British Journal of Anaesthesia

Background: Perioperative pain management modality potentially influences psychiatric morbidity and healthcare utilization. The opioids have been most commonly used for managing postoperative pain and carry a high degree of risk for creating mood disorders, anxiety, sleep disturbances, and healthcare burdens. A novel non-opioid analgesic, Suzetrigine, may be able to effectively manage postoperative pain without some of the psychological and economic risks that come from the use of opioids. In this study, we measured psychiatric outcomes and emergency department (ED) usage among postoperative patients who received either suzetrigine or opioids. Methods: This was a retrospective cohort study using the TriNetX US Collaborative Network, encompassing 64 healthcare organizations. Adult patients (> Age 18 years) who underwent surgery and received suzetrigine were compared with patients who underwent surgery and received opioids. Propensity score matching (1:1) performed to match cohorts based on demographic factors (age, gender, racial/ethnic status), social determinants of health (ICD-10 Z55-Z65), family histories of substance abuse and psychiatric disorders (Z81.x), surrogate measures of prior healthcare utilization, and pre-existing clinical severity using Elixhauser-Charlson comorbidity proxies (hypertensive diseases [I10-I15], diabetes mellitus [E08-E13], ischemic heart disease [I22-I25], and chronic pulmonary disease [J42-J47]). Matching also included behavioral risk factors (tobacco use and physical inactivity) and body mass index (BMI). Following matching, there were 2,221 patients in each cohort. The primary outcome assessed within one year after surgery was ED utilization, depression, anxiety, post-traumatic stress disorder (PTSD) and sleep disorders. Risk estimates and survival analyses were used to compare the outcomes. Results: In propensity-matched analyses, suzetrigine use was associated with a reduction in multiple psychiatric outcomes and healthcare utilization compared to opioid analgesics. There was less ED utilization in the suzetrigine cohort (5.9% v 13.1%, RR 0.45, p< .001). The psychiatric outcomes were also lower in the suzetrigine cohort than the opioid cohort, including depression (3.1% v 4.7%, RR 0.65, p= .005), anxiety (4.7% v 7.2%, RR 0.65, p< .001), PTSD (0.5% v 1.4%, RR 0.36, p= .002), and sleep disorders (4.2% v 6.0%, RR 0.71, p= .008). The survival analysis suggested an earlier onset of psychiatric diagnosis among the opioid recipients. Conclusion: In a matched real-world cohort of surgical patients, suzetrigine use was associated with lower short-term rates of selected postoperative outcomes compared with opioid analgesics. Keywords: Suzetrigine; Opioid-Sparing; Analgesia; Postoperative Outcomes; Cohort Study

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem disease characterized by profound fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction. Its pathophysiology is incompletely understood and likely involves complex interactions between immune, autonomic, and metabolic dysregulation. Despite features with potential relevance for anesthesia and perioperative care, evidence to guide anesthetic management in individuals with ME/CFS remains limited. We therefore performed a retrospective matched-pair analysis to generate clinical data on perioperative responses and identify areas for future research. Methods: We conducted a retrospective matched-pair analysis at a single tertiary center. All patients with ME/CFS undergoing general anesthesia from 2015 to 2026 were identified using ICD-10 codes (G93.3 and U09.9) with additional manual verification and matched 1:1 to controls for comparison. Patients with confounding diagnoses or American Society of Anesthesiologists physical status above III were excluded. The analysis focused on intraoperative hemodynamic parameters, including baseline, post-induction, median, and lowest recorded systolic blood pressure and heart rate, as well as early postoperative outcomes in the post-anesthesia care unit (PACU), including maximum pain scores and requirement for rescue analgesia. Results: Out of 189 individuals identified through ICD-10 codes, 15 matched pairs were included after application of exclusion criteria. ME/CFS patients exhibited lower lowest recorded intraoperative systolic blood pressure (90 [82.5-95.0] mmHg in ME/CFS vs 100 [90.0-110.0] mmHg in controls, p = 0.044) as well as lower lowest heart rate (50 [40.0-57.5] bpm in ME/CFS vs 60 [50.0-65.0] bpm in controls, p = 0.012). Vasopressor use and fluid administration did not differ, and no episodes of severe hypotension or perioperative adverse events were observed. Postoperative pain was higher in ME/CFS, with higher maximum pain scores (NRS 5.0 [4.0-6.0] in ME/CFS vs 1.0 [0.0-4.0] in controls, p = 0.008) and more frequent opioid rescue analgesia (80% in ME/CFS vs 33% in controls, p = 0.039). Postoperative nausea or vomiting, oxygen supplementation, and PACU length of stay were similar between groups. Conclusions: General anesthesia appears hemodynamically well tolerated in individuals with ME/CFS. In contrast, postoperative pain burden is increased and may require tailored analgesic strategies. Post-exertional malaise, a key disease feature with potentially delayed onset and significant impact, was not captured in this study and remains an important target for future research. These hypothesis-generating findings highlight the need for prospective studies to optimize perioperative management and evaluate patient-relevant outcomes in ME/CFS.

Objective: To quantify the effect size of four biopsychosocial amplifier loops on chronic pain outcomes through systematic review and meta-analysis, and to propose a composite meta-analytic risk index for interventional pain medicine requiring prospective validation. Methods: We searched PubMed/MEDLINE, Scopus, and the Cochrane Library through March 2026 for studies reporting adjusted odds ratios linking (1) sleep disturbance, (2) pain catastrophizing, (3) metabolic/inflammatory markers, and (4) preoperative opioid use/polypharmacy to chronic pain chronification or treatment failure. DerSimonian-Laird random-effects meta-analyses were performed per loop. Publication bias was assessed via Egger's test (k>=8). Effect sizes were integrated into a logistic regression model--the Pain Amplifier Loop Framework (PALF). Neurobiological convergence on TLR4/NF-kB microglial signaling was examined. Results: Forty-four studies (>500,000 participants) were included. Pooled odds ratios: sleep disturbance 1.80 (95% CI 1.65-1.96; k=16; I2=51%), pain catastrophizing 2.11 (1.71-2.61; k=8; I2=0%), metabolic/fat mass 2.02 (1.32-3.09; k=7), preoperative opioid use 4.48 (2.87-6.97; k=6; I2=84%), and opioid-benzodiazepine co-prescription 2.62 (1.76-3.89; k=7; I2=79%). Egger's test showed no significant asymmetry for sleep (p=0.21) or catastrophizing (p=0.84). All loops converge on TLR4/NF-kB microglial signaling. The PALF yields a Systemic Load Score and failure probability P=1/(1+e^-theta), enabling low (<0.30), moderate (0.30-0.60), and high (>=0.60) risk stratification. Conclusions: Four biopsychosocial amplifier loops independently and substantially increase chronic pain risk. The PALF proposes a transparent, hypothesis-driven composite risk index anchored in meta-analytic evidence from >500,000 participants. As a meta-analytic synthesis rather than a fitted prediction model, the PALF requires prospective multicenter validation with individual patient data before clinical application.

Background Venous thromboembolism (VTE) remains a major cause of perioperative morbidity in cranial neurosurgery, yet clinical practice varies widely, and formal guidelines are inconsistent. Understanding internationally sampled neurosurgical practice is essential for informing consensus and future trials. Methods An international, 2-stage cross-sectional, internet-based survey was conducted. Practising neurosurgeons performing elective adult cranial surgery were eligible. Descriptive statistics were used to summarise practice. Responses covered patterns of pre-operative haemostasis decision making, use and timing of mechanical and/or chemical prophylaxis, use of perioperative imaging prior to anticoagulation, and frequency of clinical assessment for VTE. Associations with geographical income status, subspecialty, and years post-certification were statistically tested. Practice heterogeneity was quantified and contextual influence was summarised using mean effect sizes across stratifying variables in order to determine domains of true equipoise. Results Of 585 responses, 456 (78%) met criteria for inclusion: representing 322 units across 78 countries (71% high-income). Thirteen per cent reported no departmental VTE plan; 23% followed no guidelines and 12% used multiple. Routine pre-operative testing almost universally included haemoglobin/platelets/haematocrit, with fibrinogen more common in high-income settings. Compared with high-income country respondents, low- and middle-income respondents reported higher haemoglobin transfusion thresholds (>90 g/dL; p<0.001) and shorter antiplatelet interruption (p[&le;]0.03), and less frequent outpatient VTE assessment (p<0.001). Mechanical prophylaxis was common (TEDs 81%, IPC 62%), typically started pre- or intra-operatively. Among those completing the chemoprophylaxis section (n=310), 57% required a CT or MRI scan before LMWH which was then initiated on average 31.4 hours after surgery. 1% of respondents did not routinely use LMWH. Many clinical decisions demonstrated statistical equipoise ie. high heterogeneity with low contextual influence. Conclusion Peri-operative haemostasis and VTE prophylaxis practices in adult elective cranial neurosurgery vary substantially worldwide, with some decisions reflecting geographical or socioeconomic differences and many others reflecting true clinical equipoise rather than contextual determinants. By mapping contemporary real-world practice across diverse health-system contexts, this study provides a necessary empirical foundation for rational trial design and future guideline development.

Background Chronic pain and depression are common disorders and leading causes of disability worldwide. They frequently co-occur and show substantial genetic correlation, indicating a shared genetic basis. However, the locus-specific architecture of this overlap remains poorly characterised and may yield important insights into the pathophysiology of their comorbidity. Methods Using the largest currently available European-ancestry genome-wide association studies of major depressive disorder (MDD) (n = 1,639,572) and multisite chronic pain (MCP) (n = 387,649), we estimated the polygenic overlap between traits using the bivariate causal mixture model (MiXeR), identified shared loci via conjunctional false discovery rate (conjFDR), and tested colocalisation with each trait and genetically regulated gene expression in 13 brain tissues. Results MiXeR analysis demonstrated a high degree of directionally consistent polygenic overlap between MDD and MCP. Subsequent conjFDR analysis identified 375 shared loci, 22 of which showed cross-trait colocalisation between the MDD and MCP signals. Gene mapping and enrichment of shared loci implicated several biological processes, including cadherin-mediated cell-cell adhesion and translational initiation. Gene expression colocalisation in brain tissue highlighted protein phosphatase 6 catalytic subunit (PPP6C) and suppressor of cancer cell invasion (SCAI) in both disorders. Conclusion Overall, these findings have enhanced our understanding of the complex relationship between chronic pain and depression by identifying shared molecular mechanisms that warrant further study as targets for prevention and treatment.

Background: Patient-reported outcome measures provide essential data on treatment quality across diverse populations. The FACE-Q Skin Cancer Module was developed to assess outcomes specific to facial skin cancer patients. Longitudinal data characterizing outcome trajectories from surgery through early recovery remain limited. Objective: We tracked how patient outcomes change from preoperatively through three months after surgery using the FACE-Q Skin Cancer Module in a prospective cohort of 288 patients undergoing facial skin cancer surgery. Methods: Participants completed the module preoperatively and at 1 week and 3 months postoperatively. Five scales were evaluated: Appearance, Psychosocial Distress, Cancer Worry, Scars, and Adverse Effects. Friedman tests assessed overall change across timepoints; paired t-tests and Wilcoxon signed-rank tests evaluated pairwise comparisons. Results: Of 288 enrolled patients (mean age 68.6+/-11.9 years, 46.5% female), 252 (87.5%) and 220 (76.4%) completed 1-week and 3-month follow-up, respectively. Facial appearance declined at 1 week (55.6 to 52.0, p=0.005) and returned to baseline by 3 months (57.0, p=0.274). Psychosocial distress increased acutely (14.5 to 19.0, p<0.001) with partial recovery at 3 months (17.1, p=0.012). Cancer worry decreased substantially (delta=-7.8, SRM=-0.54, p<0.001), and scar satisfaction improved from 1 week to 3 months (delta=+9.4, SRM=0.54, p<0.001). Adverse effects showed the largest improvement (delta=-12.8, SRM=-0.88, p<0.001). Women showed less improvement in facial appearance than men (delta=-2.2 vs +4.9, p=0.022). Clinical meaningfulness was assessed using minimally important difference thresholds: 36.9% of patients achieved meaningful improvement in appearance, 39.6% remained stable, and 23.4% experienced meaningful deterioration. Conclusions: Short-term outcomes follow a predictable pattern, with acute perioperative worsening followed by recovery by 3 months for most patients.

Pain is commonly described in sensory terms, yet its spatial characteristics-localization and distribution-are rarely quantified. We investigated whether lay beliefs about pain distribution (PD) influence theoretical decisions to seek care and treatment preferences. In a representative cross-sectional survey (N=503; 49% with pain), participants completed thought experiments in which both visually presented PD patterns (small, moderate or large) and pain intensity (NRS 2, 5, 8/10) were systemically varied. For each scenario, they rated the likelihood of (i) seeking professional help (LoSH) and (ii) taking analgesic medication (LoTM). Participants also completed a spatial-intensity trade-off task (SITT), in which they chose between a fixed 20% reduction in intensity and variable reductions in PD (20-80%). A reversed version contrasted a fixed 80% reduction in PD with variable reductions in pain intensity. LoSH and LoTM increased significantly with greater PD (p<0.001), mirroring the gradient observed for pain intensity. In the SITT, participants' choice followed a sigmoid-like function (p<0.001): 1% reduction in intensity was treated as equivalent to approximately a 3% reduction in distribution, indicating a systematic valuation of PD. This ratio was lower in individuals experiencing pain compared to pain-free individuals. Moreover, 63% reported that PD should be routinely considered in pain management alongside intensity. Results suggest that PD is not merely a trivial descriptor, but a meaningful determinant of healthcare-related decision-making beliefs. Incorporating spatial metrics into clinical assessment and research may better capture how individuals implicitly evaluate pain severity.

BackgroundPostoperative delirium (POD) is a frequent and severe neurocognitive complication following cardiac surgery, associated with poor long-term outcomes. The underlying mechanisms are unclear, and objective biomarkers are urgently needed. MethodsWe used pre- and post-operative plasma samples from 59 patients undergoing cardiac surgery in three separate studies with rigorous delirium assessment using the Confusion Assessment Method in a case-control design. Small extracellular vesicles (sEVs) were isolated from plasma, and their miRNA cargo was profiled using RNA sequencing. Target miRNAs were validated by qRT-PCR, and digital PCR (dPCR). The functional impact of the lead candidate miRNA was investigated in vitro by assessing tau phosphorylation and cell viability in HT22 neuronal cell line. ResultsThere were no differences in sEV morphology or numbers between patients with and without POD. While three candidate miRNAs were initially validated by qRT-PCR, subsequent dPCR analysis confirmed that only the perioperative change in plasma sEV-cargo miR-330-3p expression was significantly greater in patients who developed POD (n = 20) compared with those who did not (n = 20) (5.22 copies/L plasma; 95% Confidence Interval (CI), 1.187 to 9.256; p = 0.0139). Receiver operating characteristic curve analysis for this change yielded an area under the curve of 0.745 (95% CI, 0.589 to 0.901). In vitro overexpression of miR-330-3p in a neuronal cell line significantly increased the phosphorylation of tau at Ser199 (p < 0.0001) and Ser396 (p < 0.001) and reduced cell viability (p < 0.001). ConclusionsOur findings suggest that sEV-bound miR-330-3p increases in patients with POD after cardiac surgery. In vitro results suggest a potential pathogenic role for miR-330-3p, linking a systemic signal to tau-related neuronal injury. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIThis study identifies a specific perioperative increase in small extracellular vesicle (sEV)-cargo miR-330-3p in patients with postoperative delirium (POD) following cardiac surgery. C_LIO_LIWe provide the first evidence that miR-330-3p directly induces tau hyperphosphorylation and reduces neuronal viability in vitro, establishing a potential mechanistic link between systemic sEV signaling and neurodegeneration. C_LI What Are the Clinical Implications?O_LIThe measurement of perioperative change in miR-330-3p could serve as an objective biological marker to assist in the early identification and risk stratification of patients at high risk for POD. C_LIO_LIThe identified miR-330-3p/tau pathway represents a potential new therapeutic target; future interventions aimed at inhibiting this specific miRNA might help prevent or mitigate POD-related neuronal injury. C_LIO_LIThese findings emphasize the importance of monitoring dynamic sEV-cargo changes to better understand and manage perioperative neurocognitive disorders. C_LI

IntroductionThere is increasing interest in the peripheral administration of vasopressors for two main reasons: (1) to expedite vasopressor initiation in patients with refractory shock and (2) to avoid the potential complications associated with central venous catheter placement. The current evidence on the use of peripheral vasopressor administration is primarily based on single-center observational studies. There are inconsistencies in the administration of peripheral vasopressors, including catheter gauge and location, monitoring practices, vasopressor concentrations, and duration of use. This has made it difficult for institutions to develop best practice guidelines. A randomized controlled trial is needed to address this knowledge gap. Methods and analysisThe Peripheral Use of Low-dose Vasopressors for Safety and Efficacy (PULSE) in the intensive care unit is a prospective, unblinded feasibility study. Eligible patients will be 18 years or older, have no existing central venous catheter or peripherally inserted central catheter and have the presence of shock requiring a minimum vasopressor dose of any of the following: norepinephrine 0.0625 mcg/kg/min, phenylephrine 0.625 mcg/kg/min, and epinephrine 0.0625 mcg/kg/min. Fifty patients will be randomized 1:1 into either the peripheral venous catheter or central venous catheter group. The primary outcome is feasibility, defined as (1) a recruitment rate of 4 participants per month, (2) a data capture rate of [&ge;]90%, and (3) a <50% conversion rate from peripheral to central access. The secondary outcomes include the safety of peripheral vasopressor use, alive and central-line-free days, the number of attempts needed to place a catheter, volume status, in-hospital mortality rate, ICU and hospital length of stay, and patient-centred important outcomes. ImplicationsThe data collected from this study will inform the design of a definitive randomized controlled trial to assess the safety and efficacy of protocol-driven peripheral vasopressor administration. Ethics and disseminationThis study received approval (6042888) from the Queens University Health Sciences/Affiliated Teaching Hospitals Research Ethics Boards. Results of this study will be presented at critical care conferences and submitted for publication. Trial registration numberNCT06920173 (https://clinicaltrials.gov/study/NCT06920173).

ObjectivesEpidural spinal cord stimulation (SCS) is an emerging therapy for motor rehabilitation following spinal cord injury (SCI) and other motor disorders. Conventionally, SCS leads are placed along the dorsal spinal cord (SCSD), where stimulation activates large diameter afferent fibers, which indirectly activate motoneurons through reflex pathways. This leads to broad activation of flexor and extensor muscles and limited fine-tuned control of motor output. Targeting the ventral spinal cord (SCSV) may enable more direct activation of motoneuron pools, potentially improving the specificity of muscle activation; however, there is currently no established method to place leads ventrally. To address this, we evaluated the feasibility of four modified percutaneous implantation techniques to target the ventrolateral thoracolumbar spinal cord. Materials and methodsPercutaneous SCSV implantation was performed in three human cadaver torso specimens under fluoroscopic guidance. The following approaches were evaluated: sacral hiatus, transforaminal, interlaminar contralateral, and interlaminar ipsilateral. The leads in the latter 3 approaches were inserted between L1 and L5. Eighteen implants were attempted, with nine leads retained for analysis. Lead and electrode position were assessed using computed tomography (CT) with three-dimensional reconstruction, along with anatomical dissection to verify lead and electrode placement within the epidural space. ResultsSuccessful ventral epidural lead placement was achieved using all four implantation approaches. The sacral hiatus (16/16 electrodes) and transforaminal (8/8 electrodes) approaches resulted in exclusively ventrolateral placement. The interlaminar contralateral approach led to 27/32 electrodes positioned ventrolaterally and 5/32 dorsally. The interlaminar ipsilateral implantation approach led to 14/32 electrodes positioned ventrolaterally and 18/32 positioned ventromedially. ConclusionsThese findings demonstrate that ventral epidural SCS lead placement can be achieved using modified percutaneous implant techniques. The four approaches outlined here provide a clinically feasible pathway to SCSV and establishes a foundation for future clinical studies investigating SCSV for motor rehabilitation following SCI.

Abstract Objective: The objective of this study was to compare hospital length of stay and other clinical outcomes between intact fish skin graft (IFSG; Graftguide, Kerecis, Arlington, VA) and synthetic/biosynthetic dermal substitutes (SSS; Integra Dermal Regeneration Template and NovoSorb Biodegradable Temporizing Matrix) in propensity score matched burn patients using the American Burn Association Burn Care Quality Platform. Methods: This retrospective cohort study identified adult patients treated with a single dermal substitute product during hospitalization for acute burn injury. Patients receiving IFSG (n = 93) were matched 1:4 to patients receiving SSS (n = 372) using nearest neighbor propensity score matching on the logit scale. Matching covariates included total body surface area burned (TBSA), patient age, sex), burn severity classification, inhalation injury, and trauma diagnosis. The primary outcome was hospital length of stay (LOS), analyzed using a gamma generalized linear mixed model (GLMM). Secondary outcomes included the incidences of sepsis, graft loss, venous thromboembolism (VTE), and hospital acquired pressure injury (HAPI). A prespecified sensitivity analysis was performed using a broader mixed product cohort. Results: A total of 93 IFSG treated patients from 17 burn centers admitted between the years 2019 and 2025 were matched 1:4 to 372 SSS treated patients from 44 centers. Unadjusted mean LOS was 24.1 days (median 20, IQR 11 to 32) in the IFSG treated group and 36.7 days (median 31, IQR 17 to 52) in the SSS treated group representing a 12.6 day reduction. GLMM-adjusted estimated marginal mean LOS was 24.2 days (95% CI, 20.0 to 29.4) for IFSG versus 33.5 days (95% CI, 30.0 to 37.6) for SSS (ratio 0.723; p = 0.00245), representing a 9.3 day reduction. Sepsis (1.1% vs 4.6%), graft loss (3.2% vs 8.3%), VTE (2.2% vs 2.7%), and HAPI (2.2% vs 3.8%) were all numerically lower in the IFSG treated arm; although GLMM-adjusted odds ratios were not statistically significant for any individual complication. The mixed cohort sensitivity analysis (n = 229 IFSG vs 458 SSS across 67 centers) confirmed the primary finding with GLMM adjusted LOS ratio 0.716 (p = 0.0001). Conclusions: In this propensity score matched analysis of the ABA registry, IFSG was associated with a statistically significant and clinically meaningful reduction in hospital length of stay compared with synthetic/biosynthetic dermal substitutes, in requiring dermal substitution and autografting, with all complication rates, sepsis, graft loss, VTE, and HAPI, numerically lower in the IFSG-treated arm. The shorter hospitalization was not achieved at the expense of safety. These findings support IFSG as a viable alternative to synthetic dermal substitutes in burns requiring dermal substitution and autografting. Prospective studies are warranted particularly in larger burns requiring staged reconstruction.

ObjectiveThis study evaluates the impact of systemic GLP-1 receptor agonist (GLP-1RA) use on surgical wound healing in high-risk surgical populations, including patients with diabetes, and implications for perioperative planning and healing outcomes. ApproachThis pilot retrospective cohort study compared adult surgery patients with non-healing postoperative wounds by their GLP-1RA use. Outcomes included healing status, time to wound closure, and number of surgical interventions. ResultsThe cohort included 35 non-GLP-1RA users and 16 GLP-1RA users with comparable baseline characteristics, except for significant higher prevalence of venous insufficiency among users. Though median time to closure was similar for all patients, users required fewer surgical interventions and their wounds reached closure in significant difference from non-users. Among patients with diabetes, all GLP-1RA users healed significantly compared to non-users. InnovationThe impact of GLP-1RA therapy on wound healing in high-risk reconstructive and soft-tissue surgery remains poorly defined. This pilot cohort addresses that gap, offering an early signal that GLP-1RA use is associated with improved wound healing and fewer postoperative interventions. These findings may inform perioperative practice by identifying a systemic pharmacologic factor that optimizes surgical outcomes in high-risk populations. ConclusionGLP-1RA use was associated with higher healing rates and fewer interventions, particularly among patients with diabetes. These findings support a beneficial role in surgical wound healing and warrant larger multi-site studies.

Per- and polyfluoroalkyl substances (PFAS) are chemicals linked to obesity and metabolic dysfunction, but their role in bariatric surgery remains poorly understood. This prospective pilot study examined correlations between plasma PFAS concentrations, body composition, and glycemic measures in adults undergoing bariatric surgery. Thirty-two patients (91% female; 66% Black; mean age 43 years) were enrolled preoperatively; twenty-two completed follow-up at a mean 8.6 months post-surgery. Three PFAS (PFHxS, PFNA, and PFOS) were quantified by plasma liquid chromatography-mass spectrometry; body composition and insulin sensitivity were assessed by dual-energy X-ray absorptiometry and intravenous glucose tolerance testing. At baseline, higher plasma PFNA and PFOS concentrations tracked with lower total lean mass ({rho}s = -0.46 and -0.48, respectively) and lean mass index ({rho}s = -0.46 and -0.42), and PFNA was inversely correlated with body weight ({rho}s = -0.40). No baseline associations were observed with adiposity or glycemic indices. Postoperatively, PFHxS concentrations decreased (median = -1.103 ng/mL, p < 0.001), whereas PFNA and PFOS did not change. Average PFNA was positively correlated with postoperative changes in HOMA-IR ({rho}s = 0.51) and total lean mass ({rho}s = 0.49). No significant associations were observed for average PFHxS or PFOS. These findings suggest that PFNA and PFOS may be linked to reduced lean tissue at baseline, and that PFNA burden modestly tracks with attenuated metabolic and body composition recovery. In an ANCOVA, baseline PFNA was not significantly associated with postoperative HOMA-IR or total lean mass. Larger, longitudinal studies are needed to clarify how PFAS influence these associations.

BACKGROUND Point-of-care (POC) high-sensitivity cardiac troponin (hs-cTn) testing has the potential to expedite decision-making and reduce emergency department (ED) length of stay for patients presenting with possible myocardial infarction (MI) by ensuring that results are consistently available when looked for by clinicians. We assessed the real-life effectiveness and safety of implementing POC hs-cTn testing in the ED. METHODS We conducted a pragmatic, stepped-wedge cluster randomized trial. The control arm was usual care with an accelerated diagnostic pathway utilizing a single-sample rule-out step with a central laboratory hs-cTn assay. The intervention arm used the same pathway with a POC hs-cTnI. The primary effectiveness outcome was ED length of stay assessed using a generalized linear mixed model, and the safety outcome was 30-day MI or cardiac death. RESULTS Six sites participated with 59,980 ED presentations (44,747 individuals, 61{+/-}19 years, 49.5% female) from February 2023 to January 2025, in which 31,392 presentations were during the intervention arm. After adjustment for co-variates associated with length of stay, the intervention reduced length of stay by 13% (95% confidence intervals [CI], 9 to 16%. P<0.001), corresponding to a reduction of 47 minutes (95%CI, 33 to 61 minutes) from a mean length of stay in the control arm of 376 minutes. The 30-day MI or cardiac death rate was similar in the control and intervention arms (0.39% and 0.39% respectively, P=0.54). CONCLUSIONS Implementation of whole-blood hs-cTnI testing at the POC into an accelerated diagnostic pathway was safe and reduced length of stay in the ED compared with laboratory testing.

Background: Jejunal diverticulitis is an uncommon but increasingly recognized cause of acute abdomen. It can present with a range of CT findings, including peridiverticular inflammation, bowel wall thickening, and fecalized small bowel content, with perforation or abscess occurring as complications in roughly 6% of cases. Case reports note varied presentations with jejunal and ileal involvement, treatment ranging from nonoperative management with antibiotics to urgent surgical intervention. Though rare, small bowel diverticulitis, particularly involving the jejunum, can result in significant morbidity, including peritonitis and sepsis, requiring heightened clinical suspicion in elderly or immunocompromised patients. Methods: We conducted a single center retrospective review of patients diagnosed with jejunal diverticulitis in a single academic center's Emergency General Surgery registry between December 2017 and December 2024. Of 42 patients initially identified, 34 had confirmed diagnoses on chart review. Data abstracted included age, sex, imaging modality, presence of perforation, serial physical exams, lab values (CBC, lactate), ICU admission, length of stay (LOS), antibiotic duration, operative status and timing, distance of residence from our institution, disposition after index admission, and readmission within one year. Results: Of the 34 confirmed cases, 24 (71%) were perforated: 2 presented with small bowel obstruction, 16 with abscesses and/or contained perforations, and 1 with both. 19 of the 24 perforated patients required operative intervention: 9 proceeded directly to the OR, 3 on hospital day one, and 2 as late as hospital day six. Among non-operative patients treated with antibiotics alone, the average LOS was 6 days (range: 2-23). Two patients were readmitted within one year: neither had undergone surgery during their index admission and neither were related to their index admission. Overall, three patients died: two during the index admission (both perforated and operated on) and one on readmission. Conclusion: Compared to the 6% complication rate reported in prior literature, our series demonstrates a notably higher rate of perforation (71%) among patients diagnosed with jejunal diverticulitis. Operative intervention was common, though a subset of patients was successfully managed non-operatively with antibiotics. Mortality was limited to patients with significant comorbidities and complex presentations. These findings underscore the heterogeneity in presentation and outcomes and highlight the need for a standardized approach. Development of practice guidelines incorporating clinical, radiographic, and laboratory parameters may improve diagnostic accuracy and guide timely, evidence-based management of this rare but serious condition.

Background: Extreme-phenotype comparisons allowed the discovery of novel asthma genetic risk loci. However, this approach remains unexplored in epigenome-wide association studies (EWAS). We aimed to identify bulk and cell-specific methylation markers of asthma with severe exacerbations across diverse ancestry groups. Methods: We conducted a meta-EWAS of 739,543 CpGs in whole blood among 1,192 African American and Latino pediatric populations, comparing non-asthmatics and asthma exacerbators. Genome-wide CpGs were followed up for replication in a meta-analysis across 1,516 ethnically diverse participants and in a cross-tissue evaluation of 393 nasal samples. We conducted differentially methylated region (DMRs), cell-type-deconvoluted, and quantitative trait loci analyses (whole-genome sequencing n=1,668; RNA-seq n=1,209). We examined enrichment in traits, pathways, and druggable genes, and analyzed DNAm predictors of plasma proteins and aging. Results: DNAm at 505 CpGs and 119 DMRs in whole blood were associated with asthma exacerbations (p<9x10-8, {lambda}=1.05). We replicated 25 CpGs in blood cells, cross-validated 7 in nasal samples, and detected 42 cell-specific DNAm markers mainly driven by T cells. DNAm at 134 CpGs was associated with gene expression in whole blood, including 118 associations with T-cell receptor genes, and 446 CpGs were regulated by [&ge;]1 genetic variant. We found enrichment for previous associations with environmental exposures, immune disorders, immune and inflammatory pathways, and druggable genes by developmental drugs. 21 methylation-predicted plasma proteins, involved in host defense, and one lung aging clock were associated with asthma exacerbations. Conclusions: The first meta-EWAS of extreme asthma phenotypes identified hundreds of novel DNAm markers, suggesting novel methylation biomarkers and candidate drugs for asthma and supporting the role of T cells.

Background: The Therapeutic Distance framework (Paper 1) achieved AUC 0.61 for orbit-based mortality prediction in 11,627 sepsis patients. We hypothesised that incorporating state-dependent parameter relevance would substantially improve prediction. Methods: We extended the framework to 84,176 ICU patients from MIMIC-IV v3.1 across 16 clinical syndromes. Validation included full-population leave-one-out (n=59,362), head-to-head comparison against SAPS-II and logistic regression on 34,467 matched patients with bootstrap confidence intervals, temporal validation, outcome permutation, sensitivity analysis, and calibration assessment. Results: Full-population leave-one-out achieved AUC 0.832 (n=59,362). On 34,467 matched patients, Therapeutic Distance (AUC 0.841) significantly outperformed both SAPS-II (0.786; delta=+0.055, 95% CI +0.048 to +0.061, p<0.001) and logistic regression (0.788). Temporal validation showed stable performance (delta=-0.006). Outcome permutation confirmed genuine signal (AUC 0.859 to 0.498 with shuffled mortality). Sensitivity analysis demonstrated near-zero variation (delta 0.0006-0.003). The framework performed well for 8 of 16 syndromes (AUC >0.70) and failed for DKA and post-cardiac surgery (AUC <0.40). Conclusions: Therapeutic Distance provides therapy-specific risk stratification that exceeds both established severity scores and standard machine learning while remaining robust to hyperparameter choices, temporal drift, and outcome permutation.

Background Acute respiratory distress syndrome (ARDS) is characterised by substantial physiological heterogeneity, which contribute to a very variable clinical outcomes and therefore inconsistent responses to ventilatory strategies. We aimed to externally validate physiological ARDS subphenotypes previously identified using routine ventilatory and gas-exchange variables, assess their prognostic relevance across independent cohorts, and examine heterogeneity of treatment effect according to PEEP strategy. Methods Unsupervised Gaussian Mixture Modelling was used to identify physiological subphenotypes based on ventilatory mechanics and gas-exchange parameters. Labels were subsequently used to train and validate supervised classifiers using XGBoost. Prognostic relevance was assessed across three independent cohorts, including two randomised controlled trials (ALVEOLI and LOVS). Predictive enrichment for PEEP strategy was evaluated using individual patient data from ALVEOLI and LOVS (n = 1,532) using intention-to-treat analyses, applying both one-stage and two-stage fixed-effects IPD meta-analytic approaches to test for interaction between physiological subphenotype and PEEP strategy. Results Two distinct physiological subphenotypes, termed Efficient and Restrictive, were replicated across independent cohorts. Across each cohort, patients classified as Restrictive consistently exhibited higher all-cause 28-day mortality compared to Efficient patients. When pooled across studies, the Restrictive subphenotype was associated with a significantly increased risk of death (pooled odds ratio 1.75, 95% CI 1.36-2.24), with no evidence of between-study heterogeneity. Predictive analyses showed a statistically significant interaction between physiological subphenotype and PEEP strategy in the one-stage IPD model (p for interaction = 0.037), with concordant findings in the two-stage fixed-effects IPD meta-analysis (interaction OR 1.91, 95% CI 1.00-3.66; I2 = 0%). Higher PEEP was associated with increased mortality in Efficient patients and reduced mortality in Restrictive patients, indicating effect modification by physiological subphenotype. Interpretation Physiological ARDS subphenotypes derived from routinely collected bedside data provide robust and externally validated prognostic stratification across observational and randomised trial cohorts. The observed interaction with PEEP strategy suggests that underlying physiological profiles may influence treatment response, supporting the concept that physiology-based be a starting point for personalized medicine and therefore better ventilatory strategies in future clinical trials.

Background: Patient matching in intensive care databases yields sample sizes too small for individualised outcome analysis. Current AI systems provide population-level guideline summaries but omit stratification variables that may invert therapy signals at the individual level. Methods: We developed the Therapeutic Distance framework, which computes the z-standardised distance between a patient's clinical parameters and the centroid of MIMIC-IV patients who received each therapy: d(P,T) = sum of wi(T) x |(Li - mui(T)) / sigmai|. We hypothesise that patients at the same distance to a therapy (same orbit) have comparable outcomes. Six validation experiments were performed on 11,627 sepsis patients (SAPS-II 30-80) from MIMIC-IV v3.1. Results: Echo-stratified vasopressin recipients showed mortality of 30.1% (n=146, 95% CI 22.6-37.7%) versus 53.9% without echo (n=2,426, 95% CI 51.9-55.9%). Confidence intervals did not overlap (bootstrap, 1,000 resamples). However, echo-stratified patients had lower general severity (SAPS-II 49.2 vs 53.9) but higher cardiac biomarkers (troponin 1.0 vs 0.51 ng/mL), indicating that the observed difference is compatible with both severity confounding and a possible cardiac-specific vasopressin effect. Leave-one-out prediction with uniform weights achieved AUC 0.61 as a structural baseline. Conclusions: Therapeutic Distance replaces patient matching with orbit matching, substantially increasing usable sample sizes. The echo-vasopressin finding is hypothesis-generating and mechanistically plausible but not causally proven. The framework is intended as a clinical decision support signal under uncertainty, not as a causal inference method.

Background: Cardiogenic shock (CS) remains associated with high short-term mortality despite contemporary advances in care. The association between institutional cardiac capability and outcomes?particularly among transferred patients and after accounting for clinical instability?remains incompletely defined. Objectives: To evaluate the association between hierarchical hospital cardiac capability and in-hospital mortality using a latent measure of acute physiologic severity. Methods: Using the National Inpatient Sample (2016?2022), hospitals were classified into five hierarchical tiers ranging from non-PCI (Tier 1) to heart transplant/durable LVAD centers (Tier 5). Generalized structural equation modeling (GSEM) assessed the relationship between hospital tier and mortality. A latent "Acute Severity" construct?comprising cardiac arrest, acute kidney and liver injury, and mechanical ventilation?was incorporated to model the effects of clinical instability Results: Among an estimated 1,177,180 CS hospitalizations, most occurred at cardiac surgical and transplant/LVAD centers. Crude mortality declined stepwise from non-PCI hospitals (64.5%) to transplant/LVAD centers (36.5%). After adjustment, higher hospital tier was independently associated with lower mortality (Tier 2 OR 0.43 [95% CI 0.38?0.48]; Tier 3 OR 0.37 [0.32?0.43]; Tier 4 OR 0.33 [0.30?0.38]; Tier 5 OR 0.35 [0.31?0.40]). Although transfer-in status was associated with increased mortality (OR 1.39 [1.33?1.46]), this association was attenuated at cardiac surgical and transplant/LVAD centers, consistent with a mitigation of transfer associated risk. Conclusions: Higher hospital cardiac capability is independently associated with lower mortality in CS. Advanced centers are associated with mitigation transfer-associated risk, supporting regionalized hub-and-spoke systems with early referral to high-capability centers.