Citations

ABSTRACT Background The optimal timing for basal insulin initiation in diabetic ketoacidosis (DKA) remains unclear. British guidelines endorse early basal insulin (EBI), while the American Diabetes Association emphasises overlap duration with intravenous insulin, without mention of timing. This meta‐analysis evaluates whether EBI administration of basal insulin improves clinical outcomes in adults with DKA. Methods A systematic review and meta‐analysis were performed according to the PRISMA guidelines. Databases searched included MEDLINE, Embase, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials through December 11, 2024. Inclusion criteria included articles in the English‐language randomised controlled trials (RCTs) or observational studies evaluating EBI in adult DKA patients. Non‐human studies, conference abstracts, and case reports were excluded. The primary outcome for this study was hospital length of stay (LOS). Additional outcomes included intensive care unit (ICU) LOS, time to DKA resolution, hypoglycemia, and rebound hyperglycemia between EBI and usual care. Risk of bias was assessed using the Cochrane and Newcastle‐Ottawa tools. Grading of Recommendations Assessment, Development, and Evaluation was performed to evaluate the quality of evidence. Results From 1214 identified studies, eight (4 RCTs, 4 observational) met inclusion criteria for a total of 247 patients in the EBI group and 552 patients in the control group. No significant difference in hospital LOS was found (mean difference −11.17 h; 95% CI: −29.91 to 7.56). ICU LOS, time to DKA resolution, incidence of hypoglycemia, and rebound hyperglycemia also did not demonstrate any significant differences between groups. Significant heterogeneity existed across studies for most outcomes. All studies had a high risk of bias, and the quality of evidence was very low. Conclusion EBI did not result in significant differences in hospital LOS, ICU LOS, or time to DKA resolution; however, there were no increased adverse events with EBI. Current studies of early EBI have significant limitations. Future research should focus on developing high‐quality RCTs.

Abstract Background: Understanding of the diagnosis and treatment of adults with community-acquired pneumonia (CAP) has evolved thanks to new evidence, experience, and emerging technologies. This document updates evidence-based clinical practice guidelines on four key questions for the diagnosis and management of adult patients with CAP. Methods: A multidisciplinary panel integrated systematic reviews of comparative evidence with other relevant research and clinical experience, then applied Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology to produce recommendations using the Evidence to Decision Framework. Results: The panel formulated clinical recommendations that address questions related to CAP, including lung ultrasound for diagnosis, empiric antibacterial therapy if a test for a respiratory virus is positive, antibiotic duration, and the use of systemic corticosteroids. Conclusions: The panel formulated and provided the rationale for recommendations on selected diagnostic and treatment strategies for adult patients with CAP.

3569 Background: Immune checkpoint inhibitors (ICIs) are a standard treatment for gastrointestinal (GI) cancers with mismatch repair deficiency (dMMR) or microsatellite instability (MSI). However, around 50% of patients develop resistance to ICIs, during treatment or after discontinuation. In these patients, the efficacy of reuse an ICI in patients progressing during a previous ICI (rechallenge), or in patients who progressed after discontinuation (reintroduction), remains unknown. The INFLATE study evaluates the efficacy of ICI reuse in patients who progressed on or after discontinuing ICI. Methods: This is a multicenter international retrospective study from the IMMUNODIG cohort, including patients from 34 centers in France, the United States, Italy, Belgium and Spain. All patients received ICI for dMMR/MSI GI cancer. We analyzed patients who had progressed following initial ICI (ICI-1) and subsequently received a rechallenge or a reintroduction with ICI (ICI-2), either monotherapy (mono-ICI) or biotherapy (bi-ICI). Results: A total of 77 patients were included, receiving bi-ICI (N = 34) or mono-ICI (N = 43) during ICI-2. The majority (76%) had a metastatic colorectal cancer. The reason for discontinuing ICI-1 was disease progression in 53% of cases, end of treatment in 15%, toxicity in 5% and other reasons in 26%. Patients who discontinued ICI-1 due to progression received MONO-ICI-2 in 29% of cases and BI-ICI-2 in 71%, whereas those who stopped for other reasons received MONO-ICI-2 in 86% and BI-ICI-2 in 14% of cases. Efficacy results are shown in Table 1. The ORR and DCR were 26% and 79% with MONO-ICI-2, and 16% and 71% with BI-ICI-2. Among patients who discontinued ICI-1 due to progression, BI-ICI-2 (N = 29) achieved an ORR and DCR of 8% and 65%, with a median PFS of 5.5 months (95%CI 4.07-10.4). These outcomes were 17%, 67%, and 3.7 months (95%CI 2.37-NA), respectively, with MONO-ICI-2 (N = 12). For patients who discontinued ICI-1 for reasons other than progression, BI-ICI-2 (N = 5) achieved an ORR and DCR of 60% and 100%, with a median PFS not reached (95%CI 11.5-NR), while MONO-ICI-2 (N = 31) achieved 29%, 82%, and 14.2 months (95%CI 11.2–NR), respectively. Conclusions: This is the first multicenter real-world study evaluating ICI reuse in dMMR/MSI GI cancers. In patients who discontinued ICI for reasons other than progression, reintroduction of ICI therapy upon progression achieves tumor control in 85% of cases. In cases of progression on mono-ICI, Bi-ICI re-challenge achieve tumor control in two-thirds of cases and might be to consider in some patients. ORR % DCR % PFS median (95%CI) OS median (95%CI) Overall N=77 21 76 7.65 months(5.5–11.5) 27.6 months(22.2–55.7) Discontinued ICI-1 due to Progression N=41 11 68 5.03 months(3.7–8.05) 26.7 months(21.1–NR) Discontinued ICI-1 for Other Reasons N=36 33 85 14.22 months(11.24–NR) 27.6 months(22.2–NR)

Therapy dogs have been increasingly incorporated into a variety of medical treatment programs to improve patients’ treatment outcomes and wellbeing. However, research investigating the stress level of therapy dogs in this setting is limited. This is the first randomized–controlled and prospective study that investigated the wellbeing of therapy dogs in an inpatient stroke rehabilitation program. In this study, 14 therapy dog–handler pairs were embedded in an inpatient stroke rehabilitation program to provide animal-assisted treatment (AAT). These therapy dog–handler pairs actively participated in stroke rehabilitation by walking with the patient, playing fetch with the patient, and being petted/brushed by the patient, amongst various other AAT activities. To measure canine stress responses during the rehabilitation sessions, salivary cortisol and oxytocin concentrations, heart rate and heart rate variability, tympanic membrane temperature, and a behavioral evaluation were recorded before and after interactions with the patient. The results demonstrated that therapy dogs had significantly decreased heart rate and increased heart rate variability after the AAT session. Right tympanic temperature significantly increased after the session, but there was no significant difference in terms of salivary cortisol or oxytocin levels, nor in stress-related behavioral evaluations after the AAT session. Taken together, the results suggest that incorporating AAT into an inpatient stroke rehabilitation program did not induce stress in the therapy dogs, and that the therapy dogs may have been more relaxed after the session.

OBJECTIVES: To provide guidance on the reporting of norepinephrine formulation labeling, reporting in publications, and use in clinical practice. DESIGN: Review and task force position statements with necessary guidance. SETTING: A series of group conference calls were conducted from August 2023 to October 2023, along with a review of the available evidence and scope of the problem. SUBJECTS: A task force of multinational and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. INTERVENTIONS: The implications of a variation in norepinephrine labeled as conjugated salt (i.e., bitartrate or tartrate) or base drug in terms of effective concentration of norepinephrine were examined, and guidance was provided. MEASUREMENTS AND MAIN RESULTS: There were significant implications for clinical care, dose calculations for enrollment in clinical trials, and results of datasets reporting maximal norepinephrine equivalents. These differences were especially important in the setting of collaborative efforts across countries with reported differences. CONCLUSIONS: A joint task force position statement was created outlining the scope of norepinephrine-dose formulation variations, and implications for research, patient safety, and clinical care. The task force advocated for a uniform norepinephrine-base formulation for global use, and offered advice aimed at appropriate stakeholders.

Abstract Background Biomarkers for predicting the development of Ulcerative Colitis (UC) and disease-related complications are lacking. Anti-integrin αvβ6 IgG autoantibodies (anti-αvβ6) have been recently described in patients diagnosed with UC. Here, we sought to determine if anti-αvβ6 autoantibodies predate UC development and to study associations between anti-αvβ6 and disease outcomes in newly diagnosed UC patients. Methods In a unique pre-clinical IBD cohort from the PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects (PREDICTS), anti-αvβ6 were measured in longitudinal pre-diagnosis serum samples from 82 subjects who later developed UC as well as in 82 matched subjects that did not develop IBD (HC). Sample A was at the time of UC diagnosis, Sample B was at a median of 2 years before Sample A, Sample C was at a median of 4 years before Sample A and Sample D was at a median of 10 years before Sample A. In a distinct, external validation cohort (the Crohn’s and Colitis Canada Genetics Environment Microbial (GEM) Project), we tested samples from 12 subjects who later developed UC and compared those with 49 matched subjects who remained asymptomatic. Further, anti-αvβ6 were measured in 2 incident IBD cohorts (COMPASS, n=55 and OSCCAR, n=104 UC subjects) and associations between anti-αvβ6 and adverse UC-outcomes were defined using Cox proportional-hazards model. Results Anti-αvβ6 were significantly higher in the PREDICTS cohort among individuals who developed UC compared to HC up to 10 years prior to diagnosis (Figure 1A). The anti-αvβ6 seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 timepoints. Additionally, the predictive performance of anti-αvβ6 autoantibodies as assessed via area under the receiver operator curves (AUROC) with 10-fold cross validation was at least 0.8 up to 10 years before diagnosis (Figure 1B). Elevated levels of anti-αvβ6 in pre-clinical UC samples were further validated in the GEM cohort (Figure 1C). Finally, high anti-αvβ6 were associated with a composite of adverse UC-outcomes including hospitalization, disease extension, colectomy, systemic steroid use and/or escalation to biologic therapy in both incident cohorts (Figure 1D). Conclusion Anti-integrin αvβ6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

OBJECTIVES: To summarize the most impactful articles relevant to the pharmacotherapy of critically ill adult patients published in 2021. DATA SOURCE: PubMed/MEDLINE. STUDY SELECTION: Randomized controlled trials, prospective studies, or systematic review/meta-analyses of adult critical care patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2021, and December 31, 2021. DATA EXTRACTION: Candidate articles were organized by clinical domain based on the emerging themes from all studies. A modified Delphi process was applied to obtain consensus on the most impactful publication within each clinical domain based on overall contribution to scientific knowledge and novelty to the literature. DATA SYNTHESIS: The search revealed 830 articles, of which 766 were excluded leaving 64 candidate articles for the Delphi process. These 64 articles were organized by clinical domain including: emergency/neurology, cardiopulmonary, nephrology/fluids, infectious diseases, metabolic, immunomodulation, and nutrition/gastroenterology. Each domain required the a priori defined three Delphi rounds. The resultant most impactful articles from each domain included five randomized controlled trials and two systematic review/meta-analyses. Topics studied included sedation during mechanical ventilation, anticoagulation in COVID-19, extended infusion beta-lactams, interleukin-6 antagonists in COVID-19, balanced crystalloid resuscitation, vitamin C/thiamine/hydrocortisone in sepsis, and promotility agents during enteral feeding. CONCLUSIONS: This synoptic review provides a summary and perspective of the most impactful articles relevant to the pharmacotherapy of critically ill adults published in 2021.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.