Rapid uptake of adjunctive corticosteroids for critically ill adults with septic shock following publication of ADRENAL trial. A multicenter, retrospective analysis of prescribing practices in Queensland Intensive Care Units.

BACKGROUND: Septic shock is common and associated with significant morbidity and mortality. The ADRENAL trial examined the use of hydrocortisone in patients with septic shock, demonstrating no difference in patient-centred outcomes but a decrease in the time to shock resolution. The change in clinical practice related to the publication of the ADRENAL trial is currently unknown. METHODS: A retrospective cohort study examining the use of hydrocortisone in patients with septic shock was conducted in 12 intensive care units (ICUs). A segmented linear regression was performed to identify a stepwise change in hydrocortisone administration and 90-day mortality associated with the publication of the ADRENAL trial. RESULTS: We included 4,198 patients with a mean age of 58 years (standard deviation, SD17), and the median noradrenaline equivalent score (NEE) was 0.07 µg/kg/min (IQR 0.02 - 0.17). Segmented regression analysis for hydrocortisone administration identified two breakpoints, 3 months before and 6 months after publication, leading to three periods: Pre-publication, Transition and Post-publication. Compared to the pre-publication period, the Transition and Post-publication cohorts had a higher proportion of hydrocortisone administration (28% vs. 34% vs. 43%; p < 0.0001). Furthermore, after adjustment for temporal change, the transition period had a significant change in the slope of the proportion of patients receiving hydrocortisone (-0.1% per month vs. +1.4% per month; p = 0.026), whereas this was not statistically significant during the post-publication period (+0.1% per month, p = 0.66). After adjusting for confounders, the Transition and Post-publication periods were independently associated with an increase in hydrocortisone (OR 1.4, 95% CI 1.14 - 1.77; p = 0.0015 and OR 2.03; 95% CI 1.74 - 2.36; p < 0.001, respectively). Furthermore, after adjusting for confounders, when compared to the Pre-transition period, the use of hydrocortisone was associated with a statistically significant decrease in 90-day mortality (14% vs. 24% absolute difference, aHR for hydrocortisone effect -0.81; 95% CI 0.65 - 0.99; p = 0.044). CONCLUSION: Publication of the ADRENAL trial changed clinical practice in Queensland ICUs with increased prescription of hydrocortisone for patients with septic shock with an associated reduction in mortality.

Assessing the effectiveness of greater occipital nerve block in chronic migraine: a systematic review and meta-analysis.

BACKGROUND & AIMS: Chronic migraine poses a global health burden, particularly affecting young women, and has substantial societal implications. This study aimed to assess the efficacy of Greater Occipital Nerve Block (GONB) in individuals with chronic migraine, focusing on the impact of local anesthetics compared with placebo. METHODS: A meta-analysis and systematic review were conducted following the PRISMA principles and Cochrane Collaboration methods. Eligible studies included case-control, cohort, and randomized control trials in adults with chronic migraine, adhering to the International Classification of Headache Disorders, third edition (ICHD3). Primary efficacy outcomes included headache frequency, duration, and intensity along with safety assessments. RESULTS: Literature searches across multiple databases yielded eight studies for qualitative analysis, with five included in the final quantitative analysis. A remarkable reduction in headache intensity and frequency during the first and second months of treatment with GONB using local anesthetics compared to placebo has been reported. The incidence of adverse events did not differ significantly between the intervention and placebo groups. CONCLUSION: The analysis emphasized the safety and efficacy of GONB, albeit with a cautious interpretation due to the limited number of studies and relatively small sample size. This study advocates for further research exploring various drugs, frequencies, and treatment plans to enhance the robustness and applicability of GONB for chronic migraine management.

Associations between Late Lactate Clearance and Clinical Outcomes in Adults with Hyperlactataemia in the Setting of Diabetic Ketoacidosis.

Objective: This study aimed to determine the associations between lactate clearance in hyperlactataemic patients with diabetic ketoacidosis (DKA) and intensive care unit (ICU), hospital length of stay (LOS), and case-fatality. Methods: A retrospective, multicentre, cohort study of adult patients admitted to ICU with hyperlactataemia and a primary diagnosis of DKA from twelve sites in Queensland, Australia was conducted utilising pre-existing datasets that were linked for research purposes. The patients were divided into early and late lactate clearance groups; the early lactate clearance group included patients whose lactate returned to <2.0 mmol/L within 12 h, and the remainder were classified as late lactate clearance group. Results: The final dataset included 511 patients, 427 in the early lactate clearance group and 84 in the late lactate clearance group. Late lactate clearance was associated with increasing ICU LOS (ß = +15.82, 95% CI +0.05 to +31.59, p < 0.049), increasing hospital LOS (ß = +7.24, 95% CI +0.11 to 14.37, p = 0.048) and increasing Acute Physiology and Chronic Health Evaluation(APACHE) III score (ICU LOS outcome variable ß = +1.05, 95% CI +0.88 to +1.22, p < 0.001; hospital LOS outcome variable ß = +3.40, 95% CI +2.22 to 4.57, p < 0.001). Hospital case-fatality was not significantly different (2.2% in the early clearance group vs. 1.7% in the late clearance group, p = 0.496). Conclusions: In hyperlactataemic patients with DKA, late lactate clearance was associated with a statistically significant increase in both ICU and hospital LOS, though the clinical significance in both is minor.

Comparison of polymeric clip and endoloop in laparoscopic appendectomy: A systematic review and meta-analysis.

BACKGROUND: Appendicitis is a common surgical emergency with diverse clinical presentations, making its diagnosis challenging. Laparoscopic appendectomy has become the standard treatment, with various methods for appendiceal stump closure, including polymeric clips and endoloops. This study aims to compare the efficacy and safety of polymeric clips compared with endoloops in laparoscopic appendectomy. METHODS: A systematic review and meta-analysis were conducted followingPreferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Medline, Scopus, and Embase were searched for studies up to March 25, 2024. RESULTS: In total, 13 studies, including 6 randomized controlled trials, were analyzed. Polymeric clipping demonstrated significantly shorter surgical time compared with the endoloop (standardized mean difference 0.37, 95% confidence interval 0.22-0.53, P < .00001), with no difference in hospital stay or overall complications. However, the endoloop was associated with a greater incidence of intra-abdominal abscess (risk ratio 3.53, 95% confidence interval 1.56-8.00, P = .003). Other outcomes, including time from instrument application to appendiceal cutting, ileus, and surgical-site infection, showed no significant differences between the 2 techniques. CONCLUSION: Polymeric clipping appears to be superior to endoloop in terms of shorter surgical time and lower risk of intra-abdominal abscess formation in laparoscopic appendectomy for uncomplicated appendicitis. However, both techniques have similar outcomes regarding hospital stay and overall complications. Further research addressing study limitations and exploring patient-centered outcomes is warranted to guide clinical practice.

Unraveling the role of cytochrome P450 enzymes in oleanane triterpenoid biosynthesis in arjuna tree.

Triterpenoids (C30-isoprenoids) represent a major group of natural products with various physiological functions in plants. Triterpenoids and their derivatives have medicinal uses owing to diverse bioactivities. Arjuna (Terminalia arjuna) tree bark accumulates highly oxygenated ß-amyrin-derived oleanane triterpenoids (e.g., arjunic acid, arjungenin, and arjunolic acid) with cardioprotective roles. However, biosynthetic routes and enzymes remain poorly understood. We mined the arjuna transcriptome and conducted cytochrome P450 monooxygenase (P450) assays using Saccharomyces cerevisiae and Nicotiana benthamiana to identify six P450s and two P450 reductases for oxidative modifications of oleanane triterpenoids. P450 assays using oleananes revealed a greater substrate promiscuity of C-2α and C-23 hydroxylases/oxidases than C-28 oxidases. CYP716A233 and CYP716A432 catalyzed ß-amyrin/erythrodiol C-28 oxidation to produce oleanolic acid. C-2α hydroxylases (CYP716C88 and CYP716C89) converted oleanolic acid and hederagenin to maslinic acid and arjunolic acid. CYP716C89 also hydroxylated erythrodiol and oleanolic aldehyde. However, CYP714E107a and CYP714E107b catalyzed oleanolic acid/maslinic acid/arjunic acid, C-23 hydroxylation to form hederagenin, arjunolic acid and arjungenin, and hederagenin C-23 oxidation to produce gypsogenic acid, but at a lower rate than oleanolic acid C-23 hydroxylation. Overall, P450 substrate selectivity suggested that C-28 oxidation is the first P450-catalyzed oxidative modification in the arjuna triterpenoid pathway. However, the pathway might branch thereafter through C-2α/C-23 hydroxylation of oleanolic acid. Taken together, these results provided new insights into substrate range of P450s and unraveled biosynthetic routes of triterpenoids in arjuna. Moreover, complete elucidation and reconstruction of arjunolic acid pathway in S. cerevisiae and N. benthamiana suggested the utility of arjuna P450s in heterologous production of cardioprotective compounds.

Evaluating the Effectiveness and Safety of Evinacumab in Treating Hypercholesterolemia and Hypertriglyceridemia: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Cardiovascular disease remains a significant global health concern, with high low-density lipoprotein cholesterol (LDL-C) levels contributing to an increased risk. Familial hypercholesterolemia (FH) further complicates its management, necessitating additional lipid-lowering therapies. Evinacumab, an angiopoietin-like protein 3 monoclonal antibody, has emerged as a potential treatment, particularly for patients with FH, by effectively reducing LDL-C and triglyceride levels. This meta-analysis aimed to evaluate the efficacy and safety of evinacumab across diverse patient populations. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, relevant randomized controlled trials (RCTs) were systematically retrieved from multiple databases until November 24, 2023. The inclusion criteria were studies comparing evinacumab (at doses of 5 and 15 mg) to placebo, with outcomes focusing on lipid levels and adverse events. Standardized protocols were employed for data extraction and quality assessment, and statistical analysis was conducted using RevMan software. RESULTS: Four RCTs, involving 270 patients, were included in the analysis. The analysis revealed significant reductions in lipid markers, particularly with the 15-mg dose of evinacumab, including triacylglycerols (standard mean difference [SMD] = -6.09, 95% confidence interval [CI] - 14.53 to 2.36, P = 0.16), total cholesterol (SMD = - 6.20, 95% CI - 11.53 to - 0.88, P = 0.02), high-density lipoprotein cholesterol (SMD = - 0.79, 95% CI - 1.27 to - 0.31, P = 0.001), LDL-C (SMD = - 4.58, 95% CI - 9.13 to - 0.03, P = 0.05), apolipoprotein (Apo) B (SMD = - 4.01, 95% CI - 7.53 to - 0.46, P = 0.03), and Apo C3 (SMD = - 7.67, 95% CI - 12.94 to - 2.41, P = 0.004). Adverse event analysis revealed no significant association, indicating good tolerability. CONCLUSION: High-dose evinacumab (15 mg) consistently demonstrated efficacy in reducing cholesterol and other lipid markers, with favorable tolerability. Further research is warranted to comprehensively assess its safety and clinical effectiveness, emphasizing the need for additional data to support its use in managing cardiovascular disease.