Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self-perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. Principles of treatment include early antibiotic administration and operative source control. A further therapeutic option may be open abdomen (OA) management with active negative peritoneal pressure therapy (ANPPT) to remove inflammatory ascites and ameliorate the systemic damage from SCIAS. Although there is now a biologic rationale for such an intervention as well as non-standardized and erratic clinical utilization, this remains a novel therapy with potential side effects and clinical equipoise. Methods The Closed Or Open after Laparotomy (COOL) study will constitute a prospective randomized controlled trial that will randomly allocate eligible surgical patients intra-operatively to either formal closure of the fascia or use of the OA with application of an ANPTT dressing. Patients will be eligible if they have free uncontained intra-peritoneal contamination and physiologic derangements exemplified by septic shock OR a Predisposition-Infection-Response-Organ Dysfunction Score ≥ 3 or a World-Society-of-Emergency-Surgery-Sepsis-Severity-Score ≥ 8. The primary outcome will be 90-day survival. Secondary outcomes will be logistical, physiologic, safety, bio-mediators, microbiological, quality of life, and health-care costs. Secondary outcomes will include days free of ICU, ventilation, renal replacement therapy, and hospital at 30 days from the index laparotomy. Physiologic secondary outcomes will include changes in intensive care unit illness severity scores after laparotomy. Bio-mediator outcomes for participating centers will involve measurement of interleukin (IL)-6 and IL-10, procalcitonin, activated protein C (APC), high-mobility group box protein-1, complement factors, and mitochondrial DNA. Economic outcomes will comprise standard costing for utilization of health-care resources. Discussion Although facial closure after SCIAS is considered the current standard of care, many reports are suggesting that OA management may improve outcomes in these patients. This trial will be powered to demonstrate a mortality difference in this highly lethal and morbid condition to ensure critically ill patients are receiving the best care possible and not being harmed by inappropriate therapies based on opinion only. Trial registration ClinicalTrials.gov, NCT03163095.

Background: Postnatal depression (PND) describes a wide range of distressing symptoms that can occur in women following childbirth. There is substantial evidence to support the use of cognitive behaviour therapy (CBT) in the treatment of depression, and psychological therapies are recommended by the National Institute for Health and Clinical Excellence as a first-line treatment for PND. However, access is limited owing to expense, waiting lists and availability of therapists. Group CBT may, therefore, offer a solution to these problems by reducing therapist time and increasing the number of available places for treatment. Objectives: To evaluate the clinical effectiveness and cost-effectiveness of group CBT compared with currently used packages of care for women with PND. Data sources: Seventeen electronic bibliographic databases were searched (for example MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, etc.), covering biomedical, health-related, science, social science and grey literature (including current research). Databases were searched from 1950 to January 2008. In addition, the reference lists of relevant articles were checked and various health services’ related resources were consulted via the internet. Review methods: The study population included women in the postpartum period (up to 1 year), meeting the criteria of a standardised PND diagnosis using the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition, or scoring above cut-off on the Edinburgh Postnatal Depression Scale (EPDS). No exclusion was made on the basis of the standardised depression screening/case finding instrument of standardised clinical assessment tool used to define PND. All full papers were read by two reviewers (AS and DS) who made independent decisions regarding inclusion or exclusion, and consensus, where possible, was obtained by meeting to compare decisions. In the event of disagreement, a third reviewer (EK) read the paper and made the decision. All data from included quantitative studies were extracted by one reviewer (AS) using a standardised data extraction form. All data from included qualitative studies were extracted by two reviewers (AS and AB) using a standardised data extraction form with disagreements resolved by discussion. Two different data extraction forms were used, one for the quantitative papers and a second for the qualitative papers. Results: Six studies met the inclusion criteria for the quantitative review. Three were randomised controlled trials (RCTs) and three were non-randomised trials. Two studies met the inclusion criteria for the qualitative review. These were both treatment evaluations incorporating qualitative methods. Only one study was deemed appropriate for the decision problem; therefore a meta-analysis was not performed. This study indicated that the reduction in the EPDS score through group CBT compared with routine primary care (RPC) was 3.48 [95% confidence interval (CI) 0.23 to 6.73] at the end of the treatment period. At 6-month follow-up the relative reduction in EPDS score was 4.48 (95% CI 1.01 to 7.95). Three studies showed the treatment to be effective in reducing depression when compared to RPC, usual care or waiting list groups. There was no adequate evidence on which to assess group CBT compared with other treatments for PND. Two studies of group CBT for PND were included in the qualitative review. Both studies demonstrated patient acceptability of group CBT for PND, although negative feelings towards group CBT were also identified. A de novo economic model was constructed to assess the cost-effectiveness of group CBT. The base-case results indicated a cost per quality-adjusted life-year (QALY) of £46,462 for group CBT compared with RPC. The 95% CI for this ratio ranged from £37,008 to £60,728. There was considerable uncertainty in the cost per woman of running a CBT course, of the appropriateness of efficacy data to the decision problem, and the residual length of benefit associated with group CBT. These were tested using univariate sensitivity analyses. Supplementary analyses that fitted distributions to the cost of treatment and the duration of comparative advantage reported a cost per QALY of £36,062 (95% CI £20,464 to £59,262). Limitations: The cost per QALY ratio for group CBT in PND was uncertain because of gaps in the evidence base. There was little quantitative or qualitative RCT evidence to assess the effectiveness of group CBT for PND. The evidence that was available was of low quality in the main because of poor reporting of the results. Furthermore, little information was reported on concurrent treatment used in the studies, which was controlled for in only two of the studies. Conclusions: Evidence from the clinical effectiveness review provided inconsistent and low quality information on which to base any interpretations for service provision. Although three of the included studies provided some indication that group psycho-education incorporating CBT is effective compared with RPC, there is enough doubt in the quality of the study, the level of CBT implemented in the group programmes, and the applicability to a PND population to limit any interpretations significantly. It is also considered that the place of group CBT in a stepped care programme needs to be identified, as well as there being a need for a clearer referral process for group CBT.