Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis.

Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as "autoproliferation" of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies.

The Association Between Gender and Clinical Outcomes in Patients With Moderate to Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

INTRODUCTION: Traumatic brain injuries (TBIs) are a significant cause of morbidity and mortality in the United States. but have a disproportionate impact on patients based on gender. This systematic review and meta-analysis aim to compare gender differences in clinical outcomes between male and female adult trauma patients with moderate and severe TBI. METHODS: Studies assessing gender differences in outcomes following TBIs on PubMed, Google Scholar, EMBASE, and ProQuest were searched. Meta-analysis was performed for outcomes including in-hospital mortality, hospital length of stay, intensive care unit length of stay, and Glasgow outcome scale (GOS) at 6 mo. RESULTS: Eight studies were included for analysis with 26,408 female and 63,393 male patients. Meta-analysis demonstrated that males had a significantly lower risk of mortality than females (RR: 0.88; 95% CI 0.78, 0.99; P = 0.0001). Females had a shorter hospital length of stay (mean difference -1.4 d; 95% CI - 1.6 d, -1.2 d). No significant differences were identified in intensive care unit length of stay (mean difference -3.0 d; 95% CI -7.0 d, 1.1 d; P = 0.94) or GOS at 6 mo (mean difference 0.2 d; 95% CI -0.9 d, 1.4 d; P = 1). CONCLUSIONS: Compared to male patients, female patients with moderate and severe TBI had a significantly higher in-hospital mortality risk. There were no significant differences in long-term outcomes between genders based on GOS at 6 mo. These findings warrant further investigation into the etiology of these gender disparities and their impact on additional clinical outcome measures.

Single cell analysis of host response to helminth infection reveals the clonal breadth, heterogeneity, and tissue-specific programming of the responding CD4+ T cell repertoire.

The CD4+ T cell response is critical to host protection against helminth infection. How this response varies across different hosts and tissues remains an important gap in our understanding. Using IL-4-reporter mice to identify responding CD4+ T cells to Nippostrongylus brasiliensis infection, T cell receptor sequencing paired with novel clustering algorithms revealed a broadly reactive and clonally diverse CD4+ T cell response. While the most prevalent clones and clonotypes exhibited some tissue selectivity, most were observed to reside in both the lung and lung-draining lymph nodes. Antigen-reactivity of the broader repertoires was predicted to be shared across both tissues and individual mice. Transcriptome, trajectory, and chromatin accessibility analysis of lung and lymph-node repertoires revealed three unique but related populations of responding IL-4+ CD4+ T cells consistent with T follicular helper, T helper 2, and a transitional population sharing similarity with both populations. The shared antigen reactivity of lymph node and lung repertoires combined with the adoption of tissue-specific gene programs allows for the pairing of cellular and humoral responses critical to the orchestration of anti-helminth immunity.

Outcomes of Transfusion With Whole Blood, Component Therapy, or Both in Adult Civilian Trauma Patients: A Systematic Review and Meta-Analysis.

INTRODUCTION: This systematic review and meta-analysis was conducted to compare outcomes, including transfusion volume, complications, intensive care unit length of stay, and mortality for adult civilian trauma patients transfused with whole blood (WB), components (COMP), or both (WB + COMP). METHODS: A systematic review and meta-analysis were conducted using studies that evaluated outcomes of transfusion of WB, COMP, or WB + COMP for adult civilian trauma patients. A search of PubMed, Embase, and Cochrane from database inception to March 3, 2022 was conducted. The search resulted in 18,400 initial articles with 16 studies remaining after the removal of duplicates and screening for inclusion and exclusion criteria. RESULTS: This study identified an increased risk of 24-h mortality with COMP versus WB + COMP (relative risk: 1.40 [1.10, 1.78]) and increased transfusion volumes of red blood cells with COMP versus WB at 6 and 24 h, respectively (-2.26 [-3.82, -0.70]; -1.94 [-3.22, -0.65] units). There were no differences in the calculated rates of infections or intensive care unit length of stay between WB and COMP, respectively (relative risks: 1.35 [0.53, 3.46]; -0.91 [-2.64, 0.83]). CONCLUSIONS: Transfusion with WB + COMP is associated with lower 24-h mortality versus COMP and transfusion with WB is associated with a lower volume of red blood cells transfused at both 6 and 24 h. Based on these findings, greater utilization of whole blood in civilian adult trauma resuscitation may lead to improved mortality and reduced transfusion requirements.

The Parallel Structure-Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands.

The melanocortin receptors are involved in numerous physiological pathways, including appetite, skin and hair pigmentation, and steroidogenesis. In particular, the melanocortin-3 receptor (MC3R) is involved in fat storage, food intake, and energy homeostasis. Small-molecule ligands developed for the MC3R may serve as therapeutic lead compounds for treating disease states of energy disequilibrium. Herein, three previously reported pyrrolidine bis-cyclic guanidine compounds with five sites for molecular diversity (R1-R5) were subjected to parallel structure-activity relationship studies to identify the common pharmacophore of this scaffold series required for full agonism at the MC3R. The R2, R3, and R5 positions were required for full MC3R efficacy, while truncation of either the R1 or R4 positions in all three compounds resulted in full MC3R agonists. Two additional fragments, featuring molecular weights below 300 Da, were also identified that possessed full agonist efficacy and micromolar potencies at the mMC5R. These SAR experiments may be useful in generating new small-molecule ligands and chemical probes for the melanocortin receptors to help elucidate their roles in vivo and as therapeutic lead compounds.

Emergency Resuscitative Thoracotomy for Civilian Thoracic Trauma in the Field and Emergency Department Settings: A Systematic Review and Meta-Analysis.

BACKGROUND: Emergency department resuscitative thoracotomy (ED-RT) or prehospital resuscitative thoracotomy (PH-RT) is performed for trauma patients with impending or full cardiovascular collapse. This systematic review and meta-analysis analyze outcomes in patients with thoracic trauma receiving PH-RT and ED-RT. METHODS: PubMed, JAMA Network, and CINAHL electronic databases were searched to identify studies published on ED-RT or PH-RT between 2000-2020. Patients were grouped by location of procedure and type of thoracic injury (blunt versus penetrating). RESULTS: A total of 49 studies met the criteria for qualitative analysis, and 43 for quantitative analysis. 43 studies evaluated ED-RT and 5 evaluated PH-RT. Time from arrival on scene to PH-RT >5 min was associated with increased neurological complications and time from the initial encounter to PH-RT or ED-RT >10 min was associated with increased mortality. ISS ≥ 25 and absent signs of life were also associated with increased mortality. There was higher mortality in all PH-RT (93.5%) versus all ED-RT (81.8%) (P = 0.02). Among ED-RTs, a significant difference was found in mortality rate between patients with blunt (92.8%) versus penetrating (78.7%) injuries (P < 0.001). When considering only blunt or penetrating injury types, no significant difference in RT mortality rate was found between ED-RT and PH-RT (P = 0.65 and P = 0.95, respectively). CONCLUSIONS: ED-RT and PH-RT are potentially life-saving procedures for patients with penetrating thoracic injuries in extremis and with signs of life. The efficacy of this procedure is time sensitive. Moreover, there appears to be a greater mortality risk for patients with thoracic trauma receiving RT in the PH setting compared to the ED setting. More studies are needed to determine the significance of PH-RT mortality.

Identification of small molecules by screening a mixture-based scaffold compound library for treatment of alpha-1 antitrypsin deficiency.

This study aimed to identify small molecules that have the potential to treat alpha1-antitrypsin deficiency (AATD) by screening compounds available from a mixture-based scaffold library. 93 scaffold libraries (total diversity of >30 million compounds in mixture format) were screened using a cell model of AATD in order to identify samples that could either reduce intracellular aggregation of Z-form AAT protein, increase extracellular secretion of Z-AAT or both. Mixture libraries containing compounds with in vitro activity, for example library 1295, were screened further to identify individual active compounds. The mixture format of the scaffold library allowed for some preliminary structure-activity relationships to be developed and also enabled the rapid selection of a promising scaffold. Utilizing this scaffold, 1295, a collection of individual "control" compounds contained in the 1295 mixture sample were then screened. A sub-library of individual "control" compounds featuring structural diversity at position R1 (1295.R1), was screened and 7 compounds were found to reduce the intracellular accumulation of Z-AAT without affecting cell viability at a concentration of 25ug/ml (about 50 µM). Screening sub-libraries featuring structural diversity at R2 and R3 (1295.R2 and 1295.R3) identified an additional 15 active compounds. Titration experiments identified 3 compounds from the 1295.R2 library that retained activity at 5ug/ml (approx. 10uM). One compound (1295.263) from 1295.R2 decreased intracellular levels of Z-AAT without affecting cell viability and wild-type AAT levels at the concentration of 5ug/ml. Molecular docking of this compound to the Z-AAT crystal structure identified a potential binding site near the C-terminal domain, an identified polymerization site. Our results indicate that screening large mixture-based compound libraries can be used to identify small molecules that may have the potential to treat AATD and other disease.

Disparities in Adult and Pediatric Trauma Outcomes: a Systematic Review and Meta-Analysis.

BACKGROUND: Although safeguards requiring emergency care are provided regardless of a patient's payor status, disparate outcomes have been reported in trauma populations. The purpose of this systematic review and meta-analysis was to determine whether race/ethnicity or insurance status had an effect on mortality and to systematically present the literature in the adult and pediatric trauma populations during the last decade. METHODS: An online search of PubMed, Cochrane Library, Google Scholar, and SAGE Journals was performed for publications from January 2009 to March 2019. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used. The GRADE Working Group criteria were utilized to assess the evidence quality. A meta-analysis was conducted to compare mortality between insured/uninsured and Caucasian/non-Caucasian patients. RESULTS: Our search revealed 680 publications that qualified for evaluation. Of these, 41 were included in the final analysis. Twenty-six studies included adults only, nine studies included pediatric patients only, and six studies evaluated both. Twelve studies evaluated the effects of race/ethnicity, 18 examined insurance status, and 11 investigated both. Uninsured patients had 22% greater odds of death than insured patients (OR 1.22; CI 1.21-1.24). Non-Caucasian patients had 18% greater risk of death than Caucasian patients (OR 1.18; CI 1.17-1.20). CONCLUSION: Both the adult and pediatric trauma populations suffer outcome disparities based on race/ethnicity and insurance status. Overall, patients without insurance coverage and minority groups (i.e., non-Caucasians) had worse outcomes, as measured by odds of death and all-cause mortality.

Evaluating Clinical Outcomes of Laparoscopic Subtotal and Total Cholecystectomy for Complicated Acute Cholecystitis: A Systematic Review and Meta-Analysis.

INTRODUCTION: This systematic review and meta-analysis aimed to compare clinical outcomes in patients with complicated acute cholecystitis undergoing laparoscopic total vs subtotal cholecystectomy. METHODS: This systematic review and meta-analysis was conducted according to PRISMA guidelines and queried PubMed, Embase, ProQuest, Google Scholar, and Cochrane databases from inception to May 2023. The primary outcome was complication rates including common bile duct injury, wound infection, reoperation, bile leak, retained stones, and subhepatic collection, whereas secondary outcomes were in-hospital mortality and hospital length of stay. RESULTS: A total of 7 studies with 135,233 cases were included for meta-analysis. Patients who underwent laparoscopic total cholecystectomy had a significantly lower risk of postoperative bile leaks (RR: .15; 95% CI: .03, .80) and subhepatic fluid collection (RR: 0.19; 95% CI: .06, .63) and were 2.94 times less likely to die compared to those who underwent subtotal cholecystectomy (RR .34; 95% CI: .15, .77). Patients who underwent subtotal cholecystectomy had significantly longer hospital length of stay (mean difference 1.0 days; 95% CI: .5 days, 1.4 days). CONCLUSIONS: In adult patients presenting with complicated cholecystitis, management with laparoscopic subtotal cholecystectomy presents a unique complication profile with increased risk of postoperative bile leak and subhepatic fluid collection, in-hospital mortality, and longer hospital length-of-stay when used as an alternative approach to laparoscopic total cholecystectomy. Further research into the most appropriate clinical scenarios and patient populations for the use of the subtotal cholecystectomy approach may prove useful in improving its associated outcomes.

Outcomes of Preperitoneal Packing and Angioembolization for Hemorrhage Control in Hemodynamically Unstable Pelvic Fractures: A Systematic Review and Meta-Analysis.

BACKGROUND: Hemodynamically unstable pelvic fractures are often life-threatening injuries; however, the optimal management remains uncertain. This systematic review and meta-analysis aim to evaluate the most appropriate primary management of hemorrhage in adult patients with hemodynamically unstable pelvic fractures by comparing outcomes following the initial use of preperitoneal packing (PPP) vs angioembolization (AE). METHODS: A systematic search of PubMed, Embase, Google Scholar, and ProQuest databases was conducted following PRISMA guidelines. Studies assessing hemorrhage management in trauma patients with hemodynamically unstable pelvic fractures were included. The data extracted from selected articles included patient demographics, study design, and outcomes such as 24-hour PRBC transfusions, in-hospital mortality, and DVT rate. RESULTS: Eight articles were included in the systematic review. Among the included studies, 2040 patients with hemodynamically unstable pelvic fractures were analyzed. Meta-analyses revealed that treatment with PPP was associated with fewer 24-hour PRBC transfusions (mean difference = -1.0, 95% CI: -1.8 to -.2) than AE. However, no significant differences were noted in in-hospital mortality (RR: .91, 95% CI: .80-1.05) and the rate of deep vein thrombosis (RR: .89, 95% CI: .62-1.28) between groups. CONCLUSION: The findings of this study suggest that primary management with PPP was associated with fewer 24-hour PRBC transfusions compared to AE. The choice of primary management with PPP or AE did not significantly impact in-hospital mortality. Future studies should address clinical outcomes and the factors that affect them to better understand the impact of different management strategies and direct the creation of practice management guidelines.

Antigen-driven CD8 + T cell clonal expansion is a prominent feature of MASH in humans and mice.

Background and Aims: Chronic liver disease due to metabolic dysfunction-associated steatohepatitis (MASH) is a rapidly increasing global epidemic. MASH progression is a consequence of the complex interplay between inflammatory insults and dysregulated hepatic immune responses. T lymphocytes have been shown to accumulate in the liver during MASH, but the cause and consequence of T cell accumulation in the liver remain unclear. Our study aimed to define the phenotype and T cell receptor diversity of T cells from human cirrhotic livers and an animal model of MASH to begin resolving their function in disease. Approach and Results: In these studies, we evaluated differences in T cell phenotype in the context of liver disease we isolated liver resident T cell populations from individuals with cirrhosis and a murine model of MASH. Using both 5' single cell sequencing and flow cytometry we defined the phenotype and T cell receptor repertoire of liver resident T cells during health and disease. Conclusions: MASH-induced cirrhosis and diet-induced MASH in mice resulted in the accumulation of activated and clonally expanded T cells in the liver. The clonally expanded T cells in the liver expressed markers of chronic antigenic stimulation, including PD1 , TIGIT and TOX . Overall, this study establishes for the first time that T cells undergo antigen-dependent clonal expansion and functional differentiation during the progression of MASH. These studies could lead to the identification of potential antigenic targets that drive T cell activation, clonal expansion, and recruitment to the liver during MASH.

Structure-activity relationship of pyrrolidine pentamine derivatives as inhibitors of the aminoglycoside 6'- N -acetyltransferase type Ib.

Resistance to amikacin and other major aminoglycosides is commonly due to enzymatic acetylation by aminoglycoside 6'- N -acetyltransferase type I enzyme, of which type Ib [AAC(6')-Ib] is the most widespread among Gram-negative pathogens. Finding enzymatic inhibitors could be an effective way to overcome resistance and extend the useful life of amikacin. Small molecules possess multiple properties that make them attractive compounds to be developed as drugs. Mixture-based combinatorial libraries and positional scanning strategy led to the identification of a chemical scaffold, pyrrolidine pentamine, that, when substituted with the appropriate functionalities at five locations (R1 - R5), inhibits AAC(6')-Ib-mediated inactivation of amikacin. Structure-activity relationship (SAR) studies showed that while truncations to the molecule result in loss of inhibitory activity, modifications of functionalities and stereochemistry have different effects on the inhibitory properties. In this study, we show that alterations at position R1 of the two most active compounds, 2700.001 and 2700.003 , reduced inhibition levels, demonstrating the essential nature not only of the presence of an S -phenyl moiety at this location but also the distance to the scaffold. On the other hand, modifications on the R3, R4, and R5 positions have varied effects, demonstrating the potential for optimization. A correlation analysis between molecular docking values (ΔG) and the dose required for two-fold potentiation of compounds described in this and the previous studies showed a significant correlation between ΔG values and inhibitory activity. Highlights: Amikacin resistance in Gram-negatives is mostly caused by the AAC(6')-Ib enzymeAAC(6')-Ib has been identified in most Gram-negative pathogensInhibitors of AAC(6')-Ib could be used to treat resistant infectionsCombinatorial libraries and positional scanning identified an inhibitorThe lead compound can be optimized by structure activity relationship studies.

Selective agonists and antagonists of formylpeptide receptors: duplex flow cytometry and mixture-based positional scanning libraries.

The formylpeptide receptor (FPR1) and formylpeptide-like 1 receptor (FPR2) are G protein-coupled receptors that are linked to acute inflammatory responses, malignant glioma stem cell metastasis, and chronic inflammation. Although several N-formyl peptides are known to bind to these receptors, more selective small-molecule, high-affinity ligands are needed for a better understanding of the physiologic roles played by these receptors. High-throughput assays using mixture-based combinatorial libraries represent a unique, highly efficient approach for rapid data acquisition and ligand identification. We report the superiority of this approach in the context of the simultaneous screening of a diverse set of mixture-based small-molecule libraries. We used a single cross-reactive peptide ligand for a duplex flow cytometric screen of FPR1 and FPR2 in color-coded cell lines. Screening 37 different mixture-based combinatorial libraries totaling more than five million small molecules (contained in 5,261 mixture samples) resulted in seven libraries that significantly inhibited activity at the receptors. Using positional scanning deconvolution, selective high-affinity (low nM K(i)) individual compounds were identified from two separate libraries, namely, pyrrolidine bis-diketopiperazine and polyphenyl urea. The most active individual compounds were characterized for their functional activities as agonists or antagonists with the most potent FPR1 agonist and FPR2 antagonist identified to date with an EC50 of 131 nM (4 nM K(i)) and an IC50 of 81 nM (1 nM K(i)), respectively, in intracellular Ca²âº response determinations. Comparative analyses of other previous screening approaches clearly illustrate the efficiency of identifying receptor selective, individual compounds from mixture-based combinatorial libraries.

Conditional probabilistic analysis for prediction of the activity landscape and relative compound activities.

Structure-property relationships and structure-activity relationships play an important role in many research areas, such as medicinal chemistry and drug discovery. Such methods, however, have focused on providing post-hoc descriptions of such relationships based on known data. The ability for these descriptions to remain relevant when considering compounds of unknown activity, and thus the prediction of activity and property landscapes using existing data, remains little explored. In this study, we present a novel method of evaluating the ability of a compound comparison methodology to provide accurate information about a set of unknown compounds and also explore the ability of these predicted activity landscapes to prioritize active compounds over inactive. These methods are applied to three distinct and diverse sets of compounds, each with activity data for multiple targets, for a total of eight target-compound set pairs. Six methodologically distinct compound comparison methods were evaluated. We show that overall, all compound comparison methods provided an improvement in structure-activity relationship prediction over random and were able to prioritize compounds in a superior manner to random sampling, but the degree of success and therefore applicability varied markedly.

Rapid scanning structure-activity relationships in combinatorial data sets: identification of activity switches.

We present a general approach to describe the structure-activity relationships (SAR) of combinatorial data sets with activity for two biological endpoints with emphasis on the rapid identification of substitutions that have a large impact on activity and selectivity. The approach uses dual-activity difference (DAD) maps that represent a visual and quantitative analysis of all pairwise comparisons of one, two, or more substitutions around a molecular template. Scanning the SAR of data sets using DAD maps allows the visual and quantitative identification of activity switches defined as specific substitutions that have an opposite effect on the activity of the compounds against two targets. The approach also rapidly identifies single- and double-target R-cliffs, i.e., compounds where a single or double substitution around the central scaffold dramatically modifies the activity for one or two targets, respectively. The approach introduced in this report can be applied to any analogue series with two biological activity endpoints. To illustrate the approach, we discuss the SAR of 106 pyrrolidine bis-diketopiperazines tested against two formylpeptide receptors obtained from positional scanning deconvolution methods of mixture-based libraries.

The mathematics of a successful deconvolution: a quantitative assessment of mixture-based combinatorial libraries screened against two formylpeptide receptors.

In the past 20 years, synthetic combinatorial methods have fundamentally advanced the ability to synthesize and screen large numbers of compounds for drug discovery and basic research. Mixture-based libraries and positional scanning deconvolution combine two approaches for the rapid identification of specific scaffolds and active ligands. Here we present a quantitative assessment of the screening of 32 positional scanning libraries in the identification of highly specific and selective ligands for two formylpeptide receptors. We also compare and contrast two mixture-based library approaches using a mathematical model to facilitate the selection of active scaffolds and libraries to be pursued for further evaluation. The flexibility demonstrated in the differently formatted mixture-based libraries allows for their screening in a wide range of assays.

Outcomes of Pigtail Catheter Placement versus Chest Tube Placement in Adult Thoracic Trauma Patients: A Systematic Review and Meta-Analysis.

INTRODUCTION: A debate currently exists regarding the efficacy of pigtail catheters vs chest tubes in the management of thoracic trauma. This meta-analysis aims to compare the outcomes of pigtail catheters vs chest tubes in adult trauma patients with thoracic injuries. METHODS: This systematic review and meta-analysis were conducted using PRISMA guidelines and registered with PROSPERO. PubMed, Google Scholar, Embase, Ebsco, and ProQuest electronic databases were queried for studies comparing the use of pigtail catheters vs chest tubes in adult trauma patients from database inception to August 15th, 2022. The primary outcome was the failure rate of drainage tubes, defined as requiring a second tube placement or VATS, unresolved pneumothorax, hemothorax, or hemopneumothorax requiring additional intervention. Secondary outcomes were initial drainage output, ICU-LOS, and ventilator days. RESULTS: A total of 7 studies satisfied eligibility criteria and were assessed in the meta-analysis. The pigtail group had higher initial output volumes vs the chest tube group, with a mean difference of 114.7 mL [95% CI (70.6 mL, 158.8 mL)]. Patients in the chest tube group also had a higher risk of requiring VATS vs the pigtail group, with a relative risk of 2.77 [95% CI (1.50, 5.11)]. CONCLUSIONS: In trauma patients, pigtail catheters rather than chest tubes are associated with higher initial output volume, reduced risk of VATS, and shorter tube duration. Considering the similar rates of failure, ventilator days, and ICU length-of-stay, pigtail catheters should be considered in the management of traumatic thoracic injuries. STUDY TYPE: Systematic Review and meta-analysis.

Comparing Outcomes of Appendectomy Versus Non-operative Antibiotic Therapy for Acute Appendicitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Acute appendicitis is one of the most common etiologies of an acute abdomen in the emergency department and first-line standard surgical care for the condition has recently been reconsidered. We aim to evaluate the effectiveness and outcomes of surgical intervention versus non-operative antibiotic therapy in the treatment of acute appendicitis in adult and pediatric patients. METHODS: A literature search was conducted using PubMed, Google Scholar, and EMBASE. The search included all studies until January 15th, 2022. Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines were followed for abstracting data and assessing data quality and validity. Data were independently extracted by the authors of the study. Meta-analysis was performed and Cohen's Q test for heterogeneous effects was performed to determine if fixed or random-effects models were appropriate for use. RESULTS: Twelve randomized controlled trials investigating a total of 3703 acute appendicitis patients met inclusion criteria and were included in the meta-analysis. In the systematic review, eleven RCTs demonstrated that appendectomy had improved effectiveness compared to non-operative antibiotic management. The meta-analysis demonstrated that patients undergoing appendectomy had significantly higher treatment effectiveness compared with antibiotics-only treatment (98.4% vs. 73.3%, P < .0001). The meta-analysis did demonstrate a significant .54-day reduction in hospital length of stay for the appendectomy group compared to the non-operative antibiotic therapy group. CONCLUSIONS: Surgical intervention is associated with increased effectiveness of treatment and reduced in-hospital length of stay among patients with acute appendicitis. Guidelines established by institutions and surgical organizations should indicate appendectomy as the standard and superior treatment option for patients presenting with acute appendicitis.

Beta-Blocker Therapy in Patients With Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

INTRODUCTION: Traumatic brain injury (TBI), a leading cause of morbidity and mortality among trauma patients worldwide, poses the risk of secondary neurological insult due to significant catecholamine surge. We aim to investigate the effectiveness and outcomes of beta-blocker administration in patients with severe TBI. METHODS: A search through PubMed, EMBASE, JAMA network, and Google Scholar databases was conducted for relevant peer-reviewed original studies published before February 15, 2022. A standard random-effects model was used, as justified by a high Cohen's Q test. RESULTS: Twelve studies met inclusion criteria and were included in the meta-analysis. Severe TBI patients who were administered beta-blockers had a significantly reduced incidence of in-hospital mortality compared to the non-beta-blocker group (14.5% vs 19.2%). However, the beta-blocker group was reported to have a significantly greater number of ventilator days (5.58 vs 2.60 days). Similarly, intensive care unit (9.00 vs 6.84 days) and hospital (17.30 vs 11.02 days) lengths of stay (LOS) were increased in the beta-blocker group compared to those who were not administered beta-blocker therapy, but only the difference in hospital-LOS was significant. CONCLUSIONS: Beta-blockers have significantly decreased in-hospital mortality in patients with severe TBI despite being associated with an increase in ventilator days and hospital-LOS. The administration of beta-blocker therapy in the management of severe TBI may be warranted and should be discussed in future guidelines.

Gender Distribution & Rank of Authorship in Surgical Literature.

BACKGROUND: Authorship of surgical literature is important for the career advancement of surgeons, and gender disparities in authorship may hinder the representation and leadership of women within academic surgery. The aim of this systematic review and meta-analysis was to evaluate the gender distribution of first, senior, and overall authorship in peer-reviewed surgical journal studies across all surgical specialties to determine if disparities exist. METHODS: PubMed, EMBASE, and Google Scholar databases were searched for studies investigating the gender distribution of authorship of surgical literature published before December 10th, 2021. Meta-analysis was performed and Cohen's Q test for heterogenous effects was used to determine whether random or fixed-effects models were appropriate. RESULTS: Fifteen studies investigating gender distribution of authorship met inclusion, which included a total of 136,627 pooled studies. The meta-analysis demonstrated the meta-proportion of first authorship for women to be 20.6% (95% CI: 13.9, 28.2), the meta-proportion of senior authorship for women to be 11.9% (95% CI: 6.6, 18.5), and the meta-proportion of overall authorship for women to be 23% (95% CI: 16.2, 30.7). In addition, the proportion of senior authorship for women was found to be significantly lower than the proportion of overall authorship for women (11.9% versus 23.0%, P = .0106). CONCLUSION: There is a significantly smaller proportion of women who are first, senior, and overall authors in surgical literature compared to their colleagues who are men. Sustainable and effective solutions aimed at improving the representation of women surgeons in surgical research and research leadership are necessary.