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Abstract This is an interim analysis of the Beta-blocker (Propranolol) use in traumatic brain injury (TBI) based on the high-sensitive troponin status (BBTBBT) study. The BBTBBT is an ongoing double-blind placebo-controlled randomized clinical trial with a target sample size of 771 patients with TBI. We sought, after attaining 50% of the sample size, to explore the impact of early administration of beta-blockers (BBs) on the adrenergic surge, pro-inflammatory cytokines, and the TBI biomarkers linked to the status of high-sensitivity troponin T (HsTnT). Patients were stratified based on the severity of TBI using the Glasgow coma scale (GCS) and HsTnT status (positive vs negative) before randomization. Patients with positive HsTnT (non-randomized) received propranolol (Group-1; n = 110), and those with negative test were randomized to receive propranolol (Group-2; n = 129) or placebo (Group-3; n = 111). Propranolol was administered within 24 h of injury for 6 days, guided by the heart rate (> 60 bpm), systolic blood pressure (≥ 100 mmHg), or mean arterial pressure (> 70 mmHg). Luminex and ELISA-based immunoassays were used to quantify the serum levels of pro-inflammatory cytokines (Interleukin (IL)-1β, IL-6, IL-8, and IL-18), TBI biomarkers [S100B, Neuron-Specific Enolase (NSE), and epinephrine]. Three hundred and fifty patients with comparable age (mean 34.8 ± 9.9 years) and gender were enrolled in the interim analysis. Group 1 had significantly higher baseline levels of IL-6, IL-1B, S100B, lactate, and base deficit than the randomized groups (p = 0.001). Group 1 showed a significant temporal reduction in serum IL-6, IL-1β, epinephrine, and NSE levels from baseline to 48 h post-injury (p = 0.001). Patients with severe head injuries had higher baseline levels of IL-6, IL-1B, S100B, and HsTnT than mild and moderate TBI (p = 0.01). HsTnT levels significantly correlated with the Injury Severity Score (ISS) (r = 0.275, p = 0.001), GCS (r = − 0.125, p = 0.02), and serum S100B (r = 0.205, p = 0.001). Early Propranolol administration showed a significant reduction in cytokine levels and TBI biomarkers from baseline to 48 h post-injury, particularly among patients with positive HsTnT, indicating the potential role in modulating inflammation post-TBI. Trial registration: ClinicalTrials.gov NCT04508244. It was registered first on 11/08/2020. Recruitment started on 29 December 2020 and is ongoing. The study was partly presented at the 23rd European Congress of Trauma and Emergency Surgery (ECTES), April 28–30, 2024, in Estoril, Lisbon, Portugal.

Abstract Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis. To provide clinical practice recommendations on the immune function in sepsis, an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed. Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed, Web of Science, and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire. Then, the Delphi method was used to form consensus opinions, and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions. This consensus achieved satisfactory results through two rounds of questionnaire survey, with 2 statements rated as perfect consistency, 13 as very good consistency, and 9 as good consistency. After summarizing the results, a total of 14 strong recommended opinions, 8 weak recommended opinions and 2 non-recommended opinions were produced. Finally, a face-to-face discussion of the consensus opinions was performed through an online meeting, and all judges unanimously agreed on the content of this consensus. In summary, this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.

Objectives The aim of this study was to determine the incidence of post cricoid inlet patch (PC-IP) and to assess the clinical characteristics, pathological features, and treatment response. Materials and Methods A retrospective cross-sectional study was conducted from April 2016 to April 2021 in the tertiary gastroenterology unit of urban India. All patients with symptoms of globus sensation, chronic cough, heartburn, hoarseness, throat pain, dysphagia, and acid regurgitation after a thorough clinical examination underwent esophagogastroduodenoscopy by experienced endoscopists including biopsy. Sociodemographic data, symptoms and its duration, previous hospital visits, and chronic proton pump inhibitor (PPI) use were noted during the study. Results Three-thousand two-hundred fifty upper gastrointestinal endoscopies were performed during the study period. The prevalence of PC-IP was 2.7%, comprising 36.3% males and rest females. Mean age was 36.2 ± 17years. The most common symptom among these patients was globus sensation (81.8%) followed by acid regurgitation (75%), dyspepsia (64.7%), dysphagia (48.8%), throat pain (29.54%), chronic cough (22.72%), hoarseness (22.72%), and others (6.81%). Mean diameter of PC-IP was 1.5 ± 0.5 cm, more than one patch was found in 23.76% of patients. Histopathological examination showed heterotrophic gastric mucosa in 77.27%, out of which 38.23% had oxyntic type, 44.11% had mucoid type, and the rest had mixed cell type. On median follow-up after 20 months, 68.18% of patient had persistent symptoms, 77.27% were PPI responsive, and 22.73% were PPI refractory. On follow-up, 38.63% of patients had a repeat endoscopic procedure and biopsy (20.45%); none showed any changes in size or dysplasia. Conclusion Prevalence of PC-IP could be higher than the estimated. Careful examination of upper esophagus and use of narrow band imaging will increase the possibility of identifying IP. Those symptomatic patients need treatment with PPI, sometimes for long term. Ablative therapy with radiofrequency or argon plasma coagulation needs further clarification.

Abstract Background Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) represent leading causes of trauma-induced mortality, especially when co-occurring in pre-hospital settings where standard therapies are not readily available. The primary objective of this study was to determine if 17α-ethinyl estradiol-3-sulfate (EE-3-SO4) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI + HS. Methods All methods were approved by required regulatory agencies prior to study initiation. In this fully randomized, blinded preclinical study, eighty (50% females) sexually mature (190.64 ± 21.04 days old; 28.18 ± 2.72 kg) Yucatan swine were used. Sixty-eight animals received a closed-head, accelerative TBI followed by removal of approximately 40% of circulating blood volume. Animals were then intravenously administered EE-3-SO4 formulated in the vehicle at 5.0 mg/mL (dosed at 0.2 mL/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2 mL/kg over 5 min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5 h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation). Results A comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood–brain barrier breach. The percentage of animals surviving to 295 min post-injury was significantly higher for the EE-3-SO4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO4 also restored pulse pressure more rapidly post-drug administration, but did not confer any benefits in terms of shock index. Primary blood-based measurements of neuroinflammation and blood brain breach were also null, whereas secondary measurements of diffuse axonal injury suggested a more rapid return to baseline for the EE-3-SO4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO4 or Placebo administration. Conclusions EE-3-SO4 is efficacious in promoting survival and more rapidly restoring cardiovascular homeostasis following polytraumatic injuries in pre-hospital environments (rural and military) in the absence of standard therapies. Poly-therapeutic approaches targeting additional mechanisms (increased hemostasis, oxygen-carrying capacity, etc.) should be considered in future studies.

Self-expanding metal stents (SEMS) have been established beyond doubt as an effective tool in the palliative management of malignant gastrointestinal tract strictures. The advent of fully covered retrievable SEMS has allowed its use in benign oesophageal strictures and gastric outlet obstruction, which are traditionally treated with balloon or bougie dilation. Although balloon and bougie dilations are effective, strictures may be refractory, requiring repeated sessions of dilation or complex surgeries. Endoluminal stenting spares the patient from complex surgical procedures and their associated complications. Here, the authors present four cases wherein fully covered SEMS were used as an effective therapy for the restoration of the gastrointestinal lumen in non-malignant conditions.

Background: Dengue fever has become a hampering menace in New Delhi India, since the disease has become hyperendemic, due to circulation of multiple serotypes of dengue virus (DENV). This hyperendemicity poses a greater risk of secondary infections in human health system. This is a major issue which leads to apprehension amongst the researchers and health organizations and thus requires regular epidemiological surveillance. Methods: We analyzed the prevalence and serotypic distribution of dengue fever cases reported from the Southern part of New Delhi during continued surveillance from 2011 to 2017. The blood samples for the investigation were obtained from the patients suspected with dengue fever attending the OPD at a local Health Centre. The data for 2011–2016 was already published from our laboratory. The samples collected during 2017 were serotyped and characterized in the present study. Results: A total of 565 samples (59%) were positive for DENV of 958 samples tested by RT-PCR during 7 years (2011–2017). Our study has shown that most infections were caused by DENV-2 during 2011−2015. The data has shown occurrence of all four serotypes of DENV during 2015 and predominance of DENV-3 in 2016 and 2017. Further, predominant combination of DENV-1 and DENV-2 was found in most of the co-infections. To the best of our knowledge this is the first study showing the epidemiological trend of dengue fever in reference to the circulating DENV serotypes and co-infections from a hyperendemic region of New Delhi during 2011–2017. Conclusions: This hyperendemic pattern of DENV and instantaneous shift in circulation of its serotypes is likely pose a greater risk of secondary infections. Inclusion of comprehensive community and hospital surveillance of dengue fever will assist in formulation and implementation of effective control measures.

Since the beginning of the COVID-19 pandemic, many therapeutic strategies have been tried, with mixed results, to prevent and treat adult multisystem inflammatory syndrome in COVID-19 (AMIS-COVID-19). The reason behind this may the complex web of highly intertwined pathophysiologic mechanisms involved in the SARS-CoV-2 infection and the corresponding human systemic response, leading to end-organ damage, disability, and death. Colchicine, high-dose aspirin, and montelukast are being investigated currently as potential modulators of AMIS-COVID-19 in patients who fail to improve with traditional therapeutic approaches. Here, we present a patient who presented with high fevers, extreme fatigue and dyspnea, and ongoing deterioration. As part of our clinical approach, we used the simultaneous combination of the three agents listed above, capitalizing on their different respective mechanisms of action against AMIS-COVID-19. Following the initiation of therapy, the patient showed symptomatic improvement within 24 h, with the ability to return to daily activities after 72 h of continued triple-agent approach. Based on this experience, we have reviewed the immunomodulatory basis of this regimen, including potential avenues in which it may prevent the development of cytokine release syndrome (CRS) and its clinical manifestation, AMIS-COVID-19. By blocking the early stages of an inflammatory response, via diverse mechanistic pathways, the regimen in question may prove effective in halting the escalation of CRS and AMIS-COVID-19 in acutely symptomatic, nonimproving COVID-19 patients.

Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.

Background: Dengue is a rapidly emerging arthropod borne viral infection affecting tropical and sub-tropical regions of the world. Dengue is an acute febrile illness but sometimes causes more fatal complications like dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). Delhi, the capital of India has become hyper endemic for dengue virus because all the four serotypes are circulating here. Methods: The present study describes the identification of dengue virus from clinical samples collected from the suspected dengue patients from New Delhi, India during 2016. The CprM region of Dengue virus genome was analyzed for phylogenetic, selection pressure and Shannon entropy analyses. Results: The present study reports circulation of a single serotype (DENV-3) in New Delhi, during 2016. The phylogenetic analysis revealed that Indian subcontinent (genotype III) of DENV-3 was circulating in Delhi during this period. Neutral selection pressure in the analyzed region revealed relatively conserved nature of this part of the Dengue virus genome. Amino acid at 31 was positively selected and had high entropy value suggesting probability of variation at this position. Conclusions: The changing trend in circulation of dengue virus serotypes necessitates the continuous epidemiological surveillance for the dengue outbreaks in this region. Keywords: Dengue virus, Epidemiology, Phylogenetic analysis, Selection pressure, Entropy analysis

Abstract Despite efforts in prevention and intensive care, trauma and subsequent sepsis are still associated with a high mortality rate. Traumatic injury remains the main cause of death in people younger than 45 years and is thus a source of immense social and economic burden. In recent years, the knowledge concerning gender medicine has continuously increased. A number of studies have reported gender dimorphism in terms of response to trauma, shock and sepsis. However, the advantageous outcome following trauma-hemorrhage in females is not due only to sex. Rather, it is due to the prevailing hormonal milieu of the victim. In this respect, various experimental and clinical studies have demonstrated beneficial effects of estrogen for the central nervous system, the cardiopulmonary system, the liver, the kidneys, the immune system, and for the overall survival of the host. Nonetheless, there remains a gap between the bench and the bedside. This is most likely because clinical studies have not accounted for the estrus cycle. This review attempts to provide an overview of the current level of knowledge and highlights the most important organ systems responding to trauma, shock and sepsis. There continues to be a need for clinical studies on the prevailing hormonal milieu following trauma, shock and sepsis.

Abstract Background Pre-clinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking. Objective To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May 2017. The goal of the conference was to identify limitations of pre-clinical sepsis models and to propose a set of guidelines, defined as the “Minimum Quality Threshold in Pre-Clinical Sepsis Studies” (MQTiPSS), to enhance translational value of these models. Methods A total of 31 experts from 13 countries participated and were divided into 6 thematic working groups (WG): (1) study design, (2) humane modeling, (3) infection types, (4) organ failure/dysfunction, (5) fluid resuscitation, and (6) antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002–2013). Results Overall, the participants reached consensus on 29 points; 20 at “recommendation” (R) and 9 at “consideration” (C) strength. This executive summary provides a synopsis of the MQTiPSS consensus (Tables 1, 2, and 3). Detailed commentaries to all Rs and Cs are simultaneously published in three separate full-length papers. Conclusions We believe that these recommendations and considerations will serve to bring a level of standardization to pre-clinical models of sepsis and ultimately improve translation of pre-clinical findings. These guideline points are proposed as “best practices” for animal models of sepsis that should be implemented. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental.

Respiratory syncytial virus (RSV) is an important pathogen of global significance. The BA9 is one of the most predominant lineages of the BA genotype of group B RSV that has acquired a 60bp duplication in its G protein gene. We describe the local and global evolutionary dynamics of the second hyper variable region in the C- terminal of the G protein gene of the BA9 lineage. A total of 418 sequences (including 31 study and 387 GenBank strains) from 29 different countries were used for phylogenetic analysis. This analysis showed that the study strains clustered with BA (BA9 and BA8) and SAB4 genotype of group B RSV. We performed time-scaled evolutionary clock analyses using Bayesian Markov chain Monte Carlo methods. We also carried out glycosylation, selection pressure, mutational, entropy and Network analyses of the BA9 lineage. The time to the most recent common ancestor (tMRCA) of the BA genotype and BA9 lineage were estimated to be the years 1995 (95% HPD; 1987-1997) and 2000 (95% HPD; 1998-2001), respectively. The nucleotide substitution rate of the BA genotype [(4.58×10-3 (95% HPD; 3.89-5.29×10-3) substitution/site/year] was slightly faster than the BA9 lineage [4.03×10-3 (95% HPD; 4.65-5.2492×10-3)]. The BA9 lineage was categorized into 3 sub lineages (I, II and III) based on the Bayesian and Network analyses. The local transmission pattern suggested that BA9 is the predominant lineage of BA viruses that has been circulating in India since 2002 though showing fluctuations in its effective population size. The BA9 lineage established its global distribution with report from 23 different countries over the past 16 years. The present study augments our understanding of RSV infection, its epidemiological dynamics warranting steps towards its overall global surveillance.

Dengue fever is the most important arboviral disease in the tropical and sub-tropical countries of the world. Delhi, the metropolitan capital state of India, has reported many dengue outbreaks, with the last outbreak occurring in 2013. We have recently reported predominance of dengue virus serotype 2 during 2011-2014 in Delhi. In the present study, we report molecular characterization and evolutionary analysis of dengue serotype 2 viruses which were detected in 2011-2014 in Delhi. Envelope genes of 42 DENV-2 strains were sequenced in the study. All DENV-2 strains grouped within the Cosmopolitan genotype and further clustered into three lineages; Lineage I, II and III. Lineage III replaced lineage I during dengue fever outbreak of 2013. Further, a novel mutation Thr404Ile was detected in the stem region of the envelope protein of a single DENV-2 strain in 2014. Nucleotide substitution rate and time to the most recent common ancestor were determined by molecular clock analysis using Bayesian methods. A change in effective population size of Indian DENV-2 viruses was investigated through Bayesian skyline plot. The study will be a vital road map for investigation of epidemiology and evolutionary pattern of dengue viruses in India.

Dengue fever is the most prevalent arboviral disease in the tropical and sub-tropical regions of the world. The present report describes molecular detection and serotyping of dengue viruses in acute phase blood samples collected from New Delhi, India. Phylogenetic and molecular clock analysis of dengue virus serotype 1 and 3 strains were also investigated. Dengue virus infection was detected in 68.87% out of 604 samples tested by RT-PCR between 2011 & 2014. Dengue serotype 1 was detected in 25.48% samples, dengue serotype 2 in 79.56% samples and dengue serotype 3 in 11.29% samples. Dengue serotype 4 was not detected. Co-infection by more than one dengue serotype was detected in 18.26% samples. Envelope gene of 29 DENV-1 and 14 DENV-3 strains were sequenced in the study. All the DENV-1 strains grouped with the American African genotype. All DENV-3 strains were found to belong to Genotype III. Nucleotide substitution rates of dengue 1 and 3 viruses were determined in the study. Time to the most recent common ancestor (TMRCA) of dengue 1 viruses was determined to be 132 years. TMRCA of DENV-3 viruses was estimated to be 149 years. Bayesian skyline plots were constructed for Indian DENV-1 and 3 strains which showed a decrease in population size since 2005 in case of DENV- 1 strains while no change was observed in recent years in case of DENV-3 strains. The study also revealed a change in the dominating serotype in Delhi, India in recent years. The study will be helpful in formulating control strategies for the outbreaks. In addition, it will also assist in tracking the movement and evolution of this emerging virus.

Several clinical and experimental studies have demonstrated gender dimorphism in immune and organ responsiveness and in the susceptibility to and morbidity from shock, trauma, and sepsis. In this respect, cell-mediated immune responses have been shown to be depressed in males following trauma-hemorrhage, whereas they were aintained/enhanced in proestrus females. Furthermore, sex hormones have been shown to be responsible for this gender-specific immune response following adverse circulatory conditions. More specifically, studies indicate that androgens produce immunodepression following trauma-hemorrhage in males. In contrast, female sex steroids appear to exhibit immunoprotective properties following trauma and severe blood loss. With regard to the underlying mechanisms, receptors for sex hormones have been identified on various immune cells suggesting direct effects of these hormones on the immune cells. Alternatively, indirect effects of sex hormones, ie, modulation of cardiovascular responses or androgen- and estrogen-synthesizing enzymes, might contribute to gender-specific immune responses. Recent studies indicate that sex hormones, eg, dehydroepiandrosterone (DHEA), also modulate the function of peripheral blood mononuclear cells in surgical patients. Thus, the immunomodulatory properties of sex hormones/receptor antagonists/sex steroid synthesizing enzymes following trauma-hemorrhage suggests novel therapeutic strategies for the treatment of immunodepression in surgical patients.Uma série de estudos clínicos e experimentais demonstram a existência de dimorfismo sexual das respostas imunológicas e orgânicas, bem como da suscetibilidade e morbidade em relação ao choque, ao trauma e à sepse. Respostas imunes celularmente mediadas apresentam-se deprimidas em machos em resposta ao binômio trauma-hemorragia, mas conservados/enaltecidos em fêmeas em proestro. Adicionalmente demonstra-se que os hormônios sexuais são responsáveis por esta dicomotomia de resposta sexualmente específica, em condições cardiovasculares adversas. Estudos específicos indicam que os andrógenos produzem imunodepressão pós-trauma hemorragia em machos. Em contraste, esteróides sexuais femininos parecem exibir propriedades imunoprotetoras após episódios de trauma com ou sem perda importante de sangue. No terreno dos mecanismos subjacentes, foram identificados receptores para hormônios sexuais em várias células do sistema imunológico, sugerindo a existência de efeitos diretos destes hormônios sobre tais células. Alternativamente, observam efeitos indiretos de hormônios sexuais tais como modulação das respostas cardiovasculares das enzimas sintetizadores de andrógeno e estrógeno, que podem contribuir para as estas respostas sexualmente diferenciadas. Estudos recentes indicam que os hormônios sexuais, como por exemplo a dehidroepiandrosterona também modulam a função de células mononucleares da série branca em pacientes cirúrgicos. Assim, as propriedades imunomodulatórias de hormônios sexuais/antagonistas de receptores/enzimas sintetizadores de esteróides após a ocorrência de trauma ou de hemorragia sugerem o caminho para novas estratégias terapêuticas para o tratamento de imunodepressão em pacientes cirúrgicos.

Sepsis morbidity and mortality exacts a toll on patients and contributes significantly to healthcare costs. Preclinical models of sepsis have been used to study disease pathogenesis and test new therapies, but divergent outcomes have been observed with the same treatment even when using the same sepsis model. Other disorders such as diabetes, cancer, malaria, obesity, and cardiovascular diseases have used standardized, preclinical models that allow laboratories to compare results. Standardized models accelerate the pace of research and such models have been used to test new therapies or changes in treatment guidelines. The National Institutes of Health mandated that investigators increase data reproducibility and the rigor of scientific experiments and has also issued research funding announcements about the development and refinement of standardized models. Our premise is that refinement and standardization of preclinical sepsis models may accelerate the development and testing of potential therapeutics for human sepsis, as has been the case with preclinical models for other disorders. As a first step toward creating standardized models, we suggest standardizing the technical standards of the widely used cecal ligation and puncture model and creating a list of appropriate organ injury and immune dysfunction parameters. Standardized sepsis models could enhance reproducibility and allow comparison of results between laboratories and may accelerate our understanding of the pathogenesis of sepsis.

BACKGROUND:Pre-clinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking. OBJECTIVE:To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May 2017. The goal of the conference was to identify limitations of pre-clinical sepsis models and to propose a set of guidelines, defined as the "Minimum Quality Threshold in Pre-Clinical Sepsis Studies" (MQTiPSS), to enhance translational value of these models. METHODS:A total of 31 experts from 13 countries participated and were divided into 6 thematic working groups (WG): (1) study design, (2) humane modeling, (3) infection types, (4) organ failure/dysfunction, (5) fluid resuscitation, and (6) antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002-2013). RESULTS:Overall, the participants reached consensus on 29 points; 20 at "recommendation" (R) and 9 at "consideration" (C) strength. This executive summary provides a synopsis of the MQTiPSS consensus (Tables 1, 2, and 3). Detailed commentaries to all Rs and Cs are simultaneously published in three separate full-length papers. CONCLUSIONS:We believe that these recommendations and considerations will serve to bring a level of standardization to pre-clinical models of sepsis and ultimately improve translation of pre-clinical findings. These guideline points are proposed as "best practices" for animal models of sepsis that should be implemented. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental.

Introduction: Experimental studies in animals have yielded conflicting results on the role of Tumor Necrosis Factor (TNF) in sepsis and endotoxemia, with some reporting adaptive and others inappropriate effects. A meta-analysis of the available literature was performed to determine the factors explaining this discrepancy. Methods: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The protocol was registered with PROSPERO (CRD42020167384) prior to data collection. PubMed and Embase were the databases queried. Risk of bias was evaluated using the SYRCLE Risk of Bias Tool. All animal studies investigating sepsis-related mortality and modified TNF signaling were considered eligible. The exclusion criteria were: lack of mortality data, 7-day mortality rates below 10% in both wild type and TNF-altered pathway animals, and absence of an English abstract. To determine the role of TNF according to the experimental protocol, three approaches were used: first an approach based on the statistical significance of each experiment, then the pooled mortality was calculated, and finally the weighted risk ratio for mortality was assessed. Results: A total of 175 studies were included in the analysis, comprising a total of 760 experiments and involving 19,899 animals. The main species used were mice (77%) and rats (21%). The most common method of TNF pathway modulation was TNF pathway inactivation that was primarily associated with an inappropriate secretion of TNF. At the opposite, TNF injection was associated with an adaptive role of TNF. Lipopolysaccharide (LPS) injection was the most used stimulus to establish an infectious model (42%) and was strongly associated with an inappropriate role of TNF. Conversely, live bacterial models, especially the cecal ligation and puncture (CLP) model, pneumonia, meningitis, and gastrointestinal infection, were associated with an adaptive role. This was particularly evident for Listeria monocytogenes, Streptococcus pneumoniae. Conclusion: The role of TNF during infection varies depending on the experimental model used. Models that mimic clinical conditions, based on virulent bacteria that cause high mortality even at low inocula, demonstrated an adaptive role of TNF. Conversely, models based on LPS or low-pathogenic live bacteria, administered at doses well above physiological thresholds and combined with early antibiotic therapy, were associated with an inappropriate role. [ABSTRACT FROM AUTHOR]

The original version of this article unfortunately contained mistakes.

Preclinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of preclinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on preclinical sepsis modeling was held in Vienna in May, 2017. The goal of the conference was to identify limitations of preclinical sepsis models and to propose a set of guidelines, defined as the "Minimum Quality Threshold in Preclinical Sepsis Studies" (MQTiPSS), to enhance translational value of these models. A total of 31 experts from 13 countries participated and were divided into six thematic Working Groups: Study Design, Humane modeling, Infection types, Organ failure/dysfunction, Fluid resuscitation, and Antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002-2013). Overall, the participants reached consensus on 29 points; 20 at "recommendation" and nine at "consideration" strength. This Executive Summary provides a synopsis of the MQTiPSS consensus. We believe that these recommendations and considerations will serve to bring a level of standardization to preclinical models of sepsis and ultimately improve translation of preclinical findings. These guideline points are proposed as "best practices" for animal models of sepsis that should be implemented. To encourage its wide dissemination, this article is freely accessible on the Intensive Care Medicine Experimental and Infection journal websites. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection, and Intensive Care Medicine Experimental.

This is an interim analysis of the Beta-blocker (Propranolol) use in traumatic brain injury (TBI) based on the high-sensitive troponin status (BBTBBT) study. The BBTBBT is an ongoing double-blind placebo-controlled randomized clinical trial with a target sample size of 771 patients with TBI. We sought, after attaining 50% of the sample size, to explore the impact of early administration of beta-blockers (BBs) on the adrenergic surge, pro-inflammatory cytokines, and the TBI biomarkers linked to the status of high-sensitivity troponin T (HsTnT). Patients were stratified based on the severity of TBI using the Glasgow coma scale (GCS) and HsTnT status (positive vs negative) before randomization. Patients with positive HsTnT (non-randomized) received propranolol (Group-1; n = 110), and those with negative test were randomized to receive propranolol (Group-2; n = 129) or placebo (Group-3; n = 111). Propranolol was administered within 24 h of injury for 6 days, guided by the heart rate (> 60 bpm), systolic blood pressure (≥ 100 mmHg), or mean arterial pressure (> 70 mmHg). Luminex and ELISA-based immunoassays were used to quantify the serum levels of pro-inflammatory cytokines (Interleukin (IL)-1β, IL-6, IL-8, and IL-18), TBI biomarkers [S100B, Neuron-Specific Enolase (NSE), and epinephrine]. Three hundred and fifty patients with comparable age (mean 34.8 ± 9.9 years) and gender were enrolled in the interim analysis. Group 1 had significantly higher baseline levels of IL-6, IL-1B, S100B, lactate, and base deficit than the randomized groups (p = 0.001). Group 1 showed a significant temporal reduction in serum IL-6, IL-1β, epinephrine, and NSE levels from baseline to 48 h post-injury (p = 0.001). Patients with severe head injuries had higher baseline levels of IL-6, IL-1B, S100B, and HsTnT than mild and moderate TBI (p = 0.01). HsTnT levels significantly correlated with the Injury Severity Score (ISS) (r = 0.275, p = 0.001), GCS (r = − 0.125, p = 0.02), and serum S100B (r = 0.205, p = 0.001). Early Propranolol administration showed a significant reduction in cytokine levels and TBI biomarkers from baseline to 48 h post-injury, particularly among patients with positive HsTnT, indicating the potential role in modulating inflammation post-TBI. Trial registration: ClinicalTrials.gov NCT04508244. It was registered first on 11/08/2020. Recruitment started on 29 December 2020 and is ongoing. The study was partly presented at the 23rd European Congress of Trauma and Emergency Surgery (ECTES), April 28–30, 2024, in Estoril, Lisbon, Portugal. [ABSTRACT FROM AUTHOR]