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Pancreatic cancer is characterized by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered KRAS gene dosage drives progression and metastasis in pancreatic cancer. While the role of oncogenic KRAS mutations is well characterized, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrated that wild-type KRAS restrains the oncogenic impact of mutant KRAS and dramatically impacts both KRAS-mediated tumorigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increased oncogenic KRAS signaling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, lack of wild-type KRAS led to accelerated initiation but delayed tumor progression. These tumors had altered stroma and an enrichment of immunogenic gene signatures. Importantly, loss of wild-type Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of wild-type KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of wild-type KRAS in both tumor progression and therapeutic response in pancreatic cancer.

Rationale: For critically ill adults receiving invasive mechanical ventilation, the ventilator mode determines how breaths are delivered. Whether the choice of ventilator mode affects outcomes for critically ill patients is unknown. To compare the effects of three common ventilator modes (volume control, pressure control, and adaptive pressure control) on death and duration of mechanical ventilation., Methods: We conducted a pragmatic, cluster-randomized, crossover trial among adults receiving invasive mechanical ventilation in a medical ICU between November 1, 2022 and July 31, 2023. Each month, patients in the participating unit were assigned to receive volume control, pressure control, or adaptive pressure control during continuous mandatory ventilation. The primary outcome was ventilator-free days through 28 days., Results: Among 566 patients included in the primary analysis, the median number of ventilator-free days was 23 [IQR, 0-26] in the volume control group, 22 [0-26] in the pressure control group, and 24 [0-26] in the adaptive pressure control group (P=0.60). The median tidal volume was similar in the three groups, but the percentage of breaths larger than 8mL/kg of predicted body weight differed between volume control (median, 4.0%; IQR, 0.0-14.1), pressure control (10.6%; 0.0-31.5), and adaptive pressure control (4.7%; 0.0-19.2). Incidences of hypoxemia, acidemia, and barotrauma were similar in the three groups., Conclusions: Among critically ill adults receiving invasive mechanical ventilation, the use of volume control, pressure control, or adaptive pressure control did not affect the number of ventilator-free days, however, confidence intervals included differences that may be clinically meaningful.

Despite showing the greatest primate diversity on the planet, genomic studies on Amazonian primates show very little representation in the literature. With 48 geolocalized high coverage whole genomes from wild uakari monkeys, we present the first population-level study on platyrrhines using whole genome data. In a very restricted range of the Amazon rainforest, eight uakari species (Cacajao genus) have been described and categorized into the bald and black uakari groups, based on phenotypic and ecological differences. Despite a slight habitat overlap, we show that posterior to their split 0.92 Mya, bald and black uakaris have remained independent, without gene flow. Nowadays, these two groups present distinct genetic diversity and group-specific variation linked to pathogens. We propose differing hydrology patterns and effectiveness of geographic barriers have modulated the intra-group connectivity and structure of bald and black uakari populations. With this work we have explored the effects of the Amazon rainforest's dynamism on wild primates' genetics and increased the representation of platyrrhine genomes, thus opening the door to future research on the complexity and diversity of primate genomics., (© 2024. The Author(s).)

Context: Acromegaly, characterized by excessive growth hormone (GH) and insulin-like growth factor-1 (IGF-1), impacts quality of life (QoL) and mortality. Standard of care (SoC; octreotide long-acting repeatable or lanreotide autogel) treatment typically requires healthcare provider administration. CAM2029, a novel subcutaneous octreotide depot with increased bioavailability using FluidCrystal technology, enables self-administration and room-temperature storage., Objective: Assess superiority of CAM2029 versus placebo for biochemical control in patients with controlled acromegaly., Design: 24-week, multinational, randomized, double-blind, phase 3 trial (NCT04076462)., Setting: 45 sites; ten countries., Patients: 72 patients on SoC with biochemical control at screening (IGF-1 ≤upper limit of normal [ULN]; mean GH <2.5 μg/L)., Interventions: Patients were randomized 2:1 to once-monthly CAM2029 (n=48) or placebo (n=24)., Main Outcome Measures: Primary endpoint was proportion of patients with IGF-1 ≤ULN (Week 22/24 mean), with dose-reduced patients classified as non-responders; first key secondary endpoint was the same, including dose-reduced responders. Second key secondary endpoint was proportion of patients with IGF-1 ≤ULN (Week 22/24) and mean GH <2.5 μg/L (Week 24)., Results: At Week 22/24 (intention-to-treat analysis), CAM2029-treated patients demonstrated superior response rates versus placebo for IGF-1 (72.2% versus 37.5%; risk difference: 34.6, 95% confidence interval: 11.3, 57.9; p=0.0018), and combined IGF-1/GH (70.0% versus 37.5%; p=0.0035). CAM2029-treated patients had well-controlled symptoms, improved QoL and treatment satisfaction versus placebo and baseline. CAM2029 was well tolerated; safety was consistent with SoC., Conclusions: CAM2029 provides a convenient and effective treatment option for acromegaly, with superior biochemical control versus placebo. Symptom control, QoL and satisfaction were improved from baseline SoC., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Osteopathic manipulative medicine (OMM) is a unique skill set consisting of physical manipulations that treat the neuromusculoskeletal system. Although OMM can improve patient outcomes such as functionality and pain, as well as increase physician reimbursement, its use is declining. Barriers to its use include a lack of proficiency, support, reimbursement, and time. Knowledge gaps remain as to how OMM training during graduate medical education (GME) affects OMM use., Objectives: This study describes relationships between OMM exposure during GME and the use of OMM in practice., Methods: An online survey of physicians in a variety of medical fields during late 2022 assessed the impact of OMM education during postgraduate training on its use in clinical practice. Survey data were analyzed to compare training characteristics and OMM use via chi-square tests and binary logistic regression., Results: A total of 299 surveys were completed. Respondents who received formal OMM education during residency were more likely (59.8 %) to utilize OMM in medical practice than those who practiced OMM informally (37.8 %, p<0.001) and those who had no OMM exposure during residency (10.3 %, p<0.001). Respondents who trained with more osteopathic attendings (p<0.001) and co-residents (p=0.012) were also more likely to utilize OMM. Those who completed residencies that were accredited by the Accreditation Council for Graduate Medical Education (ACGME) with an Osteopathic recognition track, by the American Osteopathic Association (AOA), and were dually-accredited (ACGME/AOA), were all more likely to utilize OMM (60 %, 56 %, and 53 %, respectively) than those who completed residencies with ACGME accreditation alone (22 %, p<0.01)., Conclusions: Although OMM can improve patient outcomes, it is underutilized by Doctors of Osteopathic Medicine (DOs) in practice. Lack of training after medical school has been identified as a contributing factor to its disuse. The results of our study illustrate that there is a positive association between OMM education during postgraduate training and OMM use in clinical practice., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Background: Circulating dietary biomarkers are not direct proxies for intake, as the biomarkers reflect not only food and supplement consumption but also nutrient absorption, metabolism, and tissue distribution. Therefore, along with nutrient intake, several other upstream factors can impact dietary biomarker concentrations, including demographic, medical history, and genetic factors., Objective: The aim of this study was to explore the dietary and nondietary determinants of circulating levels of vitamins A, C, D, and E among children aged 6 months to 4 years., Methods: Plasma retinol, beta-carotene, ascorbic acid, 25(OH)D, alpha-tocopherol, and gamma-tocopherol were measured in 2887 samples from 1490 children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Dietary intake was assessed with 3-day food records. Associations of genetic and environmental factors with biomarker concentrations were examined using multivariable linear regression models with random intercepts., Results: All biomarkers except retinol were positively associated with intake of the same nutrient. Inverse associations were identified between recent gastrointestinal infection and β-carotene, ascorbic acid, and α-tocopherol, while recent respiratory infection was associated inversely with plasma retinol. Several genetic determinants of biomarker status were identified, validating previously reported findings. For some genetic and environmental exposures, we found evidence of statistical interaction with same-nutrient intake, indicating that the association between intake and biomarker concentration is dependent upon the level or status of these other exposures. For example, the association between β-carotene intake and concentration is weaker among children with a recent respiratory infection., Conclusions: Our findings suggest that non-dietary exposures including childhood infections can alter micronutrient metabolism. This summary of micronutrient determinants will facilitate improved design of future analyses exploring the role of diet in childhood chronic disease etiology through a better understanding of relevant potential confounders and mediators of the diet-outcome relationships., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

The evolution of independent lineages along replicated environmental transitions frequently results in convergent adaptation, yet the degree to which convergence is present across multiple levels of biological organization is often unclear. Additionally, inherent biases associated with shared ancestry and variation in selective regimes across geographic replicates often pose challenges for confidently identifying patterns of convergence. We investigated a system in which three species of poeciliid fishes sympatrically occur in a toxic spring rich in hydrogen sulfide (H 2 S) and an adjacent nonsulfidic stream to examine patterns of adaptive evolution across levels of biological organization. We found convergence in morphological and physiological traits and genome-wide patterns of gene expression among all three species. In addition, there were shared signatures of selection on genes encoding H 2 S toxicity targets in the mitochondrial genomes of each species. However, analyses of nuclear genomes revealed neither evidence for substantial genomic islands of divergence around genes involved in H 2 S toxicity and detoxification nor substantial congruence of strongly differentiated regions across population pairs. These non-convergent, heterogeneous patterns of genomic divergence may indicate that sulfide tolerance is highly polygenic, with shared allele frequency shifts present at many loci with small effects along the genome. Alternatively, H 2 S tolerance may involve substantial genetic redundancy, with non-convergent, lineage-specific variation at multiple loci along the genome underpinning similar changes in phenotypes and gene expression. Overall, we demonstrate variability in the extent of convergence across organizational levels and highlight the challenges of linking patterns of convergence across scales., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Penicillin allergy delabeling may benefit antimicrobial stewardship (AS). Cost of initial penicillin treatments following risk-stratified inpatient delabeling were compared to two hypothetical treatment regimens if delabeling had not occurred: (1) AS-guided and (2) Common Treatment. Penicillin allergy delabeling improved antimicrobial spectrum index, was cost-neutral, and averted unnecessary penicillin desensitizations., Competing Interests: MS is an employee of Veterans Health Administration; however, the views expressed herein are hers and do not necessarily represent those of the US Government or Veterans Health Administration. All other authors report no conflicts of interest relevant to this work., (© The Author(s) 2024.)

Montmorency cherry (MC) can improve endurance performance, but optimal pre-exercise timing of supplementation and influence of training status on efficacy are unknown. We investigated the effect of MC concentrate ingestion between 30- and 150-min pre-exercise in trained and recreational cyclists on 15-km time trial (TT) performance and exercise economy. Twenty participants (10 recreationally active, RA; 10 trained, T) completed 10 min of steady-state exercise (SSE) at 40%Δ (SSE) and a TT on four separate occasions following an unsupplemented (US), 30-, 90- or 150-min pre-exercise Montmorency cherry concentrate (MCC) supplementation conditions (MCC 30/90/150min ). Venous and capillary blood samples were taken at regular intervals pre- and post-SSE and TT. MCC significantly improved TT performance, but not exercise economy. The greatest improvement in performance occurred following MCC 90min compared to US (US 1603.1 ± 248 s vs. MCC 90min 1554.8 ± 226.7 s, 2.83% performance improvement). Performance was significantly enhanced for trained (US 1496.6 ± 173.1 s vs. MCC 90min 1466.8 ± 157.6 s) but not recreationally active participants. Capillary [lactate] and heart rate were significantly greater during the TT for the 90-min dose timing (p < 0.05). In the MCC 30min and MCC 90min conditions, plasma ferulic (US 8.71 ± 3.22 nmol. L -1 vs. MCC 30min 15.80 ± 8.69 nmol. L -1 , MCC 90min 12.65 ± 4.84 nmol. L -1 ) and vanillic acid (US 25.14 ± 10.91 nmol.L -1 vs. MCC 30min 153.07 ± 85.91 nmol. L -1 , MCC 90min 164.58 ± 59.06 nmol. L -1 ) were significantly higher pre-exercise than in US and MCC 150min conditions (p < 0.05). There was no significant change in muscle oxygenation status or plasma nitrite/nitrate concentration. MCC supplementation enhanced endurance exercise performance optimally when consumed ∼90 min pre-exercise producing maximal plasma phenolic metabolites during exercise. The ergogenic effect was greater for trained participants., (© 2024 The Author(s). European Journal of Sport Science published by Wiley‐VCH GmbH on behalf of European College of Sport Science.)

Objectives: To quantify the frequency and patterns of clinicians' use of choice frames when discussing preference-sensitive care with surrogate decision-makers in the ICU., Design: Secondary sequential content analysis., Setting: One hundred one audio-recorded and transcribed conferences between surrogates and clinicians of incapacitated, critically ill adults from a prospective, multicenter cohort study., Subjects: Surrogate decision-makers and clinicians., Interventions: None., Measurements and Main Results: Four coders identified preference-sensitive decision episodes addressed in the meetings, including topics such as mechanical ventilation, renal replacement, and overall goals of care. Prior critical care literature provided specific topics identified as preference-sensitive specific to the critical care context. Coders then examined each decision episode for the types of choice frames used by clinicians. The choice frames were selected a priori based on decision science literature. In total, there were 202 decision episodes across the 101 transcripts, with 20.3% of the decision episodes discussing mechanical ventilation, 19.3% overall goals of care, 14.4% renal replacement therapy, 14.4% post-discharge care (i.e., discharge location such as a skilled nursing facility), and the remaining 32.1% other topics. Clinicians used default framing, in which an option is presented that will be carried out if another option is not actively chosen, more frequently than any other choice frame (127 or 62.9% of decision episodes). Clinicians presented a polar interrogative, or a "yes or no question" to accept or reject a specific care choice, in 43 (21.3%) decision episodes. Clinicians more frequently presented options emphasizing both potential losses and gains rather than either in isolation., Conclusions: Clinicians frequently use default framing and polar questions when discussing preference-sensitive choices with surrogate decision-makers, which are known to be powerful nudges. Future work should focus on designing interventions promoting the informed use of these and the other most common choice frames used by practicing clinicians., Competing Interests: Dr. Hart’s institution received funding from the National Institutes of Health (NIH); she received funding from the University of Pennsylvania, the U.S. Federal Government—Veterans Administration Medical Center, and St. Luke’s Bethlehem. Drs. Hart, Steingrub, and White received support for article research from the NIH. Dr. Summer received funding from the University of Pennsylvania, Penn Medicine, Project HOME, and Boston Healthcare for the Homeless. Dr. Ogunduyile disclosed government work. Dr. Lo received funding from Takeda Pharmaceuticals, Wolters Kluwer, Blue Cross Blue Shield, and Ropes and Gray; he disclosed that he is a member of the External Advisory Committee for Vivli. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Much research has adopted a deficits-based approach to chronic pain, neglecting the study of flourishing. Using a Q-methodological framework, this study sought to explore how individuals experience, understand and perceive flourishing in the context of young people living with chronic pain. Fifty-four individuals completed a Q-sorting task, indicating their level of agreement and disagreement with 52 statements. Q-analysis generated three factors that represented clear viewpoints of participants: 'Pain is not a barrier to flourishing', 'Adapting to a new life' and 'Adopting a positive perspective'. Factors expressed the viewpoints that flexibility is key to enjoying life despite chronic pain, while resilience, management of stressors, acceptance and problem-solving may be required to flourish with chronic pain. Participants' understanding of flourishing also focused on the appreciation and enjoyment of life and achievements. This study provides a useful contribution towards furthering our understanding of flourishing in young people living with chronic pain., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Co-morbid anxiety and depression (distress) in inflammatory bowel disease (IBD) results in poorer outcomes and increased healthcare burden. IBD services require scalable treatment pathways for distress to meet this need. This real-world longitudinal study evaluates the implementation of a new integrated care pathway for distress including: 1) routine mental health screening and 2) therapist-guided, digital CBT tailored to the challenges of living with IBD (compass with adaptations for IBD: COMPASS-IBD) in a UK National Health Service (NHS) large gastroenterology service (∼ 5000 patients)., Methods: We describe a mixed-methods, observational, real-world longitudinal study. Routine mental health screening in the IBD service will identify patients with distress (using pre-defined clinical cut-offs), who will be triaged to determine appropriate treatment pathways (including participation in the COMPASS-IBD study). Participants will receive COMPASS-IBD online for ∼12 weeks (including 6 × 30-min therapist sessions). Key implementation outcomes will assess reach and adoption of the new pathway using aggregate data on uptake of mental health screening, eligibility, and consent rates for COMPASS-IBD, and number of COMPASS-IBD sessions completed. Interviews with patients and healthcare providers will primarily assess acceptability of the new pathway. Potential effectiveness will be assessed using participant questionnaires at pre-intervention, 12-weeks (post-intervention), and 6-month follow-up. The primary effectiveness outcome will be pre-post changes in distress (PHQ-ADS scores). Quantitative data will be summarised using descriptive statistics and qualitative data analysed using reflexive thematic analysis., Conclusion: Study findings will inform treatment pathways for co-morbid distress in IBD, and highlight adaptations required to increase future scalability and effectiveness., Trial Registration Number: NCT05330299 (clinicaltrials.gov)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RMM reports personal fees from training in CBT for irritable bowel syndrome outside the submitted work. She received payment for consultancy to Mahana Therapeutics, has share options in Mahana therapeutics, and is a beneficiary of a licence agreement between Mahana therapeutics and King's College London. She has received reimbursement for travel and speaker fees from EABM, APS and BABCP conferences. All other authors report no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite wide endorsement of a biopsychosocial framework for pain, social aspects of pain remain rarely addressed in the context of pain prevention and management. In this review, we aim to 1) examine the broad scope of social determinants and consequences of pain and their interactions across multiple levels of organization, and 2) provide a framework synthesizing existing concepts and potential areas for future work on social aspects of pain, drawing upon socioecological, intersectional, and life course approaches. Integrating interdisciplinary theory and evidence, we outline pathways through which multilevel social factors and pain may affect each other over time. We also provide a brief summary of intrapersonal aspects of pain, which are thought to operate at the interface between individuals and the social context. Progressing from micro- to macrolevel factors, we illustrate how social determinants of pain can directly or indirectly contribute to pain experiences, expression, risk, prognosis, and impact across populations. We consider 1) at the interpersonal level, the roles of social comparison, social relatedness, social support, social exclusion, empathy, and interpersonal conflict; 2) at the group or community level, the roles of intimacy groups, task groups, social categories, and loose associations; and 3) at the societal level, the roles of political, economic, and cultural systems, as well as their policies and practices. We present examples of multilevel consequences of pain across these levels and discuss opportunities to reduce the burden and inequities of pain by expanding multilevel social approaches in pain research and practice. PERSPECTIVE: Despite wide endorsement of a biopsychosocial framework for pain, social aspects of pain are often unclearly defined, hindering their use in pain prevention, management, and research. We summarize the scope of social aspects of pain and provide a framework synthesizing existing concepts and potential areas for future work., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Professional organizations have emphasized the growing need for pharmacists to possess advanced research skills; however, there is a scarcity of training programs aimed at nurturing clinician-scientists. This report outlines 3 critical care-focused research programs, each offering a unique approach to training clinician-scientists., Summary: Limited resources and formalized programs are available to bridge the gap between the demand for and availability of skilled clinician-scientists. Several programs have stepped forward to share their experiences in establishing and executing training initiatives aimed at cultivating skilled clinician-scientists in the critical care practice space., Conclusion: Enhancing the development of clinician-scientists for clinical and translational research is necessary in the critical care clinical pharmacy community., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Despite its widespread prevalence, the cost of cubital tunnel syndrome (CuTS) in the United States to patients and insurers is not well understood. The purpose of this study was to quantify the direct payments associated with operative treatment of CuTS. We hypothesized that CuTS represents a substantial cost to the payer in facility fees, surgeon fees and other expenses., Methods: Utilizing the MarketScan database of insured patients (commercial and Medicaid), we identified a cohort of 41,777 patients aged 18-64 years with surgically treated CuTS from 2006 to 2018. We estimated the median 90-day payments from encounters associated with cubital tunnel release (CuTR) and/or ulnar nerve transposition surgery by summing all payments for claims within 90 days after the index surgery. Published estimates of the annual number of cubital tunnel surgeries were used to calculate the annual expenditure., Results: Of 41,777 patients, the median (interquartile range [IQR]) values of total direct payments were $5,522 [$3,426, $9,541]. With an estimated 94,645 cases/year, this leads to an annual payment of more than $522 million. Index facility payments (median[IQR] $2,555 [$1,359, $4,708] were the highest, followed by index provider payments ($1,691 [$1,328, $2,217]). The median index surgeon payment (median[IQR] $905 [$707, $1,184]) represented just over half of the provider payments. Post-operative care had a median [IQR] payment of $377 ($424, $1,987). Limitations of claims databases prevented assessment of other indirect costs associated with cubital tunnel surgery., Conclusions: Payments for the surgical treatment of CuTS from the index surgery to 90 days post-operatively have an estimated median of $5,522 per patient, totaling $52 million annually. Index facility fees are responsible for more than 46% of payments, while index payments to surgeons represent approximately 16%. Defining this data is critical to understanding one component of the economic impact of CuTS., Level of Evidence: Level IV., Competing Interests: Conflicts of Interest No benefits in any form have been received or will be received related directly to this article., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background: Care management programs for chronic lung disease attempt to reduce hospitalizations, yet have not reliably achieved this goal. A key limitation of many programs is that they target patients with characteristics associated with hospitalization risk, but do not specifically modify the mechanisms that lead to hospitalization., Research Question: What are the common mechanisms underlying known patient-level risk characteristics leading to hospitalizations for acute exacerbations of chronic lung disease?, Study Design and Methods: We conducted a qualitative study of patients admitted to the University of Pennsylvania Health System with acute exacerbations of chronic lung disease between January and September 2019. We interviewed patients, their family caregivers, and their inpatient and outpatient clinicians about experiences leading up to the hospitalization. We analyzed the interview transcripts using triangulation and abductive analytic methods., Results: We conducted 69 interviews focused on the admission of 22 patients with a median age of 66 years (interquartile range, 60-70 years), of whom 16 patients (73%) were female and 14 patients (64%) were Black. We interviewed 22 patients, 14 caregivers, 19 inpatient clinicians, and 14 outpatient clinicians. We triangulated the available interview data for each patient admission and identified the underlying mechanisms of how several known patient characteristics associated with risk actually led to hospitalization. These mechanisms included limited capacity for home management of acute symptom changes, barriers to accessing care, chronic functional limitations, and comorbid behavioral health disorders. Importantly, many of the clinical, social, and behavioral mechanisms underlying hospitalizations were present for months or years before the symptoms that prompted inpatient care., Interpretation: Care management programs should be built to target specific clinical, social, and behavioral mechanisms that directly lead to hospitalization. Upstream interventions that reduce hospitalization risk are possible given that many contributory mechanisms are present for months or years before the onset of acute exacerbations.

Background: Depression is common in people with chronic kidney disease, yet little is known about how depression is identified and managed as part of routine kidney care., Objectives: The primary objective was to survey all UK adult kidney centres to understand how depression is identified and managed. A secondary objective was to broadly describe the variability in psychosocial care., Design: Online survey., Methods: The survey comprised of three sections: (1) general kidney care, (2) psychological provision and (3) social work provision., Results: 48/68 (71%) of centres responded to the general survey with 20 and 13 responses from psychological and social work module respectively. Only 31.4% reported having both in centre psychological and social work practitioners. Three centres reported no access to psychosocial provision. Of the 25 centres who reported on pathways, 36.0% reported having internal pathways for the identification and management of depression. Within services with psychological provision, screening for depression varied across modality/group (e.g., 7.1% in mild/moderate chronic kidney disease vs. 62.5% in kidney donors). Cognitive Behavioural Therapy and Acceptance and Commitment Therapy were the most common interventions offered. Most psychosocial services were aware of the National Institute for Health and Care Excellence guidelines for managing depression in long-term conditions (n = 18, 94.7%) yet few fully utilised (n = 6, 33.3%). Limited workforce capacity was evident., Conclusions: There is considerable variability in approaches taken to identify and treat depression across UK kidney services, with few services having specific pathways designed to detect and manage depression. Workforce capacity remains a significant issue., (© 2024 The Authors. Journal of Renal Care published by John Wiley & Sons Ltd on behalf of European Dialysis & Transplant Nurses Association/European Renal Care Association.)

Importance: Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant disease in the US. Although it typically carries a good prognosis, a subset of CSCCs are highly aggressive, carrying regional and distant metastatic potential. Due to its high incidence, this aggressive subset is responsible for considerable mortality, with an overall annual mortality estimated to equal or even surpass melanoma. Despite this morbidity, CSCC is excluded from national cancer registries, making it difficult to study its epidemiology and outcomes. Therefore, the bulk of the CSCC literature is composed of single-center and multi-institutional retrospective cohort analyses. Given variations in reporting measures and analyses in these studies, interpretability between studies and the ability to pool results are limited., Objective: To define standardized reporting measures for retrospective CSCC studies., Findings: An expert panel was convened to determine standardized guidelines for recording and analyzing retrospective CSCC data. A total of 13 dermatologists and dermatologic surgeons with more than 5 years of posttraining experience and considerable experience with performing CSCC outcomes research were recruited to the panel. Consensus recommendations were achieved for CSCC retrospective study reporting measures, definitions, and analyses., Conclusions and Relevance: The recommendations in this report present the potential to standardize future CSCC retrospective studies. With such standardization, future work may have greater interstudy interpretability and allow for pooled analyses.

Adeno-associated virus (AAV) gene therapy for neurological disease has gained traction due to stunning advances in capsid evolution for CNS targeting. With AAV brain delivery now in focus, conventional improvements in viral expression vectors offer a complementary route for optimizing gene delivery. We previously introduced a novel AAV gene therapy to slow amyloid aggregation in the brain based on neuronal release of an Aβ sequence variant that inhibited fibrilization of wild-type Aβ. Here we explore three coding elements of the virally delivered DNA plasmid in an effort to maximize the production of therapeutic peptide in the brain. We demonstrate that simply replacing the Gaussia luciferase signal peptide with the mouse immunoglobulin heavy chain signal peptide increased release of variant Aβ by ∼5-fold. Sequence modifications within the expressed minigene further increased peptide release by promoting γ-secretase cleavage. Addition of a cytosolic fusion tag compatible with γ-secretase interaction allowed viral transduction to be tracked by immunostaining, independent from the variant Aβ peptide. Collectively these construct modifications increased neuronal production of therapeutic peptide by 10-fold upon intracranial AAV injection of neonatal mice. These findings demonstrate that modest changes in expression vector design can yield substantial gains in AAV efficiency for therapeutic applications., Competing Interests: The authors declare no competing interests. C.T. is currently a paid employee of Eli Lilly and Co. but was not affiliated with this company or any for-profit entity at the time she contributed to this study. J.L.J. is a co-inventor on pending patent application WO 202213346, Delivery of Abeta variants for aggregation inhibition., (© 2024 The Author(s).)

Disclaimer: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time., Purpose: To compare the incidence of ICU pharmacist interventions in intensive care unit recovery center (ICU-RC) in-person and virtual clinic visits., Methods: This was a post hoc analysis of interventions implemented by ICU pharmacists among adult patients who were referred to 12 ICU-RCs across the United States and the United Kingdom between September 2019 and July 2021, as reported in a previously published study "An International, Multicenter Evaluation of Comprehensive Medication Management by Pharmacists in ICU Recovery Centers." That study included patients who received a comprehensive medication review by an ICU pharmacist. Medication-related interventions performed by an ICU pharmacist during ICU-RC in-person clinic visits were compared to those performed during virtual clinic visits., Results: There were 507 patients referred to an ICU-RC, of whom 474 patients attended a clinic visit. Of those, 472 received a comprehensive medication review, with 313 patients attending in-person visits and 159 patients attending virtual visits. The incidence of medication-related interventions implemented was higher in the ICU-RC in-person clinic group compared to the virtual clinic group (86.5% vs 79.2%, P = 0.04). There was no difference in the median number of ICU pharmacist interventions per patient between the in-person and virtual clinic groups (2 vs 2, P = 0.13). An ICU admission diagnosis was an independent predictor of medication-related interventions among all patients., Conclusion: The incidence of ICU pharmacist interventions was higher at ICU-RC in-person clinic visits compared to virtual clinic visits. Pharmacists aid in meeting the complex pharmacologic challenges of post-intensive care syndrome in both settings., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

While studies have examined the effects of schools offering in-person learning during the pandemic, this study provides analysis of student enrollment decisions (remote versus in-person) in response to schools providing in-person learning opportunities. In Connecticut during the 2020-21 school year, we find that student take-up of in-person learning opportunities was low with students on average enrolled in-person for only half of the days offered, and take-up was even lower in schools with larger shares of disadvantaged students. The provision of in-person learning opportunities has been previously shown to mitigate pandemic learning losses. By exploiting data on actual enrollment, we show that the protective benefits of in-person learning are twice as large as previously estimated once we account for the low rates of student take-up. Finally, we provide evidence suggesting that a key mechanism behind the benefits of in-person learning is alleviating the burden faced by schools and teachers in delivering remote education. First, we show that the benefits to individual students of their in-person learning are substantially smaller than the overall benefits a student receives from their school average level of in-person enrollment. Second, we show that a combination of remote and in-person learning (hybrid) with a full-time on-line presence of students when at home was worse than hybrid learning with students never or only partially online. This second finding is consistent with qualitative evidence showing that teachers found hybrid learning especially challenging when having to manage both in-person and remote students for the entire class period., Competing Interests: Competing interests statement:S.L.R. and M.J.S. are currently working on separate CCERC grants related to post-pandemic recovery efforts in the State of Connecticut. The authors have no other competing interests to disclose.

Introduction: Current critical care practice does not integrate social determinants of health (SDOH) in systematic or standardized ways. Routine assessment of SDOH in the intensive care unit (ICU) may improve clinical decision-making, patient- and family-centered outcomes, and clinician well-being. Given the appropriateness and feasibility of SDOH assessment in the ICU is unknown, we aimed to understand how ICU clinicians think about and use SDOH., Methods: We conducted semi-structured interviews with clinicians focused on barriers to and facilitators of assessing SDOH during critical illness and perceptions on screening for SDOH in the ICU. We used chart-stimulated recall to assist clinicians in reflecting on how SDOH applied to and was used in patients' care. After deidentifying interviews, we analyzed transcripts guided by a thematic analysis approach using a combination of inductive and deductive coding, the latter framed within the Centers for Disease Control SDOH Healthy People framework., Results: We completed interviews with 30 clinicians, in a variety of professional roles. The majority of clinicians self-identified as men (17, 56.7%) of White race (25, 83.3%). Clinicians contextualize their use of SDOH within three frames of reference: 1) their own identity and experiences; 2) their relationships and communication with patients and caregivers; and 3) immediate structures of care around ICU patients including clinician advocacy, care transitions, and readmission. Clinicians identified that discussing SDOH could allow them to recognize bias faced by their patients, elucidate drivers of critical illness, and navigate communication with patients caregivers. Clinicians worried about ICU-specific factors impeding the discussion of SDOH including time contraints and acuity, high stakes and emotions, and negative anticipatory emotions., Discussion: Clinicians gather SDOH during critical illness both to understand their patients' stories and provide individualized care, which may lead to better clinician satisfaction and patient- and family-centered care outcomes. Educational and operational efforts to increase SDOH assessment and use in critical care should also gather and integrate the perspectives of patients and caregivers regarding the collection and use of SDOH in the ICU.

Diagnosing and monitoring inflammatory bowel diseases, such as Crohn's disease, involves the use of endoscopic imaging, biopsies and serology. These infrequent tests cannot, however, identify sudden onsets and severe flare-ups to facilitate early intervention. Hence, about 70% of patients with Crohn's disease require surgical intestinal resections in their lifetime. Here we report wireless, miniaturized and implantable temperature sensors for the real-time chronic monitoring of disease progression, which we tested for nearly 4 months in a mouse model of Crohn's-disease-like ileitis. Local measurements of intestinal temperature via intraperitoneally implanted sensors held in place against abdominal muscular tissue via two sutures showed the development of ultradian rhythms at approximately 5 weeks before the visual emergence of inflammatory skip lesions. The ultradian rhythms showed correlations with variations in the concentrations of stress hormones and inflammatory cytokines in blood. Decreasing average temperatures over the span of approximately 23 weeks were accompanied by an increasing percentage of inflammatory species in ileal lesions. These miniaturized temperature sensors may aid the early treatment of inflammatory bowel diseases upon the detection of episodic flare-ups., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes., Methods: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete., Findings: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo., Interpretation: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults., Funding: National Institutes of Health and the US Department of Veterans Affairs., Competing Interests: Declaration of interests The following declarations of interest are reported outside of the submitted work. MFM reports grants from the National Institutes of Health (NIH) and the US Department of Veterans Affairs. LMB reports grants from the NIH and the American Association of Critical Care Nurses. MNG reports grants from the NIH, the Agency for Healthcare Research and Quality, and the US Centers for Disease Control and Prevention; consulting fees for a role as scientific advisor for Endpoint Health; honoraria for grand rounds presentation at Yale University (New Haven, CT, USA); travel support from the American Thoracic Society executive committee; and participation on the data safety monitoring board for a trial on monoclonal antibodies for COVID-19, funded by Regeneron (NCT04452318). AM reports consulting fees from Zoll, Eli Lilly, LivaNova, and Jazz Pharmaceuticals; and a philanthropic contribution from ResMed to the University of California San Diego (La Jolla, CA, USA). BAK reports grants from the NIH, payment for expert testimony for a medicolegal case in the state of Indiana (USA), payment for participation on a data safety monitoring board for the PANDORA trial, and a leadership role as president of the American Delirium Society. SSC reports grants from the NIH and direct payments for participation on the data safety monitoring board of an NIH-funded study unrelated to delirium. CLH reports grants from the NIH. PR reports grants from the NIH and the US Department of Defense, payment and travel support for a continuing medical education event at the Johns Hopkins School of Medicine, and previous leadership of the Association of Academic Anesthesiology Chairs and Society of Academic Associations of Anesthesiology and Perioperative Medicine. BTP reports leadership as co-chair of the Society of Critical Care Medicine ICU Liberation Committee. PPP reports grants from the NIH. NEB reports grants from the NIH and travel support for the Society of Intensive Care Medicine Singapore annual meeting. CGH reports consulting fees for Sedana Medical. MBP reports grants from CSL Behring, the NIH, and the US Department of Defense; royalties for serving as an associate editor with Elsevier on a surgical textbook; travel support for continuing medical education events with the Eastern Association for the Surgery of Trauma, Society of University Surgeons, and American College of Surgeons; a patent for image-derived prognostic models unrelated to this work; participation on a data safety monitoring board for Liberate Medical; and leadership as treasurer for the Eastern Association for the Surgery of Trauma. JLS reports honoria for presentations for the Society of Critical Care Medicine, American College of Chest Physicians, the Chilean Society of Critical Care Medicine, and the Spanish Society of Hospital Pharmacy; travel support for meetings with the Society of Critical Care Medicine, the Saudi Society of Clinical Pharmacy, and the Chilean Society of Critical Care Medicine; and leadership on committees with the Society of Critical Care Medicine. EWE reports grant support from the NIH and the US Department of Veterans Affairs, honoraria for continuing medical education lectures sponsored by Pfizer, and study support (investigational drug provision, no direct payments) from Eli Lilly. TDG reports grants from the NIH, research funding from Ceribell, and personal fees from Haisco Pharmaceutical and Lungpacer Medical. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: Telemedicine Critical Care (TCC) improves adherence to evidence based protocols associated with improved mortality among patients receiving invasive mechanical ventilation (IMV). We sought to evaluate the relationship between hospital availability of TCC and outcomes among patients receiving IMV., Materials and Methods: We performed a cross-sectional study of 66,522 adults who received IMV for non-postoperative acute respiratory failure at 318 non-federal hospitals in New York, Massachusetts, Maryland, and Florida in 2018. Hospital-level TCC availability was ascertained from the 2018 American Hospital Association Annual Survey. The primary outcome was in-hospital mortality. Secondary outcomes included the composite of tracheostomy or reintubation and duration of IMV. We used two-level hierarchical multivariable regression models to investigate the association between TCC availability and outcomes., Results: 20,270 (30.5%) patients were admitted into 89 TCC-available hospitals. There was no difference between TCC and non-TCC-available hospitals in mortality (odds ratio [OR] 0.94, 99% confidence interval [CI] 0.84-1.05), composite of tracheostomy or reintubation (OR 0.95 [0.82-1.11], or duration of IMV (OR 0.95 [0.83-1.09]). There was no difference in outcomes among the subgroup of patients with acute respiratory distress syndrome., Conclusions: Hospital TCC availability was not associated with improved outcomes among patients receiving IMV., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: There is a lack of integrated treatment for chronic pain and opioid use disorder (OUD). Yoga and physical therapy (PT) may improve pain and physical function of people living with (PLW) chronic low back pain (CLBP) and may also reduce opioid craving and use, but PLW with OUD face barriers to accessing these interventions. We hypothesize that compared to treatment as usual (TAU), providing yoga and PT onsite at opioid treatment programs (OTPs) will be effective at improving pain, opioid use, and quality of life among people with CLBP and OUD, and will be cost-effective., Methods: In this hybrid type-1 effectiveness-implementation study, we will randomly assign 345 PLW CLBP and OUD from OTPs in the Bronx, NY, to 12 weeks of onsite yoga, onsite PT, or TAU. Primary outcomes are pain intensity, opioid use, and cost-effectiveness. Secondary outcomes include physical function and overall well-being., Discussion: This trial tests an innovative, patient-centered approach to combined management for pain and OUD in real-world settings. We rigorously examine the efficacy of yoga and PT onsite at OTPs as nonpharmacologic, cost-effective treatments among people with CLBP and OUD who face barriers to integrated care., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JLS, VG, JLG, HRP, LAU, SN receive current grant support from NIH/NIDA. MNB, LAU, and VG receive current grant support for NIH/NIMH. LAU receives current grant support form NIH/NCCIH, NIH/NIA, and PCORI. JLS receives current grant support from AHRQ. VG receives current grant support from NIAID as part of the Einstein-Rockefeller-CUNY-CFAR. JLG receives an honorarium for contributing to AHRQ’s Opioids in Older Adults Technical Expert Panel and co-chairs the Geriatric and Older Adults Special Interest group at the Association for Multidisciplinary Education and Research in Substance use and Addiction (AMERSA) and the Alcohol, Tobacco, and Other Drug Use Special Interest Group for the American Geriatrics Society. LAU co-Chairs the Integrative Health & Spirituality Special Interest Group for the Society of Behavioral Medicine and participates on a Data Safety Monitoring Board or Advisory Board for 1R01AT012069; R61AG080615, R01DA057443, and R61MH129407. MRS is a paid contributor to UptoDate. MBH receives a consulting fee from EHE Medical—Medical Advisory Board. Yoga for Arthritis is a DBA sole proprietorship that provides continuing education programs for yoga professionals to work safely with chronic pain populations; it includes intellectual property developed by SMH who does not receive financial payments but does own the business. LAU co-Chairs the Integrative Health & Spirituality Special Interest Group for the Society of Behavioral Medicine and participates on a Data Safety Monitoring Board or Advisory Board for 1R01AT012069; R61AG080615, R01DA057443, and R61MH129407. LAU’s spouse is has stock options and is employed by Abbvie Pharmaceuticals, a company unrelated to this topic. Pfizer provided active and placebo varenicline until 2/2022 for a research study conducted by SN and funded by NIH/NIDA (R01DA042813).

Abstract: With the rise in nurse practitioner (NP) residency programs, evaluations have largely focused on retention and competency completion for residents. There is a need for expanded evaluation to ensure the sustainability of NP residency programs, to ensure timely adaptations to address resident satisfaction, and to solidify a long-term pathway of NPs well prepared for rural practice. We created a family nurse practitioner (FNP) residency program with a comprehensive evaluation framework to prepare residents for practice in rural settings. The evaluation framework was developed through collaborative engagement of an external evaluation team, program leadership, and clinical site representatives. The evaluation framework of the FNP residency program combined resident assessment and holistic program evaluation, using a rapid continuous quality improvement (QI) approach. The evaluation considered three distinct perspectives: the resident, the peer coach, and the clinical site. The rapid continuous QI approach allowed program leadership to respond swiftly to programmatic challenges, improve the residency program in response to residents' reported experiences, and emphasize sustainability for continued program impact, while assessing residents' learning and performance. The program's data-driven evaluation approach has demonstrated its success in meeting the goals of the Health Resources and Services Administration funding by increasing the number of primary care providers in rural settings. The program's expansion and continued success have further validated the efficacy of this evaluation framework in assessing, improving, and ensuring the sustainability of APRN residency programs. This article calls for the adoption of similar evaluation strategies in future residency programs to promote their long-term success and impact in rural health care settings., Competing Interests: Competing interests: The authors report no conflicts of interest., (Copyright © 2024 American Association of Nurse Practitioners.)

Stress is a major risk factor for several neuropsychiatric disorders in women, including postpartum depression. During the postpartum period, diminished ovarian hormone secretion increases susceptibility to developing depressive symptoms. Pleiotropic peptide hormones, like prolactin, are markedly released during lactation and suppress hypothalamic-pituitary-adrenal axis responses in women and acute stress-induced behavioral responses in female rodents. However, the effects of prolactin on chronic stress-induced maladaptive behaviors remain unclear. Here, we used chronic variable stress to induce maladaptive physiology in ovariectomized female rats and concurrently administered prolactin to assess its effects on several depression-relevant behavioral, endocrine, and neural characteristics. We found that chronic stress increased sucrose anhedonia and passive coping in saline-treated, but not prolactin-treated rats. Prolactin treatment did not alter stress-induced thigmotaxis, corticosterone (CORT) concentrations, hippocampal cell activation or survival. However, prolactin treatment reduced basal CORT concentrations and increased dopaminergic cells in the ventral tegmental area. Further, prolactin-treated rats had reduced microglial activation in the ventral hippocampus following chronic stress exposure. Together, these data suggest prolactin mitigates chronic stress-induced maladaptive behaviors and physiology in hypogonadal females. Moreover, these findings imply neuroendocrine-immune mechanisms by which peptide hormones confer stress resilience during periods of low ovarian hormone secretion., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Among survivors of critical illness, prescription of potentially inappropriate medications (PIM) at hospital discharge is thought to be an important, modifiable patient safety concern. To date, there are little empirical data evaluating this issue., Research Question: The objective of this study was to determine the frequency of PIM prescribed to survivors of acute respiratory failure (ARF) at hospital discharge and explore their association with readmissions or death within 90 days of hospital discharge., Study Design and Methods: Prospective multicenter cohort study of ARF survivors admitted to ICUs and discharged home. Prospective of new PIMs with a high-adverse-effect profile ("high impact") at discharge was the primary exposure. Potential inappropriateness was determined by a structured consensus process using Screening Tool of Older Persons' Prescriptions-Screening Tool to Alert to Right Treatment, Beers' criteria, and clinical context of prescriptions by a multidisciplinary team. Covariate balancing propensity score was used for the primary analysis., Results: Of the 195 Addressing Post Intensive Care Syndrome-01 (APICS-01) patients, 169 (87%) had ≥1 new medications prescribed at discharge, with 154 (91.1%) prescribed with one or more high-impact (HI) medications. Patients were prescribed a median of 5 [3-7] medications, of which 3 [1-4] were HI. Twenty percent of HI medications were potentially inappropriate. Medications with significant central nervous system side-effects were most prescribed potentially inappropriately. Forty-six (30%) patients experienced readmission or death within 90 days of hospital discharge. After adjusting for prespecified covariates, the association between prescription of potentially inappropriate HI medications and the composite primary outcome did not meet the prespecified threshold for statistical significance (risk ratio: 0.54; 0.26-1.13; p = 0.095) or with the constituent endpoints: readmission (risk ratio: 0.57, 0.27-1.11) or death (0.7, 0.05-9.32)., Conclusion: At hospital discharge, most ARF survivors are prescribed medications with a high-adverse-effect profile and approximately one-fifth are potentially inappropriate. Although prescription of such medications was not associated with 90-day readmissions and mortality, these results highlight an area for additional investigation., (Copyright © 2024 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Lactoferrin (LF) is a major component of human milk. LF supplementation (currently bovine) supports the immune system and helps maintain iron homeostasis in adults. No recombinant human lactoferrin (rhLF) is available for commercial food use. To determine the extent to which rhLF (Effera™) produced by Komagataella phaffii digests similarly to hmLF, a validated in vitro digestion protocol was carried out. Bovine LF (bLF) was used as an additional control, as it is approved for use in various food categories. This study compared the extent of intact protein retention and the profile of peptides released in hmLF, bLF and rhLF (each with low and high iron saturation) across simulated adult gastric and intestinal digestion using gel electrophoresis, ELISA and LC-MS. Intact LF retention across digestion was similar across LF types, but the highest iron-saturated hmLF had greater retention in the simulated gastric fluid than all other sample types. Peptides identified in digested hmLF samples strongly correlated with digested rhLF samples (0.86 < r < 0.92 in the gastric phase and 0.63 < r < 0.70 in the intestinal phase), whereas digested bLF samples were significantly different. These findings support the potential for rhLF as a food ingredient for human consumption.

Adipose tissue and skeletal muscle dysfunction play a central role in cardiometabolic morbidity. Ashwagandha and Andrographis are purported to have anti-inflammatory and antioxidant activity, but this is based on exposure of cells to the parent compounds ignoring phytochemical absorption and metabolism. We explored the anti-inflammatory/antioxidant effects of ashwagandha and Andrographis in ex vivo human models of skeletal muscle and adipose tissue. Healthy participants supplemented with 2000 mg/day Andrographis (n = 10) or 1100 mg/day ashwagandha (n = 10) for 28 days. Sera collected pre (D0) and post (D28) supplementation were pooled by timepoint and added to adipose explant (AT) and primary human myotube (SKMC) culture media (15% v / v ) for treatment. A Taqman panel of 56 genes was used to quantify these. In AT, treatment with ashwagandha sera decreased the expression of genes involved in antioxidant defence and inflammatory response ( CCL5 , CD36 , IL6 , IL10 , ADIPOQ , NFEL2 , UCP2 , GPX3 , GPX4 ; geometric 95% CI for fold change > 1) and altered the expression of genes involved in fatty acid metabolism. In SKMC, ashwagandha sera altered FOXO1 and SREBF1 expression. Andrographis sera decreased IL18 and SERPINEA3 expression in AT. This physiologically relevant in vitro screening characterises the effects of ashwagandha in AT to guide future clinical trials.

Tagmentation combines DNA fragmentation and sequencing adapter addition by leveraging the transposition activity of the bacterial cut-and-paste Tn5 transposase, to enable efficient sequencing library preparation. Here we present an open-source protocol for the generation of multi-purpose hyperactive Tn5 transposase, including its benchmarking in CUT&Tag, bulk and single-cell ATAC-seq. The OpenTn5 protocol yields multi-milligram quantities of pG-Tn5 E54K, L372P protein per liter of E. coli culture, sufficient for thousands of tagmentation reactions and the enzyme retains activity in storage for more than a year.

Purpose: Autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) define pre-clinical autoimmune thyroid disease (AITD) which can progress to either clinical hypo- or hyperthyroidism. We determined the age at seroconversion in children genetically at risk for type 1 diabetes., Methods: TPOAb and TgAb seropositivity were determined in 5066 healthy children with HLA DR3 or DR4 containing haplogenotypes from The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Children seropositive on the cross-sectional initial screen at 8-13 years of age had longitudinally collected samples (from 3.5 months of age) screened retrospectively and prospectively for thyroid autoantibodies to identify the age at seroconversion. First-appearing autoantibody was related to sex, HLA genotype, family history of AITD, and subsequent thyroid dysfunction and disease., Results: The youngest appearance of TPOAb and TgAb was 10 and 15 months of age, respectively. Girls had higher incidence rates of both autoantibodies. Family history of AITD was associated with a higher risk of TPOAb hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.17, 3.08; and TgAb HR 2.55, 95% CI 1.91, 3.41. The risk of progressing to hypo- or hyperthyroidism was not different between TgAb and TPOAb, but children with both autoantibodies appearing at the same visit had a higher risk compared to TPOAb appearing first (HR 6.34, 95% CI 2.72, 14.76)., Main Conclusion: Thyroid autoantibodies may appear during the first years of life, especially in girls, and in children with a family history of AITD. Simultaneous appearance of both autoantibodies increases the risk for hypo- or hyperthyroidism., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Namaste Care offers practical skills for healthcare providers, volunteers, and families to meaningfully engage individuals with dementia in activities (e.g., music, massage, reminiscing, socialization, aromatherapy, snacks). A hospital-based specialized dementia care unit for patients with mid- to late-stage dementia offered an adapted version of the Namaste Care program, which was called Meaningful Moments. The aim of this study was to assess the acceptability and preliminary effects of this novel approach using trained volunteers for older adults with mid- to late-stage dementia., Methods: A mixed methods multiphase design was used. Qualitative description was used to explore acceptability of the Meaningful Moments program delivered over 6 months through focus groups (e.g., charge nurses, therapeutic recreationists, nurses, social workers) and individual interviews with one volunteer and two family members. A prospective pre-post-test study design was used to evaluate the preliminary effects of the program for patients with dementia and family members. Outcomes included quality of life, neuropsychiatric symptoms, and pain for patients with dementia and family carer role stress and the quality of visits for families. Data were collected from June 2018 to April 2019. Descriptive analyses of participants' characteristics were expressed as a mean (standard deviation [SD]) for continuous variables and count (percent) for categorical variables. Focus group and individual interview data were analyzed using thematic analysis. The generalized estimating equations (GEE) method was used to assess change in the repeated measures outcome data., Results: A total of 15 patients received the Meaningful Moments interventions. Families, staff, and volunteers perceived that patients experienced benefits from Meaningful Moments. Staff, volunteers, and families felt fulfilled in their role of engaging patients in the Meaningful Moments program. Individualized activities provided by volunteers were perceived as necessary for the patient population. There were no statistically significant improvements in patient outcomes. There was a statistically significant decline in family carer role stress., Conclusions: Using a one-on-one approach by volunteers, patients experienced perceived benefits such as improved mood and opportunities for social interactions. There is a need for tailored activities for older adults with advanced dementia through practical strategies that can offer benefit to patients., (© 2024. The Author(s).)

Opioid overdose accounts for nearly 75,000 deaths per year in the United States, representing a leading cause of mortality amongst the prime working age population (25-54 years). At overdose levels, opioid-induced respiratory depression becomes fatal without timely administration of the rescue drug naloxone. Currently, overdose survival relies entirely on bystander intervention, requiring a nearby person to discover and identify the overdosed individual, and have immediate access to naloxone to administer. Government efforts have focused on providing naloxone in abundance but do not address the equally critical component for overdose rescue: a willing and informed bystander. To address this unmet need, we developed the Naloximeter: a class of life-saving implantable devices that autonomously detect and treat overdose, with the ability to simultaneously contact first-responders. We present three Naloximeter platforms, for both fundamental research and clinical translation, all equipped with optical sensors, drug delivery mechanisms, and a supporting ecosystem of technology to counteract opioid-induced respiratory depression. In small and large animal studies, the Naloximeter rescues from otherwise fatal opioid overdose within minutes. This work introduces life-changing, clinically translatable technologies that broadly benefit a susceptible population recovering from opioid use disorder.

A deficits-based approach to adolescent chronic pain currently dominates the literature, to the exclusion of positive approaches, such as flourishing. Addressing this knowledge gap, this study examined the relationships between flourishing and pain-related outcomes in adolescent chronic pain. Seventy-nine adolescents aged 11-24 years were asked to complete self-report measures of three domains of flourishing and four pain-related outcomes. Correlation coefficients and four hierarchical linear regression analyses were conducted, controlling for age and gender. Flourishing mental health was associated with, and significantly contributed to explaining, anxiety and depressive symptoms, and social and family functioning impairment. Benefit finding and posttraumatic growth were each associated with social and family functioning impairment, while posttraumatic growth was also associated with anxiety and depressive symptoms. Additionally, benefit finding significantly contributed to explaining pain intensity. Study findings underscore the importance of assessing the relationships between flourishing and pain-related outcomes in adolescents with chronic pain., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Vancomycin, an antibiotic with activity against Methicillin-resistant Staphylococcus aureus (MRSA), is frequently included in empiric treatment for community-acquired pneumonia (CAP) despite the fact that MRSA is rarely implicated in CAP. Conducting polymerase chain reaction (PCR) testing on nasal swabs to identify the presence of MRSA colonization has been proposed as an antimicrobial stewardship intervention to reduce the use of vancomycin. Observational studies have shown reductions in vancomycin use after implementation of MRSA colonization testing, and this approach has been adopted by CAP guidelines. However, the ability of this intervention to safely reduce vancomycin use has yet to be tested in a randomized controlled trial., Methods: STOP-Vanc is a pragmatic, prospective, single center, non-blinded randomized trial. Adult patients with suspicion for CAP who are receiving vancomycin and admitted to the Medical Intensive Care Unit at Vanderbilt University Medical Center will be screened for eligibility. Eligible patients will be enrolled and randomized in a 1:1 ratio to either receive MRSA nasal swab PCR testing in addition to usual care (intervention group), or usual care alone (control group). PCR testing results will be transmitted through the electronic health record to the treating clinicians. Primary providers of intervention group patients with negative swab results will also receive a page providing clinical guidance recommending discontinuation of vancomycin. The primary outcome will be vancomycin-free hours alive, defined as the number of hours alive and free of the use of vancomycin within the first seven days following trial enrollment estimated using a proportional odds ratio model. Secondary outcomes include 30-day all-cause mortality and time alive off vancomycin., Discussion: STOP-Vanc will provide the first randomized controlled trial data regarding the use of MRSA nasal swab PCR testing to guide antibiotic de-escalation. This study will provide important information regarding the effect of MRSA PCR testing and antimicrobial stewardship guidance on clinical outcomes in an intensive care unit setting., Trial Registration: This trial was registered on ClinicalTrials.gov on February 22, 2024. (ClinicalTrials.gov identifier: NCT06272994)., Competing Interests: Competing interests {28} The authors declare that they have no competing interests.

Background: Social determinants of health (SDOHs) mediate outcomes of critical illness. Increasingly, professional organizations recommend screening for social risks. Yet, how clinicians should identify and then incorporate SDOHs into acute care practice is poorly defined., Research Question: How do medical ICU clinicians currently operationalize SDOHs within patient care, given that SDOHs are known to mediate outcomes of critical illness?, Study Design and Methods: Using ethnographic methods, we observed clinical work rounds in three urban ICUs within a single academic health system to capture use of SDOHs during clinical care. Adults admitted to the medical ICU with respiratory failure were enrolled prospectively sequentially. Observers wrote field notes and narrative excerpts from rounding observations. We also reviewed electronic medical record documentation for up to 90 days after ICU admission. We then qualitatively coded and triangulated data using a constructivist grounded theory approach and the Centers for Disease Control and Prevention Healthy People SDOHs framework., Results: Sixty-six patients were enrolled and > 200 h of observation of clinical work rounds were included in the analysis. ICU clinicians infrequently integrated social structures of patients' lives into their discussions. Social structures were invoked most frequently when related to: (1) causes of acute respiratory failure, (2) decisions regarding life-sustaining therapies, and (3) transitions of care. Data about common SDOHs were not collected in any systematic way (eg, food and housing insecurity), and some SDOHs were discussed rarely or never (eg, access to education, discrimination, and incarceration)., Interpretation: We found that clinicians do not incorporate many areas of known SDOHs into ICU rounds. Improvements in integration of SDOHs should leverage the multidisciplinary team, identifying who is best suited to collect information on SDOHs during different time points in critical illness. Next steps include clinician-focused, patient-focused, and caregiver-focused assessments of feasibility and acceptability of an ICU-based SDOHs assessment.

Background: Pediatric trauma disproportionately affects low- and middle-income countries, particularly the pediatric trauma systems, are frequently limited. This study assessed the patterns of pediatric traumatic injuries and treatment at the only free-standing public children's hospital in East Africa as well as the implementation and sustainability of the trauma registry., Methods: A prospective pediatric trauma registry was established at Shoe4Africa Children's Hospital (S4A) in Eldoret, Kenya. All trauma patients over a six-month period were enrolled. Descriptive analyses were completed via SAS 9.4 to uncover patterns of demographics, trauma mechanisms and injuries, as well as outcomes. Implementation was assessed using the RE-AIM framework., Results: The 425 patients had a median age of 5.14 years (IQR 2.4, 8.7). Average time to care was 267.5 min (IQR 134.0, 625.0). The most common pediatric trauma mechanisms were falls (32.7 %) and burns (17.7 %), but when stratified by age group, toddlers had a higher risk of sustaining injuries from burns and poisonings. Over half (56.2 %) required an operation during the hospitalization. Overall, implementation of the registry was limited by the clinical burden and inadequate personnel. Sustainability of the registry was limited by finances., Conclusions: This is the first study to describe the trauma epidemiology from a Kenyan public pediatric hospital. Maintenance of the trauma registry failed due to cost. Streamlining global surgery efforts through implementation science may allow easier development of trauma registries to then identify modifiable risk factors to prevent trauma and long-term outcomes to understand associated disability., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024. Published by Elsevier Ltd.)

A growing proportion of individuals adopt family caregiving roles. Family caregivers are the primary providers of long-term care in the United States yet limited federal policy supports exist, despite the known negative impacts of caregiving. There is also limited information about the prevalence of youth/young adult caregivers and the impacts of caregiving at formative ages in the United States. Our objective is to estimate the prevalence of youth caregivers and examine the association of caregiving with educational investments. We use the American Time Use Survey (2013-2019) to identify and describe youth caregivers (aged 15-18) and young adult caregivers (aged 19-22) and compare them with non-caregiving peers. We estimate that there are approximately 1,623,000 youth caregivers and 1,986,000 young adult caregivers, corresponding to 9.2% and 12.7% of these age groups, respectively. However, there is a wide range in the estimated prevalence per year, from approximately 364,000 to 2.8 million youth caregivers and from 353,000 to 2.2 million young adult caregivers, depending on caregiver definition. Unlike adult caregivers, we find that young men and women were nearly equally likely to provide care. We also find that non-White individuals are disproportionately represented as youth caregivers. Compared with non-caregiving peers, both youth and young adult caregivers are less likely to be enrolled in school and, among those enrolled in school, spend significantly less time on educational activities. Considering the association of caregiving among youth/young adults and education, policies supporting youth and young adult caregivers are critical., (Copyright © 2024 The Authors.)

Background: To evaluate the clinical efficacy of COMPASS, a therapist-supported digital therapeutic for reducing psychological distress (anxiety/depression) in people living with long-term physical health conditions (LTCs)., Methods: A two-armed randomized-controlled trial recruiting from LTC charities. Participants with anxiety and/or depression symptoms related to their LTC(s) were randomized (concealed allocation via independent administrator) to COMPASS (access to 11 tailored modules plus five thirty-minute therapist support sessions) or standard charity support (SCS). Assessments were completed online pre-randomization, at 6- and 12-weeks post-randomization. Primary outcome was Patient Health Questionnaire Anxiety and Depression Scale; PHQ-ADS measured at 12-weeks. Analysis used intention-to-treat principles with adjusted mean differences estimated using linear mixed-effects models. Data-analyst was blinded to group allocation., Results: 194 participants were randomized to COMPASS ( N = 94) or SCS ( N = 100). At 12-weeks, mean level of psychological distress was 6.82 (95% confidence interval; CI 4.55-9.10) points lower ( p < 0.001) in the COMPASS arm compared with SCS (standardized mean difference of 0.71 (95% CI 0.48-0.95)). The COMPASS arm also showed moderate significant treatment effects on secondary outcomes including depression, anxiety and illness-related distress and small significant effects on functioning and quality-of-life. Rates of adverse events were comparable across the arms. Deterioration in distress at 12-weeks was observed in 2.2% of the SCS arm, and no participants in the COMPASS arm., Conclusion: Compared with SCS, COMPASS digital therapeutic with minimal therapist input reduces psychological distress at post-treatment (12-weeks). COMPASS offers a potentially scalable implementation model for health services but its translation to these contexts needs further evaluating., Trial Registration: NCT04535778.

Harmful algal bloom (HAB) toxins consumed by marine predators through fish prey can be lethal but studies on the resulting population consequences are lacking. Over the past approximately 20 years there have been large regional declines in some harbour seal populations around Scotland. Analyses of excreta (faeces and urine from live and dead seals and faecal samples from seal haulout sites) suggest widespread exposure to toxins through the ingestion of contaminated prey. A risk assessment model, incorporating concentrations of the two major HAB toxins found in seal prey around Scotland (domoic acid (DA), and saxitoxins (STX)), the seasonal persistence of the toxins in the fish and the foraging patterns of harbour seals were used to estimate the proportion of adults and juveniles likely to have ingested doses above various estimated toxicity thresholds. The results were highly dependent on toxin type, persistence, and foraging regime as well as age class, all of which affected the proportion of exposed animals exceeding toxicity thresholds. In this preliminary model STX exposure was unlikely to result in mortalities. Modelled DA exposure resulted in doses above an estimated lethal threshold of 1900 µg/kg body mass affecting up to 3.8 % of exposed juveniles and 5.3 % of exposed adults. Given the uncertainty in the model parameters and the limitations of the data these conclusions should be treated with caution, but they indicate that DA remains a potential factor involved in the regional declines of harbour seals. Similar risks may be experienced by other top predators, including small cetaceans and seabirds that feed on similar prey in Scottish waters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Over the past decade, there has been increased utilization of medical cannabis (MC) in the United States. Few studies have described sociodemographic and clinical factors associated with MC use after certification and more specifically, factors associated with use of MC products with different cannabinoid profiles. Methods: We conducted a longitudinal cohort study of adults ( N =225) with chronic or severe pain on opioids who were newly certified for MC in New York State and enrolled in the study between November 2018 and January 2022. We collected data over participants' first 3 months in the study, from web-based assessment of MC use every 2 weeks (unit of analysis). We used generalized estimating equation models to examine associations of sociodemographic and clinical factors with (1) MC use (vs. no MC use) and (2) use of MC products with different cannabinoid profiles. Results: On average, 29% of the participants used predominantly high delta-9-tetrahydrocannabinol (THC) MC products within the first 3 months of follow-up, 30% used other MC products, and 41% did not use MC products. Non-Hispanic White race, pain at multiple sites, and past 30-day sedative use were associated with a higher likelihood of MC use (vs. no MC use). Current tobacco use, unregulated cannabis use, and enrollment in the study during the COVID-19 pandemic were associated with a lower likelihood of MC use (vs. no MC use). Among participants reporting MC use, female gender and older age were associated with a lower likelihood of using predominantly high-THC MC products (vs. other MC products). Conclusion: White individuals were more likely to use MC after certification, which may be owing to access and cost issues. The findings that sedative use was associated with greater MC use, but tobacco and unregulated cannabis were associated with less MC use, may imply synergism and substitution that warrant further research. From the policy perspective, additional measures are needed to ensure equitable availability of and access to MC. Health practitioners should check patients' history and current use of sedative, tobacco, and unregulated cannabis before providing an MC recommendation and counsel patients on safe cannabis use. clinicaltrials.gov (NCT03268551).

Regulating transcription allows organisms to respond to their environment, both within a single generation (plasticity) and across generations (adaptation). We examined transcriptional differences in gill tissues of fishes in the Poecilia mexicana species complex (family Poeciliidae), which have colonized toxic springs rich in hydrogen sulfide (H 2 S) in southern Mexico. There are gene expression differences between sulfidic and non-sulfidic populations, yet regulatory mechanisms mediating this gene expression variation remain poorly studied. We combined capped-small RNA sequencing (csRNA-seq), which captures actively transcribed (i.e. nascent) transcripts, and messenger RNA sequencing (mRNA-seq) to examine how variation in transcription, enhancer activity, and associated transcription factor binding sites may facilitate adaptation to extreme environments. csRNA-seq revealed thousands of differentially initiated transcripts between sulfidic and non-sulfidic populations, many of which are involved in H 2 S detoxification and response. Analyses of transcription factor binding sites in promoter and putative enhancer csRNA-seq peaks identified a suite of transcription factors likely involved in regulating H 2 S-specific shifts in gene expression, including several key transcription factors known to respond to hypoxia. Our findings uncover a complex interplay of regulatory processes that reflect the divergence of extremophile populations of P. mexicana from their non-sulfidic ancestors and suggest shared responses among evolutionarily independent lineages.

Background: Adults living with HIV have disproportionately high chronic pain, prescription opioid use, history of substance use, and incarceration. While incarceration can have long-lasting health impacts, prior studies have not examined whether distant (>1 year prior) incarceration is associated with opioid use for chronic pain, or with opioid misuse or opioid use disorder among people living with HIV and chronic pain., Methods: We conducted a secondary analysis of a prospective cohort study of adults living with HIV and chronic pain. The independent variables were any distant incarceration and drug-related distant incarceration (both dichotomous). Dependent variables were current long-term opioid therapy, current opioid misuse, and current opioid use disorder. A series of multivariate logistic regression models were conducted, adjusting for covariates., Results: In a cohort of 148 participants, neither distant incarceration nor drug-related incarceration history were associated with current long-term opioid therapy. Distant incarceration was associated with current opioid misuse (AOR 3.28; 95% CI: 1.41-7.61) and current opioid use disorder (AOR 4.40; 95% CI: 1.54-12.56). Drug-related incarceration history was also associated with current opioid misuse (AOR 4.31; 95% CI: 1.53-12.17) and current opioid use disorder (AOR 7.28; 95% CI: 2.06-25.71)., Conclusions: The positive associations of distant incarceration with current opioid misuse and current opioid use disorder could indicate a persistent relationship between incarceration and substance use in people living with HIV and chronic pain. Additional research on opioid use among formerly incarcerated individuals in chronic pain treatment is needed., (© 2024. The Author(s).)

Hypertrophic cardiomyopathy (HCM) remains the most common cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule sarcomere inhibitors are promising novel therapeutics for the management of obstructive HCM (oHCM) patients and have shown efficacy in left ventricular outflow tract obstruction (LVOTO) relief. The objective of this study was to explore the 6-, 24-, and 48-hour (h) pharmacodynamic effects of the cardiac myosin inhibitor, CK-586, in six purpose-bred cats with naturally occurring oHCM. A blinded, randomized, five-treatment group, crossover preclinical trial was conducted to assess the pharmacodynamic effects of CK-586 in this oHCM model. Dose assessments and select echocardiographic variables were assessed five times over a 48-h period. Treatment with oral CK-586 safely ameliorated LVOTO in oHCM cats. CK-586 treatment dose-dependently eliminated obstruction (reduced LVOTOmaxPG), increased measures of systolic chamber size (LVIDs Sx), and decreased select measures of heart function (LV FS% and LV EF%) in the absence of impact on heart rate. At all tested doses, a single oral CK-586 dose resulted in improved or resolved LVOTO with well-tolerated, dose-dependent, reductions in LV systolic function. The results from this study pave the way for the potential use of CK-586 in both the veterinary and human clinical setting., (© 2024. The Author(s).)

Recent preclinical studies demonstrate a direct pathological role for the interleukin-6 (IL-6) pathway in mediating structural and functional delirium-like phenotypes in animal models of acute lung injury. Tocilizumab, an IL-6 pathway inhibitor, has shown reduced duration of ventilator dependency and mortality in critically ill patients with COVID-19. In this study, we test the hypothesis that tocilizumab is associated with reduced delirium/coma prevalence in critically ill patients with COVID-19. 253 patients were included in the study cohort, 69 in the tocilizumab group and 184 in the historical control group who did not receive tocilizumab. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) with a positive score indicating delirium. Coma was defined as a Richmond Agitation-Sedation Scale score of - 4 or - 5. Tocilizumab was associated with significantly greater number of days alive without delirium/coma (tocilizumab [7 days (IQR: 3-9 days)] vs control [3 days (IQR: 1-8 days)]; p < 0.001). These results remained significant after adjusting for age, sex, sepsis, Charlson Comorbidity Index, Sequential Organ Failure Assessment score, and median daily dose of analgesics/sedatives ( β ^  = 0.671, p = 0.010). There were no significant differences in mortality ( β ^  = - 0.204, p = 0.561), ventilator duration ( β ^  = 0.016, p = 0.956), and ICU or hospital length of stay ( β ^  = - 0.134, p = 0.603; β ^  = 0.003, p = 0.991, respectively). Tocilizumab use was associated with significantly increased number of days without delirium/coma. Confirmation of these findings in randomized prospective studies may inform a novel paradigm of pharmacological amelioration of delirium/coma during critical illness., (© 2024. The Author(s).)

Stimulator of IFN genes (STING) is a promising target for adjuvants utilized in in situ cancer vaccination approaches. However, key barriers remain for clinical translation, including low cellular uptake and accessibility, STING variability necessitating personalized STING agonists, and interferon (IFN)-independent signals that can promote tumor growth. Here, we identify C100, a highly deacetylated chitin-derived polymer (HDCP), as an attractive alternative to conventional STING agonists. C100 promotes potent anti-tumor immune responses, outperforming less deacetylated HDCPs, with therapeutic efficacy dependent on STING and IFN alpha/beta receptor (IFNAR) signaling and CD8 + T cell mediators. Additionally, C100 injection synergizes with systemic checkpoint blockade targeting PD-1. Mechanistically, C100 triggers mitochondrial stress and DNA damage to exclusively activate the IFN arm of the cGAS-STING signaling pathway and elicit sustained IFNAR signaling. Altogether, these results reveal an effective STING- and IFNAR-dependent adjuvant for in situ cancer vaccines with a defined mechanism and distinct properties that overcome common limitations of existing STING therapeutics., Competing Interests: Declaration of interests E.C.L. is a co-founder and equity holder of AilseVax that aims to develop adjuvants for cancer vaccination. R.W.W., J.L.T., and N.M.W. are equity holders of AilseVax. E.C.L., R.W.W., and J.L.T. are inventors on patent WO 2022/113022 A1 – Use of C100: Immunotherapy for cancer., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)