Autonomous circadian rhythms in the human hepatocyte regulate hepatic drug metabolism and inflammatory responses.

Critical aspects of physiology and cell function exhibit self-sustained ~24-hour variations termed circadian rhythms. In the liver, circadian rhythms play fundamental roles in maintaining organ homeostasis. Here, we established and characterized an in vitro liver experimental system in which primary human hepatocytes display self-sustained oscillations. By generating gene expression profiles of these hepatocytes over time, we demonstrated that their transcriptional state is dynamic across 24 hours and identified a set of cycling genes with functions related to inflammation, drug metabolism, and energy homeostasis. We designed and tested a treatment protocol to minimize atorvastatin- and acetaminophen-induced hepatotoxicity. Last, we documented circadian-dependent induction of pro-inflammatory cytokines when triggered by LPS, IFN-ß, or Plasmodium infection in human hepatocytes. Collectively, our findings emphasize that the phase of the circadian cycle has a robust impact on the efficacy and toxicity of drugs, and we provide a test bed to study the timing and magnitude of inflammatory responses over the course of infection in human liver.

The ground is the limit: epidemiology of skydiving accidents over 25 years and in 2.1 million jumps in the Netherlands with sub-analysis of injuries reported by medical professionals in the past five years.

BACKGROUND: Skydiving is the fastest nonmotorized sport; and consequently is not without risk. In the last decades, skydiving has become considerably safer but injuries and fatalities still occur. Incidents are reported to and administered by the Royal Netherlands Aeronautical Association (KNVvL). From 1995 to 2020, 2715 incidents were reported; of which 1503 resulted in injury and 26 in fatality. There is a need for more information available on the particular type, severity, and factors which contribute to skydiving-related injuries worldwide. This study aims to investigate patterns in occurrence rates, examine demographic and skydiving-related factors linked to injuries, and analyze the types and severity of injuries relating to these contributing factors. METHODS: The Dutch KNVvL database - covering more than 25 years of data - was examined for contributing factors. An analysis of the severity and types of injury resulting from incidents over the last five years were matched with a search of hospital databases. RESULTS: The rate of injuries pattern increases starting from 2016, with novice jumpers having the highest risk of injury. Most injuries occur during the landing phase. The lower extremities and the spine are most affected, with fractures being the most prevalent type of injury. More than half of the patients were admitted to hospital, with 10% requiring surgery, resulting in months of rehabilitation. CONCLUSION: This study is the first in the Netherlands, and only the second worldwide to analyze technical incident databases in combination with data from medical information systems. Skydiving accidents of experienced jumpers should be considered as 'high-energy trauma,' therefore treatment should follow standard trauma guidelines. In less experienced skydivers, it is critical to conduct a secondary survey to assess the extremities adequately. Clinicians should also pay attention to friction burns that can arise due to friction between the skin and skydive equipment, a phenomenom that is already known in road traffic accidents.

European military surgical teams in combat theater: A survey study on deployment preparation and experience.

INTRODUCTION: Adequate (predeployment) training of the nowadays highly specialized Western military surgical teams is vital to ensure a broad range of surgical skills to treat combat casualties. This survey study aimed to assess the self-perceived preparedness, training needs, deployment experience, and post-deployment impact of surgical teams deployed with the Danish, Dutch, or Finnish Armed Forces. Study findings may facilitate a customized predeployment training. METHODS: A questionnaire was distributed among Danish, Dutch, and Finnish military surgical teams deployed between January 2013 and December 2020 (N = 142). The primary endpoint of self-perceived preparedness ratings, and data on the training needs, deployment experiences, and post-deployment impacts were compared between professions and nations. RESULTS: The respondents comprised 35 surgeons, 25 anesthesiologists, and 39 supporting staff members, with a response rate of 69.7 % (99/142). Self-perceived deployment preparedness was rated with a median of 4.0 (IQR 4.0-4.0; scale: 1 [very unprepared]-5 [more than sufficient]). No differences were found among professions and nations. Skills that surgeons rated below average (median <6.0; scale: 1 [low]-10 [high]) included tropical disease management and maxillofacial, neurological, gynecological, ophthalmic, and nerve repair surgery. The deployment caseload was most often reported as <1 case per week (41/99, 41.4 %). The need for professional psychological help was rated at a median of 1.0 (IQR 1.0-1.0; scale: 1 [not at all]-5 [very much]). CONCLUSIONS: Military surgical teams report overall adequate preparedness for deployment. Challenges remain for establishing broadly skilled teams because of a low deployment caseload and ongoing primary specializations. Additional training and exposure were indicated for several specialism-specific skill areas. The need for specific training should be addressed through customized predeployment programs.

Inhalable point-of-care urinary diagnostic platform.

Although low-dose computed tomography screening improves lung cancer survival in at-risk groups, inequality remains in lung cancer diagnosis due to limited access to and high costs of medical imaging infrastructure. We designed a needleless and imaging-free platform, termed PATROL (point-of-care aerosolizable nanosensors with tumor-responsive oligonucleotide barcodes), to reduce resource disparities for early detection of lung cancer. PATROL formulates a set of DNA-barcoded, activity-based nanosensors (ABNs) into an inhalable format. Lung cancer-associated proteases selectively cleave the ABNs, releasing synthetic DNA reporters that are eventually excreted via the urine. The urinary signatures of barcoded nanosensors are quantified within 20 min at room temperature using a multiplexable paper-based lateral flow assay. PATROL detects early-stage tumors in an autochthonous lung adenocarcinoma mouse model with high sensitivity and specificity. Tailoring the library of ABNs may enable not only the modular PATROL platform to lower the resource threshold for lung cancer early detection tools but also the rapid detection of chronic pulmonary disorders and infections.

Impact of accidental hypothermia in trauma patients: A retrospective cohort study.

BACKGROUND: Trauma patients with hypothermia have substantial increases in mortality and morbidity. In severely injured patients, hypothermia is common with a rate up to 50% in various geographic areas. This study aims to elucidate the incidence, predictors, and impact of hypothermia on outcomes in severely injured patients. METHODS: This was a retrospective cohort study which included trauma patients with an Injury Severity Score (ISS) ≥ 16 admitted to a level 1 trauma center in the Netherlands between January 1, 2015 and December 31, 2021. Primary outcome was incidence of hypothermia on arrival at the emergency department. Factors associated with hypothermia were identified. Secondary outcomes were transfusion requirement, mortality, and intensive care unit (ICU) admission. Logistic regression analysis was used to identify associations. RESULTS: A total of 2032 severely injured patients were included of which 257 (12.6%) were hypothermic on hospital arrival. Predictors for hypothermia on hospital arrival included higher ISS, prehospital intubation, cervical spine immobilization, winter months, systolic blood pressure (SBP) < 90 mmHg and Glasgow Coma Scale (GCS) ≤ 8. Hypothermia was independently associated with transfusion requirement (OR, 2.68; 95% CI, 1.94 - 3.73; p < 0.001), mortality (OR, 2.12; 95% CI, 1.40 - 3.19; p < 0.001) and more often ICU admission (OR, 1.81; 95% CI, 1.10 - 2.97, p = 0.019). CONCLUSIONS: In this study, hypothermia was present in 12.6% of severely injured patients. Hypothermia was associated with increased transfusion requirement, mortality, and ICU admission. Identified predictors for hypothermia included the severity of injury, intubation, and immobilization, as well as winter season, SBP < 90 mmHg, and GCS ≤ 8.

Cesena guidelines: WSES consensus statement on laparoscopic-first approach to general surgery emergencies and abdominal trauma.

BACKGROUND: Laparoscopy is widely adopted across nearly all surgical subspecialties in the elective setting. Initially finding indication in minor abdominal emergencies, it has gradually become the standard approach in the majority of elective general surgery procedures. Despite many technological advances and increasing acceptance, the laparoscopic approach remains underutilized in emergency general surgery and in abdominal trauma. Emergency laparotomy continues to carry a high morbidity and mortality. In recent years, there has been a growing interest from emergency and trauma surgeons in adopting minimally invasive surgery approaches in the acute surgical setting. The present position paper, supported by the World Society of Emergency Surgery (WSES), aims to provide a review of the literature to reach a consensus on the indications and benefits of a laparoscopic-first approach in patients requiring emergency abdominal surgery for general surgery emergencies or abdominal trauma. METHODS: This position paper was developed according to the WSES methodology. A steering committee performed the literature review and drafted the position paper. An international panel of 54 experts then critically revised the manuscript and discussed it in detail, to develop a consensus on a position statement. RESULTS: A total of 323 studies (systematic review and meta-analysis, randomized clinical trial, retrospective comparative cohort studies, case series) have been selected from an initial pool of 7409 studies. Evidence demonstrates several benefits of the laparoscopic approach in stable patients undergoing emergency abdominal surgery for general surgical emergencies or abdominal trauma. The selection of a stable patient seems to be of paramount importance for a safe adoption of a laparoscopic approach. In hemodynamically stable patients, the laparoscopic approach was found to be safe, feasible and effective as a therapeutic tool or helpful to identify further management steps and needs, resulting in improved outcomes, regardless of conversion. Appropriate patient selection, surgeon experience and rigorous minimally invasive surgical training, remain crucial factors to increase the adoption of laparoscopy in emergency general surgery and abdominal trauma. CONCLUSIONS: The WSES expert panel suggests laparoscopy as the first approach for stable patients undergoing emergency abdominal surgery for general surgery emergencies and abdominal trauma.

Enhanced perioperative care in emergency general surgery: the WSES position paper.

Enhanced perioperative care protocols become the standard of care in elective surgery with a significant improvement in patients' outcome. The key element of the enhanced perioperative care protocol is the multimodal and interdisciplinary approach targeted to the patient, focused on a holistic approach to reduce surgical stress and improve perioperative recovery. Enhanced perioperative care in emergency general surgery is still a debated topic with little evidence available. The present position paper illustrates the existing evidence about perioperative care in emergency surgery patients with a focus on each perioperative intervention in the preoperative, intraoperative and postoperative phase. For each item was proposed and approved a statement by the WSES collaborative group.

2023 WSES guidelines for the prevention, detection, and management of iatrogenic urinary tract injuries (IUTIs) during emergency digestive surgery.

Iatrogenic urinary tract injury (IUTI) is a severe complication of emergency digestive surgery. It can lead to increased postoperative morbidity and mortality and have a long-term impact on the quality of life. The reported incidence of IUTIs varies greatly among the studies, ranging from 0.3 to 1.5%. Given the high volume of emergency digestive surgery performed worldwide, there is a need for well-defined and effective strategies to prevent and manage IUTIs. Currently, there is a lack of consensus regarding the prevention, detection, and management of IUTIs in the emergency setting. The present guidelines, promoted by the World Society of Emergency Surgery (WSES), were developed following a systematic review of the literature and an international expert panel discussion. The primary aim of these WSES guidelines is to provide evidence-based recommendations to support clinicians and surgeons in the prevention, detection, and management of IUTIs during emergency digestive surgery. The following key aspects were considered: (1) effectiveness of preventive interventions for IUTIs during emergency digestive surgery; (2) intra-operative detection of IUTIs and appropriate management strategies; (3) postoperative detection of IUTIs and appropriate management strategies and timing; and (4) effectiveness of antibiotic therapy (including type and duration) in case of IUTIs.

Source control in emergency general surgery: WSES, GAIS, SIS-E, SIS-A guidelines.

Intra-abdominal infections (IAI) are among the most common global healthcare challenges and they are usually precipitated by disruption to the gastrointestinal (GI) tract. Their successful management typically requires intensive resource utilization, and despite the best therapies, morbidity and mortality remain high. One of the main issues required to appropriately treat IAI that differs from the other etiologies of sepsis is the frequent requirement to provide physical source control. Fortunately, dramatic advances have been made in this aspect of treatment. Historically, source control was left to surgeons only. With new technologies non-surgical less invasive interventional procedures have been introduced. Alternatively, in addition to formal surgery open abdomen techniques have long been proposed as aiding source control in severe intra-abdominal sepsis. It is ironic that while a lack or even delay regarding source control clearly associates with death, it is a concept that remains poorly described. For example, no conclusive definition of source control technique or even adequacy has been universally accepted. Practically, source control involves a complex definition encompassing several factors including the causative event, source of infection bacteria, local bacterial flora, patient condition, and his/her eventual comorbidities. With greater understanding of the systemic pathobiology of sepsis and the profound implications of the human microbiome, adequate source control is no longer only a surgical issue but one that requires a multidisciplinary, multimodality approach. Thus, while any breach in the GI tract must be controlled, source control should also attempt to control the generation and propagation of the systemic biomediators and dysbiotic influences on the microbiome that perpetuate multi-system organ failure and death. Given these increased complexities, the present paper represents the current opinions and recommendations for future research of the World Society of Emergency Surgery, of the Global Alliance for Infections in Surgery of Surgical Infection Society Europe and Surgical Infection Society America regarding the concepts and operational adequacy of source control in intra-abdominal infections.

ECLAPTE: Effective Closure of LAParoTomy in Emergency-2023 World Society of Emergency Surgery guidelines for the closure of laparotomy in emergency settings.

Laparotomy incisions provide easy and rapid access to the peritoneal cavity in case of emergency surgery. Incisional hernia (IH) is a late manifestation of the failure of abdominal wall closure and represents frequent complication of any abdominal incision: IHs can cause pain and discomfort to the patients but also clinical serious sequelae like bowel obstruction, incarceration, strangulation, and necessity of reoperation. Previous guidelines and indications in the literature consider elective settings and evidence about laparotomy closure in emergency settings is lacking. This paper aims to present the World Society of Emergency Surgery (WSES) project called ECLAPTE (Effective Closure of LAParoTomy in Emergency): the final manuscript includes guidelines on the closure of emergency laparotomy.

Prehospital Active and Passive Warming in Trauma Patients.

OBJECTIVE: Hypothermia is common among trauma patients and can lead to a serious rise in morbidity and mortality. This study was performed to investigate the effect of active and passive warming measures implemented in the prehospital phase on the body temperature of trauma patients. METHODS: In a multicenter, multinational prospective observational design, the effect of active and passive warming measures on the incidence of hypothermia was investigated. Adult trauma patients who were transported by helicopter emergency medical services (HEMS) or ground emergency medical services with an HEMS physician directly from the scene of injury were included. Four HEMS/ground emergency medical services programs from Canada, the United States, and the Netherlands participated. RESULTS: A total of 80 patients (n = 20 per site) were included. Eleven percent had hypothermia on presentation, and the initial evaluation occurred predominantly within 60 minutes after injury. In-line fluid warmers and blankets were the most frequently used active and passive warming measures, respectively. Independent risk factors for a negative change in body temperature were transportation by ground ambulance (odds ratio = 3.20; 95% confidence interval, 1.06-11.49; P = .03) and being wet on initial presentation (odds ratio = 3.64; 95% confidence interval, 0.99-13.36; P = .05). CONCLUSION: For adult patients transported from the scene of injury to a trauma center, active and passive warming measures, most notably the removal of wet clothing, were associated with a favorable outcome, whereas wet patients and ground ambulance transport were associated with an unfavorable outcome with respect to temperature.

Assessing and managing frailty in emergency laparotomy: a WSES position paper.

Many countries are facing an aging population. As people live longer, surgeons face the prospect of operating on increasingly older patients. Traditional teaching is that with older age, these patients face an increased risk of mortality and morbidity, even to a level deemed too prohibitive for surgery. However, this is not always true. An active 90-year-old patient can be much fitter than an overweight, sedentary 65-year-old patient with comorbidities. Recent literature shows that frailty-an age-related cumulative decline in multiple physiological systems, is therefore a better predictor of mortality and morbidity than chronological age alone. Despite recognition of frailty as an important tool in identifying vulnerable surgical patients, many surgeons still shun objective tools. The aim of this position paper was to perform a review of the existing literature and to provide recommendations on emergency laparotomy and in frail patients. This position paper was reviewed by an international expert panel composed of 37 experts who were asked to critically revise the manuscript and position statements. The position paper was conducted according to the WSES methodology. We shall present the derived statements upon which a consensus was reached, specifying the quality of the supporting evidence and suggesting future research directions.

WSES consensus guidelines on sigmoid volvulus management.

Sigmoid volvulus is a common surgical emergency, especially in elderly patients. Patients can present with a wide range of clinical states: from asymptomatic, to frank peritonitis secondary to colonic perforation. These patients generally need urgent treatment, be it endoscopic decompression of the colon or an upfront colectomy. The World Society of Emergency Surgery united a worldwide group of international experts to review the current evidence and propose a consensus guidelines on the management of sigmoid volvulus.

CRISPR-Cas-amplified urinary biomarkers for multiplexed and portable cancer diagnostics.

Synthetic biomarkers, bioengineered sensors that generate molecular reporters in diseased microenvironments, represent an emerging paradigm in precision diagnostics. Despite the utility of DNA barcodes as a multiplexing tool, their susceptibility to nucleases in vivo has limited their utility. Here we exploit chemically stabilized nucleic acids to multiplex synthetic biomarkers and produce diagnostic signals in biofluids that can be 'read out' via CRISPR nucleases. The strategy relies on microenvironmental endopeptidase to trigger the release of nucleic acid barcodes and polymerase-amplification-free, CRISPR-Cas-mediated barcode detection in unprocessed urine. Our data suggest that DNA-encoded nanosensors can non-invasively detect and differentiate disease states in transplanted and autochthonous murine cancer models. We also demonstrate that CRISPR-Cas amplification can be harnessed to convert the readout to a point-of-care paper diagnostic tool. Finally, we employ a microfluidic platform for densely multiplexed, CRISPR-mediated DNA barcode readout that can potentially evaluate complex human diseases rapidly and guide therapeutic decisions.

The new timing in acute care surgery (new TACS) classification: a WSES Delphi consensus study.

BACKGROUND: Timely access to the operating room for emergency general surgery (EGS) indications remains a challenge across the globe, largely driven by operating room availability and staffing constraints. The "timing in acute care surgery" (TACS) classification was previously published to introduce a new tool to triage the timely and appropriate access of EGS patients to the operating room. However, the clinical and operational effectiveness of the TACS classification has not been investigated in subsequent validation studies. This study aimed to improve the TACS classification and provide further consensus around the appropriate use of the new TACS classification through a standardized Delphi approach with international experts. METHODS: This is a validation study of the new TACS by a selected international panel of experts using the Delphi method. The TACS questionnaire was designed as a web-based survey. The consensus agreement level was established to be ≥ 75%. The collective consensus agreement was defined as the sum of the percentage of the highest Likert scale levels (4-5) out of all participants. Surgical emergency diseases and correlated clinical scenarios were defined for each of the proposed classes. Subsequent rounds were carried out until a definitive level of consensus was reached. Frequencies and percentages were calculated to determine the degree of agreement for each surgical disease. RESULTS: Four polling rounds were carried out. The new TACS classification provides 6 colour-code classes correlated to a precise timing to surgery, defined scenarios and surgical condition. The WHITE colour-code class was introduced to rapidly (within a week) reschedule cancelled or postponed surgical procedures. Haemodynamic stability is the main tool to stratify patients for immediate surgery or not in the presence of sepsis/septic shock. Fifty-one surgical diseases were included in the different colour-code classes of priority. CONCLUSION: The new TACS classification is a comprehensive, simple, clear and reproducible triage system which can be used to assess the severity of the patient and the surgical disease, to reduce the time to access to the operating room, and to manage the emergency surgical patients within a "safe" timeframe. By including well-defined surgical diseases in the different colour-code classes of priority, validated through a Delphi consensus, the new TACS improves communication among surgeons, between surgeons and anaesthesiologists and decreases conflicts and waste and waiting time in accessing the operating room for emergency surgical patients.

Interprofessional simulation of acute care for nursing and medical students: interprofessional competencies and transfer to the workplace.

BACKGROUND: Teamwork and communication are essential tools for doctors, nurses and other team members in the management of critically ill patients. Early interprofessional education during study, using acute care simulation, may improve teamwork and communication between interprofessional team members on the long run. METHODS: A comparative sequential quantitative-qualitative study was used to understand interprofessional learning outcomes in nursing and medical students after simulation of acute care. Students were assigned to a uni- or interprofessional training. Questionnaires were used to measure short and long term differences in interprofessional collaboration and communication between the intervention and control group for nursing and medical students respectively. Semi-structured focus groups were conducted to gain a better understanding of IPE in acute simulation. RESULTS: One hundred and ninety-one students participated in this study (131 medical, 60 nursing students). No differences were found between the intervention and control group in overall ICCAS scores for both medical and nursing students (p = 0.181 and p = 0.441). There were no differences in ICS scores between the intervention and control group. Focus groups revealed growing competence in interprofessional communication and collaboration for both medical and nursing students. CONCLUSIONS: Interprofessional simulation training did show measurable growth of interprofessional competencies, but so did uniprofessional training. Both medical and nursing students reported increased awareness of perspective and expertise of own and other profession. Furthermore, they reported growing competence in interprofessional communication and collaboration in transfer to their workplace.

Self-efficacy and application of skills in the workplace after multidisciplinary trauma masterclass participation: a mixed methods survey and interview study.

PURPOSE: The most complex injuries are usually least often encountered by trauma team members, limiting learning opportunities at work. Identifying teaching formats that enhance trauma skills can guide future curricula. This study evaluates self-assessed technical and nontechnical trauma skills and their integration into novel work situations for multidisciplinary trauma masterclass participants. METHODS: This mixed methods study included participants of a multidisciplinary 3-day trauma masterclass. Ratings of trauma skills were collected through pre- and postcourse questionnaires with 1-year follow-up. Qualitative semi-structured interviews 9 months postcourse focused on the course format and self-perceived association with technical and nontechnical skills applied at work. RESULTS: Response rates of pre- and postcourse questionnaires after 1 day, 3 months, and 1 year were respectively 72% (51/71), 85% (60/71), 34% (24/71), and 14% (10/71). Respondents were surgeons (58%), anesthesiologists (31%), and scrub nurses (11%). Self-efficacy in nontechnical (mean 3.4, SD 0.6 vs. mean 3.8, SD 0.5) and technical (mean 2.9, SD 0.6 vs. mean 3.6, SD 0.6) skills significantly increased postcourse (n = 40, p < 0.001). Qualitative interviews (n = 11) demonstrated that increased self-efficacy in trauma skills was the greatest benefit experienced at work. Innovative application of skills and enhanced reflection demonstrate adaptive expertise. Small-group case discussions and the operative porcine laboratory were considered the most educational working formats. The experienced faculty and unique focus on multidisciplinary teamwork were highly valued. CONCLUSION: Course participants' self-assessed work performance mostly benefited from greater self-efficacy and nontechnical skills. Future trauma curricula should consider aligning the teaching strategies accordingly.

Detectability of Small Low-Attenuation Lesions With Deep Learning CT Image Reconstruction: A 24-Reader Phantom Study.

BACKGROUND. Iterative reconstruction (IR) techniques are susceptible to contrast-dependent spatial resolution, limiting overall radiation dose reduction potential. Deep learning image reconstruction (DLIR) may mitigate this limitation. OBJECTIVE. The purpose of our study was to evaluate low-contrast detectability performance and radiation-saving potential of a DLIR algorithm in comparison with filtered back projection (FBP) and IR using a human multireader noninferiority study design and task-based observer modeling. METHODS. A dual-phantom construct, consisting of a low-contrast detectability module (21 low-contrast hypoattenuating objects in seven sizes [2.4-10.0 mm] and three contrast levels [-15, -10, -5 HU] embedded within liver-equivalent background) and a phantom, was imaged at five radiation exposures (CTDIvol range, 1.4-14.0 mGy; size-specific dose estimate, 2.5-25.0 mGy; 90%-, 70%-, 50%-, and 30%-reduced radiation levels and full radiation level) using an MDCT scanner. Images were reconstructed using FBP, hybrid IR (ASiR-V), and DLIR (TrueFidelity). Twenty-four readers of varying experience levels evaluated images using a two-alternative forced choice. A task-based observer model (detectability index [d']) was calculated. Reader performance was estimated by calculating the AUC using a noninferiority method. RESULTS. Compared with FBP and IR methods at routine radiation levels, DLIR medium and DLIR high settings showed noninferior performance through a 90% radiation reduction (except DLIR medium setting at 70% reduced level). The IR method was non-inferior to routine radiation FBP only for 30% and 50% radiation reductions. No significant difference in d' was observed between routine radiation FBP and DLIR high setting through a 70% radiation reduction. Reader experience was not correlated with diagnostic accuracy (R2 = 0.005). CONCLUSION. Compared with FBP or IR methods at routine radiation levels, certain DLIR algorithm weightings yielded noninferior low-contrast detectability with radiation reductions of up to 90% as measured by 24 human readers and up to 70% as assessed by a task-based observer model. CLINICAL IMPACT. DLIR has substantial potential to preserve contrast-dependent spatial resolution for the detection of hypoattenuating lesions at decreased radiation levels in a phantom model, addressing a major shortcoming of current IR techniques.