Interventions to mitigate cancer-related medical financial hardship: A systematic review and meta-analysis.

BACKGROUND: This study systematically reviewed interventions mitigating financial hardship in patients with cancer and assessed effectiveness using a meta-analytic method. METHODS: PubMed, Cochrane, Scopus, CINAHL, and Web of Science were searched for articles published in English during January 2000-April 2023. Two independent reviewers selected prospective clinical trials with an intervention targeting and an outcome measuring financial hardship. Quality appraisal and data extraction were performed independently by two reviewers using a quality assessment tool. A random-effects model meta-analysis was performed. Reporting followed the preferred reporting items for systematic review and meta-analyses guidelines. RESULTS: Eleven studies (2211 participants; 55% male; mean age, 59.29 years) testing interventions including financial navigation, financial education, and cost discussion were included. Financial worry improved in only 27.3% of 11 studies. Material hardship and cost-related care nonadherence remained unchanged in the two studies measuring these outcomes. Four studies (373 participants; 37% male, mean age, 55.88 years) assessed the impact of financial navigation on financial worry using the comprehensive score of financial toxicity (COST) measure (score range, 0-44; higher score = lower financial worry) and were used for meta-analysis. There was no significant change in the mean of pooled COST score between post- and pre-intervention (1.21; 95% confidence interval, -6.54 to 8.96; p = .65). Adjusting for pre-intervention COST, mean change of COST significantly decreased by 0.88 with every 1-unit increase in pre-intervention COST (p = .02). The intervention significantly changed COST score when pre-intervention COST was ≤14.5. CONCLUSION: A variety of interventions have been tested to mitigate financial hardship. Financial navigation can mitigate financial worry among high-risk patients.

A retrospective observational study of daytime and nighttime transfers from the intensive care unit: through the lens of critical care response teams.

PURPOSE: To evaluate the impact of nighttime compared with daytime transfers from the intensive care unit (ICU) on mortality in a hospital with a critical care response team (CCRT). METHODS: We performed a retrospective observational study of ICU patients transferred between January 2011 and July 2013 who received CCRT follow-up. The transferred patients were divided into cohorts of daytime and nighttime transfers. A multivariable logistic regression model was used to identify independent predictors of mortality after ICU transfer. RESULTS: There were 1,857 patients included in the study. With the exception of Multiple Organ Dysfunction Score on admission, transfers to a step-down unit, and lower urine output, there were no differences in the baseline characteristics, clinical events identified by CCRTs, and the number of CCRT interventions performed between daytime and nighttime transfers. Patients transferred at night were at higher risk of death in the univariate analysis but not in the multivariate analysis. Independent predictors of mortality included older age (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.002 to 1.04), transfer to a medical service (OR, 1.96; 95% CI, 1.11 to 3.43), CCRT identification of hypoxemic respiratory failure (OR, 5.86; 95% CI, 3.11 to 11.04), decreased level of consciousness (OR, 3.14; 95% CI, 1.23 to 8.02), hypotension (OR, 3.69; 95% CI, 1.36 to 10.01), and longer CCRT duration of follow-up (OR, 1.02; 95% CI, 1.004 to 1.03). CONCLUSIONS: Nighttime transfer from the ICU was not an independent predictor of mortality. We identified unique predictors of mortality, including clinical events that CCRTs identified in patients immediately after ICU transfer. Future studies are required to validate these predictors of mortality in transferred ICU patients.

RéSUMé: OBJECTIF: Évaluer l'impact sur la mortalité des transferts de nuit par rapport aux transferts de jour de l'unité de soins intensifs (USI) dans un hôpital disposant d'une équipe d'intervention en soins intensifs (EISI). MéTHODE: Nous avons réalisé une étude observationnelle rétrospective des patients de l'USI transférés entre janvier 2011 et juillet 2013 suivis par l'EISI. Les patients transférés ont été divisés en cohortes de transferts de jour et de nuit. Un modèle de régression logistique multivariée a été utilisé pour identifier les prédicteurs indépendants de mortalité après un transfert de l'USI. RéSULTATS: L'étude a inclus 1857 patients. À l'exception du Score de défaillance multiviscérale, des transferts à une unité de soins intermédiaires et de la réduction du débit d'urine, aucune différence n'a été notée dans les caractéristiques de base, les événements cliniques identifiés par l'EISI et le nombre d'interventions de l'EISI effectuées entre les transferts de jour et de nuit. Les patients transférés la nuit étaient plus à risque de décès dans l'analyse univariée, mais pas dans l'analyse multivariée. Les prédicteurs indépendants de mortalité comprenaient un âge avancé (rapport de cotes [RC], 1,02; intervalle de confiance [IC] 95 %, 1,002 à 1,04), le transfert à un service médical (RC, 1,96; IC 95 %, 1,11 à 3,43), l'identification par l'EISI d'une insuffisance respiratoire hypoxémique (RC, 5,86; IC 95 %, 3,11 à 11,04), la diminution du niveau de conscience (RC, 3,14; IC 95%, 1,23 à 8,02), l'hypotension (RC, 3,69; IC 95%, 1,36 à 10,01), et une durée plus longue de suivi par l'EISI (RC, 1,02; IC 95 %, 1,004 à 1,03). CONCLUSION: Le transfert nocturne de l'USI n'est pas un prédicteur indépendant de mortalité. Nous avons identifié des prédicteurs particuliers de mortalité, notamment les événements cliniques identifiés par l'EISI chez les patients immédiatement après leur transfert de l'USI. Des études futures sont nécessaires pour valider ces prédicteurs de mortalité chez les patients transférés des soins intensifs.

External validation of a prognostic model for intensive care unit mortality: a retrospective study using the Ontario Critical Care Information System.

PURPOSE: To externally validate an intensive care unit (ICU) mortality prediction model that was created using the Ontario Critical Care Information System (CCIS), which includes the Multiple Organ Dysfunction Score (MODS). METHODS: We applied the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) recommendations to a prospective longitudinal cohort of patients discharged between 1 July 2015 and 31 December 31 2016 from 90 adult level-3 critical care units in Ontario. We used multivariable logistic regression with measures of discrimination, calibration-in-the-large, calibration slope, and flexible calibration plots to compare prediction model performance of the entire data set and for each ICU subtype. RESULTS: Among 121,201 CCIS records with ICU mortality of 11.3%, the C-statistic for the validation data set was 0.805. The C-statistic ranged from 0.775 to 0.846 among the ICU subtypes. After intercept recalibration to adjust the baseline risk, the mean predicted risk of death matched actual ICU mortality. The calibration slope was close to 1 with all CCIS data and ICU subtypes of cardiovascular and community hospitals with low ventilation rates. Calibration slopes significantly less than 1 were found for ICUs in teaching hospitals and community hospitals with high ventilation rates whereas coronary care units had a calibration slope significantly higher than 1. Calibration plots revealed over-prediction in high risk groups to a varying degree across all cohorts. CONCLUSIONS: A risk prediction model primarily based on the MODS shows reproducibility and transportability after intercept recalibration. Risk adjusting models that use existing and feasible data collection can support performance measurement at the individual ICU level.

RéSUMé: OBJECTIF: Nous souhaitions faire une validation externe d'un modèle de prédiction de la mortalité aux unités de soins intensifs (USI) créé en utilisant le Système d'information sur les soins aux malades en phase critique (SISMPC) de l'Ontario, qui comporte le Score de défaillance multisystémique (MODS). MéTHODE: Nous avons appliqué les recommandations de communication transparente d'un modèle de prédiction multivarié pour le pronostic ou le diagnostic individuel TRIPOD à une cohorte longitudinale prospective de patients. Ces patients devaient avoir reçu leur congé entre le 1er juillet 2015 et le 31 décembre 2016 de 90 unités de soins intensifs de niveau 3 pour adultes en Ontario. Nous avons utilisé une méthode de régression logistique multivariée accompagnée de mesures de discrimination, d'étalonnage global, de pentes d'étalonnage et de graphiques d'étalonnage afin de comparer la performance du modèle de prédiction pour l'ensemble des données dans son intégralité et pour chaque sous-type d'USI. RéSULTATS: Parmi les 121 201 dossiers du SISMPC présentant une mortalité à l'USI de 11,3 %, la statistique C pour l'ensemble de données de validation était 0,805. La statistique C allait de 0,775 à 0,846 parmi les sous-types d'USI. Après réétalonnage de l'ordonnée afin d'ajuster le risque de base, le risque prédit moyen de décès correspondait à la mortalité réelle à l'USI. La pente d'étalonnage était proche de 1 pour toutes les données du SISMPC et tous les sous-types d'USI des hôpitaux cardiovasculaires et communautaires ayant de faibles taux de patients ventilés. Des pentes d'étalonnage significativement inférieures à 1 ont été observées pour les USI dans les hôpitaux universitaires et les hôpitaux communautaires ayant des taux de patients ventilés élevés, alors que les unités de soins coronariens présentaient une pente d'étalonnage significativement supérieure à 1. Les courbes d'étalonnage ont révélé une sur-prédiction dans les groupes à risque élevé à des degrés variables dans toutes les cohortes. CONCLUSION: Un modèle de prédiction du risque se fondant principalement sur le score MODS a montré sa reproductibilité et son applicabilité après réétalonnage de l'ordonnée. Les modèles d'ajustement du risque qui s'appuient sur des collectes de données existantes et réalisables peuvent aider à mesurer la performance au niveau de l'USI individuelle.

Anti-Ebola therapy for patients with Ebola virus disease: a systematic review.

BACKGROUND: Management of Ebola virus disease (EVD) has historically focused on infection prevention, case detection and supportive care. Several specific anti-Ebola therapies have been investigated, including during the 2014-2016 West African outbreak. Our objective was to conduct a systematic review of the effect of anti-Ebola virus therapies on clinical outcomes to guide their potential use and future evaluation. METHODS: We searched PubMed, EMBASE, Global Health, Cochrane Library, African Index Medicus, WHOLIS (inception-9 April 2018), and trial registries for observational studies or clinical trials, in any language, that enrolled patients with confirmed EVD who received therapy targeting Ebola virus and reported on mortality, symptom duration, or adverse effects. RESULTS: From 11,257 citations and registered trials, we reviewed 55 full-text citations, of which 35 met eligibility criteria (1 randomized clinical trial (RCT), 8 non-randomized comparative studies, 9 case series and 17 case reports) and collectively examined 21 anti-Ebola virus agents. The 31 studies performed during the West African outbreak reported on 4.8% (1377/28616) of all patients with Ebola. The only RCT enrolled 72 patients (0.25% of all patients with Ebola) and compared the monoclonal antibody ZMapp vs. standard care (mortality, 22% vs. 37%; 95% confidence interval for risk difference, - 36 to 7%). Studies of convalescent plasma, interferon-ß-1a, favipiravir, brincidofovir, artesunate-amodiaquine and TKM-130803 were associated with at least moderate risk of bias. CONCLUSIONS: Research evaluating anti-Ebola virus agents has reached very few patients with EVD, and inferences are limited by non-randomized study designs. ZMapp has the most promising treatment signal.

Care of victims of suicide bombing

Summary: Suicide bombers often target crowds. This commentary discusses the additional features required in a medical response beyond conventional mass casualty care, including forensic documentation, preservation of evidence, suspect tissue identification and viral status, victim counselling and postexposure prophylaxis. We propose a pathway for care of victims of a suicide bomb, adapting elements from protocols for child abuse, sexual assault and needle-stick exposure.

Utilization profile of the Canadian-led coalition Role 2 Medical Treatment Facility in Iraq: the growing requirement for multinational interoperability

Background: The Canadian Armed Forces deployed a Role 2 Medical Treatment Facility (R2MTF) to Iraq in November 2016 as part of Operation IMPACT. We compared the multinational interoperability required of this R2MTF with that of similar facilities previously deployed by Canada or other nations. Methods: We reviewed data (Nov. 4, 2016, to Oct. 3, 2017) from the electronic Disease and Injury Surveillance Report and the Daily Medical Situation Report. Clinical activity was stratified by Global Burden of Diseases category, ICD-10 code, mechanism of injury, services used, encounter type, nationality and blood product usage. We reviewed the literature to identify utilization profiles for other MTFs over the last 20 years. Results: In total, 1487 patients were assessed. Of these, 5.0% had battle injuries requiring damage-control resuscitation and/or damage-control surgery, with 55 casualties requiring medical evacuation after stabilization. Trauma and disease non-battle injuries accounted for 44% and 51% of patient encounters, respectively. Other than dental conditions, musculoskeletal disorders accounted for most presentations. Fifty-seven units of fresh frozen plasma and 64 units of packed red blood cells were used, and the walking blood bank was activated 7 times. Mass casualty activations involved coordination of health care and logistical resources from more than 12 countries. In addition to host nation military and civilian casualties, patients from 15 different countries were treated with similar frequency. Conclusion: The experience of the Canadian R2MTF in Iraq demonstrates the importance of multinational interoperability in providing cohesive medical care in coalition surgical facilities. Multinational interoperability derives from a unique relationship between higher medical command collaboration, international training and adherence to common standards for equipment and clinical practice.

Contexte: Les Forces armées canadiennes ont déployé une installation de traitement médical de rôle 2 (ITMR2) en Iraq en novembre 2016 dans le cadre de l'opération IMPACT. Nous avons comparé l'interopérabilité multinationale requise par cette ITMR2 à celle d'installations semblables déjà déployées par le Canada ou d'autres pays. Méthodes: Nous avons examiné les données (du 4 novembre 2016 au 3 octobre 2017) du rapport électronique de surveillance des maladies et des blessures et du rapport quotidien sur la situation médicale. L'activité clinique a été stratifiée selon la catégorie du fardeau mondial des maladies, le code de la CIM­10, le mécanisme de traumatisme, les services utilisés, le type de contact, la nationalité et l'utilisation de produits sanguins. Enfin, nous avons aussi examiné la littérature pour déterminer les profils d'utilisation d'autres ITM au cours des 20 dernières années. Résultats: Au total, 1487 patients ont été évalués. De ce nombre, 5,0 % avaient subi des blessures au combat qui nécessitaient une réanimation ou une intervention chirurgicale de contrôle des dommages, ou les deux, et 55 blessés avaient eu besoin d'évacuation médicale après stabilisation. Les traumatismes et les maladies non liées au combat représentaient respectivement 44 % et 51 % des contacts avec les patients. Outre les troubles dentaires, les troubles musculosquelettiques étaient à l'origine de la plupart des présentations. Par ailleurs, 57 unités de plasma frais congelé et 64 unités de concentré de globules rouges ont été utilisées, et la banque de sang ambulante a été activée 7 fois. La mobilisation nécessaire pour traiter un nombre massif de victimes a nécessité la coordination des soins de santé et des ressources logistiques de plus de 12 pays. En plus des victimes militaires et civiles du pays hôte, des patients de 15 pays différents ont été traités à une fréquence semblable. Conclusion: L'expérience de l'ITMR2 canadienne en Iraq démontre l'importance de l'interopérabilité multinationale quant à la prestation de soins médicaux cohérents dans les installations chirurgicales de la coalition. L'interopérabilité multinationale découle d'une relation unique s'appuyant sur la collaboration des membres du commandement médical supérieur, de la formation internationale et le respect de normes communes pour l'équipement et la médecine clinique.

The effect of aerosolized indomethacin on lung inflammation and injury in a rat model of blunt chest trauma

Background: Acute lung contusion from blunt chest trauma (BCT) is characterized by an intense inflammatory response in the pulmonary parenchyma, which is associated with acute lung injury (ALI), acute respiratory distress syndrome and ventilator-associated pneumonia. We hypothesized that aerosolized indomethacin may reduce pulmonary inflammation and ALI in a rat model of BCT. Methods: Sprague-Dawley rats were anesthetized and received a tracheotomy for administration of aerosolized medication through a catheter. The BCT procedure involved free-dropping a hollow metal weight (200 g) from a height of 25.5, 38.3 or 51.2 cm onto the right thorax. We administered 1 mg/kg of indomethacin or 1 mL/kg of saline intratracheally 15 minutes after BCT. The sham group had a similar procedure without the exposure to BCT and treatment. Three hours postimpact, we obtained arterial blood gas and analyzed bronchoalveolar lavage for protein concentration, polymorphonuclear leukocytes (PMN) and cytokine levels, and lung tissue samples were taken for histopathological analysis. Results: The rats' mean arterial pressure and heart rate dropped immediately postimpact but recovered close to that of the sham group after 30 minutes in both control and treatment groups. Compared to BCT alone, indomethacin significantly reduced the total protein level in the lungs (1.06 ± 0.39 mg/mL v. 3.75 ± 1.95 mg/mL, p = 0.006) and alveolar FD-70 leak (0.23 ± 0.19 µg/mL v. 0.53 ± 0.19 µg/mL, p = 0.02). Indomethacin also significantly attenuated the acute inflammatory response in percent PMN (13.33 ±7.5% v. 28.0 ± 12.96%, p = 0.04). Tumour necrosis factor-α and interleukin-6 decreased in the indomethacin group, but the decreases were not significant compared with other groups. Conclusion: Aerosolized indomethacin has a protective effect against alveloar tissue permeability and inflammatory response induced by BCT.

Contexte: La contusion pulmonaire aiguë causée par un traumatisme thoracique fermé (TTF) se caractérise par une intense réaction inflammatoire dans le parenchyme pulmonaire, liée à une atteinte pulmonaire aiguë (APA), à un syndrome de détresse respiratoire et à la pneumonie associée à la ventilation mécanique. Nous avons émis l'hypothèse que l'indométacine en aérosol pouvait réduire l'inflammation pulmonaire et l'APA dans un modèle murin de TTF. Méthodes: Des rats Sprague-Dawley ont été anesthésiés et ont subi une trachéotomie pour l'administration du médicament en aérosol par un cathéter. Le TTF a été infligé par un poids de métal creux (200 g) en chute libre d'une hauteur de 25,5, 38,3 ou 51,2 cm sur le thorax droit. Nous avons administré 1 mg/kg d'indométacine ou 1 mL/kg de solution saline dans la trachée 15 minutes après le TTF. Un groupe a été soumis à une intervention similaire fictive, sans exposition au TTF ni au traitement. Trois heures après l'impact, nous avons obtenu des gaz artériels et analysé le liquide de lavage bronchoalvéolaire pour connaître les taux de protéines, de leucocytes polymorphonucléaires (PMN) et de cytokines; nous avons aussi prélevé des échantillons de tissu pulmonaire pour des analyses histopathologiques. Résultats: La pression artérielle et la fréquence cardiaque moyennes des rats ont immédiatement chuté après l'impact, mais sont revenues près des valeurs du groupe soumis à l'intervention fictive après 30 minutes dans le groupe témoin et le groupe traité. Comparativement au TTF seul, l'indométacine a significativement réduit le taux de protéines totales dans les poumons (1,06 ± 0,39 mg/mL c. 3,75 ± 1,95 mg/mL, p = 0,006) et la fuite alvéolaire de FD-70 (0,23 ± 0,19 µg/mL c. 0,53 ± 0,19 µg/mL, p = 0,02). L'indométacine a aussi significativement atténué la réaction inflammatoire aiguë en pourcentage de PMN (13,33 ±7,5 % c. 28,0 ± 12,96 %, p = 0,04). Le facteur de nécrose tumorale α et l'interleukine-6 ont diminué dans le groupe sous indométacine, mais ces baisses n'ont pas été significatives comparativement aux autres groupes. Conclusion: L'indométacine en aérosol exerce un effet protecteur contre la perméabilité du tissu alvéolaire et la réaction inflammatoire induite par le un TTF.

Proposed specifications of a mobile operating room for far-forward surgery

Summary: Provision of initial surgery to casualties within one hour of injury is associated with better survival. Where evacuation options are limited, surgery within the "golden hour" may have to occur close to the point of injury. Interventions close to the point of injury are limited by the adverse environment. Far-forward surgery has a long history going back to Dominique Larrey of the Napoleonic Army. We reviewed previous reports and used our own experience of far-forward surgery to describe the specifications of the ideal mobile operating room that would address some of these environmental barriers.

Carbon monoxide releasing molecule-3 improves myocardial function in mice with sepsis by inhibiting NLRP3 inflammasome activation in cardiac fibroblasts.

The NLRP3 inflammasome is an intracellular multiple-protein complex that controls the maturation and release of interleukin (IL)-1ß and IL-18. Endogenous carbon monoxide (CO) is anti-inflammatory. The aim of this study was to assess the effects/mechanisms of CO-releasing molecule-3 (CORM-3)-dependent modulation of the NLRP3 inflammasome in cardiac fibroblasts (CF) and its effect on myocardial function in sepsis. CF were treated with CORM-3 or inactive CORM-3 (iCORM-3) before NLRP3 inflammasome priming with lipopolysaccharides (LPS) or following activation with adenosine triphosphate (ATP). In parallel, cardiomyocytes (CM) were challenged with supernatants of LPS/ATP-stimulated CF or a cytokine mixture (Cyto-mix) containing IL-1ß, IL-18, and HMGB1. In vivo, mice were treated with CORM-3 before or after LPS to induce sepsis (endotoxemia). Pretreatment of CF with CORM-3 prevented an LPS-induced increase in NLRP3 and pro-IL-1ß expression. Treatment of CF with CORM-3 before ATP prevented ATP-induced activation of the NLRP3 inflammasome. Challenging CF with LPS/ATP promoted NLRP3 interactions with adaptor ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), which was prevented by CORM-3. Challenging CM with supernatants of CF with LPS/ATP or Cyto-mix (IL-1ß, IL-18, and HMGB1) resulted in CM apoptosis, which was attenuated with either a CORM-3 or IL-1 receptor antagonist. Finally, myocardial NLRP3 inflammasome activation and myocardial dysfunction in septic mice were abolished by CORM-3. In NLRP3-deficient mice with sepsis, CORM-3 did not show additional benefits in improving myocardial function. Our results indicate that CORM-3 suppresses NLRP3 inflammasome activation by blocking NLRP3 interactions with the adaptor protein ASC and attenuates myocardial dysfunction in mice with sepsis.

Cardiomyocyte-fibroblast interaction contributes to diabetic cardiomyopathy in mice: Role of HMGB1/TLR4/IL-33 axis.

Diabetic cardiomyopathy (DiCM) is characterized by myocardial fibrosis and dysfunction. In rodent models of diabetes myocardial HMGB1 increases while IL-33 decreases. The major cardiac cell type expressing HMGB1 is the myocyte while the primary IL-33 expressing cell is the fibroblast. The aim of this study was to delineate the extracellular communication pathway(s) between cardiomyocytes and fibroblasts that contributes to murine DiCM. The streptozotocin (STZ)-induced murine model of diabetes and a cardiomyocyte/fibroblast co-culture challenged with high glucose were used. In STZ mice, myocardial HMGB1 expression was increased while IL-33 expression decreased (immunofluorescence and Western blot). In addition, STZ mice had an increased myocardial collagen deposition and myocardial dysfunction (pressure-volume loop analysis). An HMGB1 inhibitor (A-box) or exogenous IL-33 prevented the myocardial collagen deposition and dysfunction. In the cardiomyocyte/fibroblast co-culture model, HG increased cardiomyocyte HMGB1 secretion, decreased fibroblast IL-33 expression, and increased fibroblast collagen I production. Further, using A-box and HMGB1 shRNA transfected myocytes, we found that cardiomyocyte-derived HMGB1 dramatically potentiated the HG-induced down-regulation of IL-33 and the increase in collagen I expression in the fibroblasts. The potentiating effects of the cardiomyocytes was diminished when toll-like receptor 4 deficient (TLR4(-/-)) fibroblasts were co-cultured with wild-type myocytes. Finally, TLR4(-/-) mice with diabetes had increased myocardial expression of HMGB1, but failed to down-regulate IL-33. The diabetes-induced myocardial collagen deposition and cardiac dysfunction were significantly attenuated in TLR4(-/-) mice. In conclusion, our findings support a role for "cardiomyocyte HMGB1-fibroblast TLR4/IL-33 axis" in the development of myocardial fibrosis and dysfunction in a murine model of diabetes.

The impact of "early" versus "late" initiation of renal replacement therapy in critical care patients with acute kidney injury: a systematic review and evidence synthesis.

BACKGROUND: The optimal timing of initiating renal replacement therapy (RRT) in critical illness complicated by acute kidney injury (AKI) is not clearly established. Trials completed on this topic have been marked by contradictory findings as well as quality and heterogeneity issues. Our goal was to perform a synthesis of the evidence regarding the impact of "early" versus "late" RRT in critically ill patients with AKI, focusing on the highest-quality research on this topic. METHODS: A literature search using the PubMed and Embase databases was completed to identify studies involving critically ill adult patients with AKI who received hemodialysis according to "early" versus "late"/"standard" criteria. The highest-quality studies were selected for meta-analysis. The primary outcome of interest was mortality at 1 month (composite of 28- and 30-day mortality). Secondary outcomes evaluated included intensive care unit (ICU) and hospital length of stay (LOS). RESULTS: Thirty-six studies (seven randomized controlled trials, ten prospective cohorts, and nineteen retrospective cohorts) were identified for detailed evaluation. Nine studies involving 1042 patients were considered to be of high quality and were included for quantitative analysis. No survival advantage was found with "early" RRT among high-quality studies with an OR of 0.665 (95 % CI 0.384-1.153, p = 0.146). Subgroup analysis by reason for ICU admission (surgical/medical) or definition of "early" (time/biochemical) showed no evidence of survival advantage. No significant differences were observed in ICU or hospital LOS among high-quality studies. CONCLUSIONS: Our conclusion based on this evidence synthesis is that "early" initiation of RRT in critical illness complicated by AKI does not improve patient survival or confer reductions in ICU or hospital LOS.

Diagnosis of Febrile Illnesses Other Than Ebola Virus Disease at an Ebola Treatment Unit in Sierra Leone.

Patients with febrile illnesses presenting to an Ebola treatment unit in Sierra Leone had a wide range of diagnoses other than Ebola virus disease. Rapid diagnostic tests were useful in confirming these diagnoses, reducing the length of patient stay with valuable consequences. These alternative diagnoses should assist in future planning.

Preclinical Studies on Mechanisms Underlying the Protective Effects of Propranolol in Traumatic Brain Injury: A Systematic Review.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity amongst trauma patients. Its treatment is focused on minimizing progression to secondary injury. Administration of propranolol for TBI maydecrease mortality and improve functional outcomes. However, it is our sense that its use has not been universally adopted due to low certainty evidence. The literature was reviewed to explore the mechanism of propranolol as a therapeutic intervention in TBI to guide future clinical investigations. Medline, Embase, and Scopus were searched for studies that investigated the effect of propranolol on TBI in animal models from inception until June 6, 2023. All routes of administration for propranolol were included and the following outcomes were evaluated: cognitive functions, physiological and immunological responses. Screening and data extraction were done independently and in duplicate. The risk of bias for each individual study was assessed using the SYCLE's risk of bias tool for animal studies. Three hundred twenty-three citations were identified and 14 studies met our eligibility criteria. The data suggests that propranolol may improve post-TBI cognitive and motor function by increasing cerebral perfusion, reducing neural injury, cell death, leukocyte mobilization and p-tau accumulation in animal models. Propranolol may also attenuate TBI-induced immunodeficiency and provide cardioprotective effects by mitigating damage to the myocardium caused by oxidative stress. This systematic review demonstrates that propranolol may be therapeutic in TBI by improving cognitive and motor function while regulating T lymphocyte response and levels of myocardial reactive oxygen species. Oral or intravenous injection of propranolol following TBI is associated with improved cerebral perfusion, reduced neuroinflammation, reduced immunodeficiency, and cardio-neuroprotection in preclinical studies.

Endogenous HMGB1 contributes to ischemia-reperfusion-induced myocardial apoptosis by potentiating the effect of TNF-α/JNK.

High-mobility group box 1 (HMGB1) is a nuclear protein that has been implicated in the myocardial inflammation and injury induced by ischemia-reperfusion (I/R). The purpose of the present study was to assess the role of HMGB1 in myocardial apoptosis induced by I/R. In vivo, myocardial I/R induced an increase in myocardial HMGB1 expression and apoptosis. Inhibition of HMGB1 (A-box) ameliorated the I/R-induced myocardial apoptosis. In vitro, isolated cardiac myocytes were challenged with anoxia-reoxygenation (A/R; in vitro correlate to I/R). A/R-challenged myocytes also generated HMGB1 and underwent apoptosis. Inhibition of HMGB1 attenuated the A/R-induced myocyte apoptosis. Exogenous HMGB1 had no effect on myocyte apoptosis. However, inhibition of HMGB1 attenuated myocyte TNF-α production after the A/R was challenged; surprisingly, HMGB1 itself did not induce myocyte TNF-α production. Exogenous TNF-α induced a moderate proapoptotic effect on the myocytes, an effect substantially potentiated by coadministration of HMGB1. It is generally accepted that apoptosis induced by TNF-α is regulated by the balance of activation of c-Jun NH(2)-terminal kinase (JNK) and NF-κB. Indeed, in the present study, TNF-α increased the phosphorylation status of JNK and p65, a subunit of NF-κB; HMGB1 greatly potentiated TNF-α-induced JNK phosphorylation. Furthermore, inhibition of JNK (SP-600125) prevented the myocyte apoptosis induced by a TNF-α/HMGB1 cocktail. Finally, A/R increased HMGB1 production in both wild-type and toll-like receptor 4-deficient myocytes; however, deficiency in toll-like receptor 4 diminished A/R-induced myocyte apoptosis, TNF-α, and JNK activation. Our results indicate that myocyte-derived HMGB1 and TNF-α work in concert to promote I/R-induced myocardial apoptosis through JNK activation.

Effects of trauma-related cues on pain processing in posttraumatic stress disorder: an fMRI investigation.

BACKGROUND: Imaging studies of pain processing in primary psychiatric disorders are just emerging. This study explored the neural correlates of stress-induced analgesia in individuals with posttraumatic stress disorder (PTSD). It combined functional magnetic resonance imaging (fMRI) and the traumatic script-driven imagery symptom provocation paradigm to examine the effects of trauma-related cues on pain perception in individuals with PTSD. METHODS: The study included 17 patients with PTSD and 26 healthy, trauma-exposed controls. Participants received warm (nonpainful) or hot (painful) thermal stimuli after listening to a neutral or a traumatic script while they were undergoing an fMRI scan at a 4.0 T field strength. RESULTS: Between-group analyses revealed that after exposure to the traumatic scripts, the blood oxygen level-dependent (BOLD) signal during pain perception was greater in the PTSD group than the control group in the head of the caudate. In the PTSD group, strong positive correlations resulted between BOLD signal and symptom severity in a number of brain regions previously implicated in stress-induced analgesia, such as the thalamus and the head of the caudate nucleus. Trait dissociation as measured by the Dissociative Experiences Scale correlated negatively with the right amygdala and the left putamen. LIMITATIONS: This study included heterogeneous traumatic experiences, a different proportion of military trauma in the PTSD versus the control group and medicated patients with PTSD. CONCLUSION: These data indicate that in patients with PTSD trauma recall will lead in a state-dependent manner to greater activation in brain regions implicated in stress-induced analgesia. Correlational analyses lend support to cortical hyperinhibition of the amygdala as a function of dissociation.

Erythropoietin improves skeletal muscle microcirculation through the activation of eNOS in a mouse sepsis model.

BACKGROUND: Sepsis and septic shock remain the major causes of morbidity and mortality in intensive care units. One mechanism that leads to organ failure is microcirculatory dysfunction. Erythropoietin (EPO) is a glycoprotein produced by the kidney that primarily regulates erythropoiesis, but it also can exert hemodynamic, anti-inflammatory, and tissue protective effects. We previously reported that administration of EPO to septic mice improves mouse skeletal muscle capillary perfusion and tissue bioenergetics. The objective of this study was to explore the potential mechanism(s) involved. METHODS: Sepsis was induced by intraperitoneal (i.p.) injection of a fecal suspension (12.5 g in 0.5 saline/mouse) in mice. At 18 hours after sepsis induction, a single dose of rHuEPO (400 U/kg) was given to the mice. Mouse capillary perfusion density and nicotinamide adenine dinucleotide (NADH) fluorescence in skeletal muscle were observed using intravital microscopy. Endothelial cells derived from the skeletal muscle were treated with rHuEPO (5 U/mL) and endothelial nitric oxide synthase (eNOS) activation and activity were assessed. RESULTS: Septic mice had decreased capillary perfusion density and increased tissue NADH fluorescence indicating impaired tissue bioenergetics, whereas animals treated with rHuEPO demonstrated an improvement in capillary perfusion density and decreased skeletal muscle NADH fluorescence. The beneficial effect of rHuEPO did not occur in septic mice treated with l-NAME (an NOS inhibitor, 20 mg/kg) or mice genetically deficient in eNOS. Treatment of endothelial cells with rHuEPO resulted in activation of eNOS as indicated by increased eNOS phosphorylation and NO production. CONCLUSIONS: Our results suggest that eNOS plays an important role in mediating the beneficial effect of rHuEPO on microcirculation in this septic mouse model.

The Role 3 Multinational Medical Unit at Kandahar Airfield 2005-2010.

In late 2005, Canadian Forces Health Services (CFHS) was tasked with the command of the NATO Role 3 Multinational Medical Unit (R3MMU) on Kandahar Airfield in southern Afghanistan. Preparations drew on past experience and planning. Eight complete hospital contingents were trained and deployed in rotation. Near-reality simulation training was undertaken with the combat brigade, including complete deployment of the field hospital in the exercise area. Standard operating procedures (SOP) were developed and applied by each rotation so successfully that they were adopted by the new command in late 2009. The Canadian period at R3MMU had the highest survival rate ever recorded for victims of war. Lessons learned are being applied among victims of the conflict and trauma. The experience of the R3MMU was used to successfully deploy a hospital as part of the earthquake relief effort in Haiti in 2010.The training protocols and SOP are being applied to disaster preparedness in Canadian civilian hospitals.

Utilization profile of the trauma intensive care unit at the Role 3 Multinational Medical Unit at Kandahar Airfield between May 1 and Oct. 15, 2009.

BACKGROUND: In the war against the Taliban, Canada was the lead North Atlantic Treaty Organization (NATO) nation to provide medical and surgical care to NATO soldiers, Afghanistan National Army soldiers, Afghanistan Nation Police, civilians working in and outside Kandahar Airfield and Afghanistan civilians at the Role 3 Multinational Medical Unit (R3MMU) from February 2006 to October 2009. METHODS: We obtained data from the Joint Theatre Trauma Registry between May 1 and Oct. 15, 2009; 188 patients were admitted to the R3MMU intensive care unit (ICU). We analyzed the ICU data according to types and causes of trauma, mechanical ventilation prevalence, ICU medical and surgical complications, blood products utilization, length of stay in the ICU and mortality. RESULTS: The admitting services were general surgery (35%), neurosurgery (29%), orthopedic surgery (18%) and internal medicine (3%). Improvised explosive devices (46%) and gunshot wounds (26%) were the main causes of ICU admissions. The mean injury severity score for all patients admitted to the ICU was 37, and 81% of ICU patients required mechanical ventilation for a mean duration of 3 days. The main ICU complications were coagulopathy (6.4%), aspiration pneumonia (4.3%), pneumothorax (3.7%) and wound infection (2.7%). The following blood products were most used: packed red blood cells (55%), fresh frozen plasma (54%), platelets (29%) and cryoprecipitate (23%). The average length of stay in the ICU was 4.3 days, and the survival rate was 93%. CONCLUSION: The high survival rate suggests that ICU care is a necessary and vital resource for a trauma hospital in a war zone.

Establishing Healthcare Worker Performance and Safety in Providing Critical Care for Patients in a Simulated Ebola Treatment Unit: Non-Randomized Pilot Study.

Improving the provision of supportive care for patients with Ebola is an important quality improvement initiative. We designed a simulated Ebola Treatment Unit (ETU) to assess performance and safety of healthcare workers (HCWs) performing tasks wearing personal protective equipment (PPE) in hot (35 °C, 60% relative humidity) or thermo-neutral (20 °C, 20% relative humidity) conditions. In this pilot phase to determine the feasibility of study procedures, HCWs in PPE were non-randomly allocated to hot or thermo-neutral conditions to perform peripheral intravenous (PIV) and midline catheter (MLC) insertion and endotracheal intubation (ETI) on mannequins. Eighteen HCWs (13 physicians, 4 nurses, 1 nurse practitioner; 2 with prior ETU experience; 10 in hot conditions) spent 69 (10) (mean (SD)) minutes in the simulated ETU. Mean (SD) task completion times were 16 (6) min for PIV insertion; 33 (5) min for MLC insertion; and 16 (8) min for ETI. Satisfactory task completion was numerically higher for physicians vs. nurses. Participants' blood pressure was similar, but heart rate was higher (p = 0.0005) post-simulation vs. baseline. Participants had a median (range) of 2.0 (0.0-10.0) minor PPE breaches, 2.0 (0.0-6.0) near-miss incidents, and 2.0 (0.0-6.0) health symptoms and concerns. There were eight health-assessment triggers in five participants, of whom four were in hot conditions. We terminated the simulation of two participants in hot conditions due to thermal discomfort. In summary, study tasks were suitable for physician participants, but they require redesign to match nurses' expertise for the subsequent randomized phase of the study. One-quarter of participants had a health-assessment trigger. This research model may be useful in future training and research regarding clinical care for patients with highly infectious pathogens in austere settings.