British Journal of Anaesthesia

BackgroundThere is disparity between the incidence of malignant hyperthermia (MH) reactions and the prevalence of variants in the RYR1 gene associated with susceptibility to MH (where susceptibility is determined by in vitro contracture tests). Our aims were to use clinical and genetic data from the UK to explain this disparity and to examine if these data are consistent with the clinical risk of MH being inherited as an autosomal dominant trait. MethodsClinical MH and genotyping data were extracted from the UK MH registry. The numbers of general anaesthetics delivered in the UK were estimated from national surveys and reports, with population data obtained from government statistics. The prevalence of RYR1 variants in the UK population was estimated using UK Biobank data. The incidence of MH reactions 1988-93 was used to estimate the prevalence of the clinical risk of MH in the UK. Bayesian modelling, calibrated against actual data, was used to evaluate the likely mode of inheritance of the clinical risk of MH and the relative risk of clinical MH associated with different RYR1 variants. ResultsThe probability of index cases developing MH with each general anaesthetic can be expressed as a constant hazard of 0.46 (95% CI 0.42 - 0.50, n=375). We used peak incidence data (1988-93) to estimate the prevalence of the risk of MH as 1 in 44,000 (95% credibility interval, 1 in 40,000 to 1 in 48,000). The incidence of MH has declined over the past 22 years but the rate of decline is inconsistent with autosomal dominant inheritance (P < 10-10). The risk of MH varied by up to 150-fold between carriers of 28 recurrent RYR1 variants. ConclusionThese findings support a threshold inheritance model for clinical MH and have implications for diagnostics, both genotyping and in vitro contracture test phenotyping.

BackgroundIntraoperative opioid administration for cardiac surgery varies greatly, with most of this variability arising from anesthesiologist and institutional practices. Anesthesiologists administer intraoperative opioids via intermittent boluses and continuous infusions. Real-world data have shown infusion administration to be a strong determinant of high intraoperative opioid exposure, but whether bolus or infusion administration of sufentanil affects post-operative outcomes is unknown. MethodsWe conducted a prospective, randomized, single-blind controlled trial to compare the impact of intraoperative intermittent bolus administration versus continuous infusion of sufentanil on time to extubation in adult patients undergoing nonemergent cardiac surgery with cardiopulmonary bypass at a single tertiary referral university hospital in the United States. ResultsThe primary endpoint was the time from operating room departure to extubation in the intensive care unit. The study was terminated early for futility after an interim analysis of 50 subjects. The infusion group received statistically higher doses of intraoperative opioid. The per-protocol analysis found no statistical difference in time to extubation between the bolus group (median 2.9 hours) and infusion group (median 2.6 hours). Secondary outcomes, including post-operative pain scores, opioid consumption, ICU length of stay, and hospital stay, and adverse event rates were comparable between groups. ConclusionsIntraoperative administration of sufentanil via bolus or infusion results in similar time to extubation and recovery metrics. Since continuous infusions are a strong predictor of higher total intraoperative opioid doses, protocols emphasizing administration via intermittent boluses may reduce opioid exposure without compromising recovery. Key PointsO_ST_ABSQuestionC_ST_ABSDoes the method of intraoperative sufentanil administration, either by intermittent bolus or infusion, affect weaning from mechanical ventilation in the intensive care unit after cardiac surgery? FindingsThe method of sufentanil administration did not affect time to extubation after cardiac surgery, but the infusion group received significantly higher intraoperative opioid doses compared to the intermittent bolus group. MeaningIntermittent opioid bolus administration may reduce intraoperative opioid dosage without negatively impacting recovery after cardiac surgery.

IntroductionPostoperative complications after major surgery have substantial impacts on morbidity and resource utilisation. We investigated whether adding high-dimensional metabolomic and proteomic data to standard clinical variables would improve the prediction of a range of postoperative complications. MethodsWe analysed data from UK Biobank, a large prospective cohort study. Participants who underwent major surgery and had metabolomic and/or proteomic data were included. The primary outcomes were postoperative atrial fibrillation, acute kidney injury, acute myocardial infarction, delirium, stroke and surgical site infection. We trained machine learning models (elastic net penalised regression) with a range of feature sets to predict these outcomes. For outcomes where sample sizes were below recommended levels for predictive modelling, we employed transfer learning from the non-postoperative domain. We compared the predictive performance (AUROC, sensitivity, specificity) of models using only baseline clinical variables with those integrating single- and multiomic datasets. ResultsThe dataset included 158,156 individuals undergoing qualifying surgery. The numbers of cases with omic data varied across outcome phenotypes and feature sets: metabolomic: 144-1596, proteomic: 27-289 and multiomic: 15-219. Baseline clinical models achieved robust predictive performance (AUROC 0.72-0.88, sensitivity 0.71-0.80). The addition of metabolomic and/or proteomic features, using a variety of integration approaches, provided no clinically meaningful improvement in performance across any of the clinical phenotypes. Transfer learning from the non-postoperative domain improved model performance and stability but did not outperform baseline clinical models. ConclusionsThe addition of metabolomic and/or proteomic data from samples collected at a temporal distance from surgery does not improve pre-operative risk prediction compared to standard clinical variables. The lack of incremental predictive value likely reflects the extended gap between biobank sampling and the surgical event. The success of transfer learning from non-postoperative settings suggests shared biological risk between chronic and acute phenotypes.

BackgroundPropofol dosing guidelines recommend age-based reductions because hypnotic sensitivity increases in older adults. Most real-world evaluations of induction practice, however, have relied on total weight-normalized dose (mg/kg) rather than estimating cerebral exposure using pharmacokinetic models. Because age-related pharmacokinetic changes alter the relationship between administered dose and peak effect-site concentration (Ce,max), mg/kg surrogates may misrepresent true age-dependent exposure during induction. MethodsA retrospective reconstruction of 250,640 adult anesthetic inductions was performed using high-fidelity EHR medication timestamps. Propofol effect-site concentration trajectories were simulated at 1-second resolution using the Eleveld model. Ce,maxwas benchmarked against age-adjusted hypnotic requirements (Ce50) derived from the Eleveld model (standardized to a target Bispectral Index{approx} 47). Age-exposure relationships were estimated using covariate-adjusted natural cubic splines, controlling for BMI, sex, and ASA physical status. ResultsFrom young adulthood (18-24 years) to the oldest cohort (85-89 years), weight-normalized induction doses were reduced by 32% (3.16 to 2.16 mg/kg). However, modeled Ce,max declined by only 17% (3.70 to 3.06 {micro}g/mL), while the estimated physiological requirement declined by 34% (3.37 to 2.21 {micro}g/mL), creating a widening titration offset with age. At age 75, the adjusted probability of exceeding the individual hypnotic requirement was 89.6% (95% CI: 89.3-89.8%). Notably, 54.7% (95% CI: 54.2-55.2%) of 75-year-old patients achieved peak exposures exceeding the aver-age requirement of a healthy 20-year-old, indicating persistent anchoring of exposure to youthful levels. Findings were robust across model specifications and inclusion criteria. ConclusionsIn over a quarter-million inductions, real-world age-based dose re-ductions did not produce proportional reductions in peak propofol brain exposure. Achieved concentrations declined far more slowly than modeled geriatric sensitivity increases, consistent with systematic over-exposure in older adults. These findings suggest that weight-based dosing heuristics inadequately capture age-dependent exposure and support a transition toward exposure-informed and neurophysiologically guided induction titration in geriatric anesthesia.

BackgroundBuprenorphine use in the intensive care unit (ICU) remains not well studied despite growing perioperative guidance supporting its continuation and initiation for patients with opioid use disorder (OUD). Trauma ICU admissions represent a critical opportunity to address untreated OUD, as well as continuation of an already established treatment plan for OUD, yet barriers limit its adoption in this setting. MethodsThis single-center quality improvement study evaluated for inpatient buprenorphine prescribing patterns following provider education at a tertiary academic trauma center. Adult trauma ICU patients with OUD admitted between 2016-2024 were identified through the institutional trauma registry. Patients with pre-admission buprenorphine were excluded, yielding a cohort of 95 patients: 24 buprenorphine-exposed (initiated in the hospital) and 71 controls. Primary outcomes included pain scores and opioid requirements (morphine milligram equivalents, MME) during the first 48 hours. Secondary outcomes included hospital length of stay (LOS), discharge disposition, and 90-day readmission. ResultsBaseline characteristics were similar between groups. No statistically significant differences were observed in first recorded pain scores (median 8 vs. 10; p=0.35), mean 48-hour pain scores (7.40 vs. 7.76; p=0.44), or total opioid consumption (232 vs. 119 mg MME; p=0.45). Median hospital LOS (16 vs. 19 days; p=0.48) and 90-day readmission rates (42.3% vs. 33.3%; p=0.40) were also comparable. ConclusionInpatient buprenorphine initiation in trauma ICU patients with OUD was not associated with worse pain control, increased opioid requirements, or adverse clinical outcomes. These findings support the integration of buprenorphine into critical care pathways as a safe strategy to address OUD during hospitalization and improve long-term recovery continuity.

BackgroundPostoperative delirium (POD) is a common complication of surgery. It is associated with a number of detrimental effects, including mortality and healthcare costs. We sought to determine whether common comorbidity indices are predictors of POD. MethodsUsing the Medical Information Mart for Intensive Care (MIMIC)-IV database, we identified 8022 abdominal surgery procedures across 7212 adult patients. We calculated both the Charlson comorbidity index (CCI) and the Elixhauser comorbidity index (ECI) for each procedure and used logistic regression to predict postoperative delirium, which was defined as delirium within 30 days following the procedure. ResultsModels based on either the CCI and ECI were predictive of postoperative delirium (area under the receiver-operator characteristic curve (AUC-ROC) of 0.622 and 0.652, respectively). However, the addition of other factors known to be associated with delirium improved model performance (AUC-ROC of 0.680). ConclusionsBoth the CCI and ECI are predictors of postoperative delirium in patients undergoing abdominal surgery. Addition of factors known to be associated with delirium renders additional predictive value and should be included in models that predict postoperative delirium.

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.

BackgroundSpinal anesthesia for cesarean delivery commonly causes maternal hypotension, which may compromise uteroplacental perfusion and maternal comfort. Guidelines recommend maintaining maternal blood pressure near baseline with prophylactic vasopressor strategies, yet titration remains reactive. We evaluated an autoregressive with exogenous input (ARX) decision-support algorithm that provides real-time forecasts of maternal mean arterial pressure (MAP) to support vasopressor management during cesarean delivery under spinal anesthesia. MethodsIn this single-center, open-label, prospective pilot study, 20 pregnant patients at term undergoing elective cesarean delivery under spinal anesthesia received standard care supplemented by ARX-generated MAP predictions at 1-, 2- and 3-minute horizons. Clinicians titrated phenylephrine per institutional protocol while reviewing ARX predictions, retaining full autonomy for dosing decisions. Predictive performance was quantified using root mean square error (RMSE), mean absolute error (MAE), coefficient of determination (R{superscript 2}), and fraction of improvement in total error (FIT). ARX-guided patients were matched 1:2 to nonconcurrent controls (n = 40) on attending anesthesiologist and intrathecal bupivacaine dose, with nearest-neighbor matching on age and body mass index. Exploratory outcomes included hypotension (MAP <80% of baseline), phenylephrine dose, maternal nausea, and neonatal outcomes. For minute-level hypotension classification performance, sensitivity/specificity (and related metrics) were estimated using generalized estimating equations (GEE) to account for within-patient clustering of repeated observations. ResultsOne-minute-ahead ARX predictions achieved a mean ({+/-}SD) RMSE of 3.71 {+/-} 3.26 mmHg and MAE of 2.75 {+/-} 2.52 mmHg, with R{superscript 2} 0.34 {+/-} 0.63 and FIT 21.1% {+/-} 18.7%. Predictive performance decreased at longer horizons. For hypotension prediction, one-minute-ahead GEE-estimated population-average sensitivity and specificity were 57.39% and 99.74%, respectively. During the observation window, in exploratory comparisons with matched nonconcurrent controls, ARX-guided patients had a shorter duration of hypotension (0.8 {+/-} 1.9 vs 3.0 {+/-} 3.8 minutes; P = .005) and a lower incidence of hypotension (25.0% vs 52.5%; P = .033), but a higher phenylephrine dose (1823 {+/-} 659 vs 974 {+/-} 328 {micro}g; P = .001). Maternal nausea incidence was lower in the ARX group compared with matched nonconcurrent controls (5% vs 35%; P = .014), with similar neonatal outcomes. ConclusionsIn this prospective pilot study, an ARX decision-support algorithm provided accurate 1-minute-ahead MAP forecasts and was associated with higher phenylephrine dosing and shorter maternal hypotension duration compared with matched nonconcurrent controls. These findings support further evaluation in larger, randomized trials. Summary statementIn this prospective pilot study of 20 patients undergoing cesarean delivery under spinal anesthesia, an autoregressive with exogenous input (ARX) decision-support algorithm provided real-time blood pressure forecasts and was associated with a shorter hypotension duration but higher phenylephrine dose compared with matched nonconcurrent controls. These preliminary data support further evaluation of ARX-guided, algorithmic vasopressor management in larger, multicenter trials. Key PointsO_LIQuestion: In pregnant patients at term undergoing elective cesarean delivery under spinal anesthesia, can a real-time ARX algorithm accurately forecast MAP and support vasopressor management? C_LIO_LIFindings: One-minute-ahead forecasts were accurate (RMSE 3.71 mmHg), and ARX-guided care was associated with a shorter duration of hypotension and a higher phenylephrine dose versus matched nonconcurrent controls C_LIO_LIMeaning: Real-time MAP forecasting is feasible and warrants randomized evaluation to confirm clinical benefit and characterize trade-offs. C_LI

BackgroundThe transition from acute to chronic pain represents a failure of physiological resolution. While systemic immune cell counts and androgen levels have been associated with this transition, the specific molecular mediators remain poorly understood. We sought to identify the functional proteomic drivers of long-term pain persistence and determine their independence from systemic factors. MethodsWe identified a longitudinal persistence cohort (N=3,221) within the UK Biobank who reported acute pain at baseline and were followed for resolution or persistence. Using the Olink Explore 3072 platform, we screened 2,923 serum proteins. Multivariable competition models were employed to evaluate the independent predictive power of top proteomic hits alongside systemic monocyte counts and circulating free testosterone levels, adjusted for age and sex. ResultsOur proteome-wide screen identified Lactoperoxidase (LPO) as a dominant and highly significant predictor of pain persistence. In the fully adjusted competition model, each standard deviation increase in LPO was associated with a 59% increase in the odds of persistence (OR 1.59, 95% CI 1.25-2.07, p < 0.001). Notably, after accounting for LPO, systemic monocyte counts (OR 0.93, p = 0.55) and testosterone levels (OR 0.82, p = 0.46) were no longer significant predictors. Nogo Receptor (RTN4R) also remained a significant predictor in independent models (OR 1.44, p = 0.002). ConclusionsThese exploratory findings demonstrate that long-term pain persistence is associated with specific functional molecular signatures rather than broad systemic cell quantity. The dominance of LPO suggests that secretory peroxidase-driven pathways may be a primary barrier to pain resolution. Furthermore, the association of RTN4R identifies neural repair inhibition as a candidate driver of persistence. These proteins are candidates for further mechanistic investigation.

BackgroundThe evolving nature of patient concerns during pregnancy and delivery, including labor pain, plays a key role in guiding antenatal counseling about labor and delivery, but the timing of these concerns has not been well characterized. Understanding when labor pain becomes a prominent concern for pregnant patients can inform the timing of antenatal education about labor analgesia. ObjectiveThis study aimed to determine how labor pain ranks among pregnancy-related concerns identified by nulliparous pregnant patients and how the relative prominence of these concerns changes across gestation. MethodWe conducted a prospective, single-center longitudinal cohort study of 53 English-speaking, nulliparous patients. Participants ranked their top seven concerns from a list of 13 pregnancy-related concerns, including labor pain, at 20, 24-, 28-, 32-, and 36-weeks gestation. Rankings were scored from 1 (lowest-ranked concern) to 7 (highest-ranked concern), with the six unranked concerns assigned a score of zero. Changes in labor pain concern scores over time were assessed using linear mixed-effects models, adjusting for maternal characteristics and pregnancy- and fetal-related complications. ResultsThe score for concern about labor pain management increased with advancing gestational age, with mean adjusted rank scores increasing from 1.4 at 20 weeks to 3.8 at 36 weeks (P < 0.001). No demographic or clinical covariates were significantly associated with labor pain score. Peak scores were most commonly reported at 28- and 36-weeks gestation. DiscussionWhile labor pain became a greater salient concern along pregnancy, for some nulliparous patients, concern about labor pain arose as early as 20th week gestation, with significant individual variation in the timing of these concerns.

BackgroundPostoperative delirium is a common complication in surgical patients, and is associated with a multitude of negative outcomes, including mortality, dementia, and increased healthcare costs. Therefore, a better understanding of what factors contribute to postoperative delirium, especially those that can be easily obtained, is important. MethodsWe conducted a retrospective cohort study using patients from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Adult patients undergoing procedures in abdominal surgery who did not have pre-existing delirium were included in the study. Overall, we included 8022 procedures across 7212 patients. For each admission, we extracted values obtained from common blood tests, the Charlson and Elixhauser comorbidity score, and patient demographic information. We used stepwise logistic regression to identify predictive factors of postoperative delirium in this cohort. ResultsThe model isolated factors well known to be associated with postoperative delirium, such as age, comorbidity (as represented by the Elixhauser comorbidity score), and Parkinsons disease. The model also selected variables that are less studied, such as minimum preoperative platelets and maximum preoperative sodium levels. We hypothesize that the former is associated with postoperative delirium as a surrogate marker for inflammation as an acute phase reactant, and the second due to it being a marker for cerebral edema and altered neurotransmission. ConclusionPreoperative blood tests contain valuable information that can be used alongside patient demographics and past medical history to better predict the risk of postoperative delirium.

ObjectivePostoperative pain outcomes following spinal fusion surgery remain difficult to predict, as structural and surgical indicators alone offer limited insight into who will experience meaningful relief. A substantial proportion of patients continue to report persistent pain after surgery, underscoring the need for objective markers that can help identify those at risk of poor recovery. Peak alpha frequency (PAF) has emerged as a promising trait-like neural signature of pain sensitivity in experimental models, where individuals with slower PAF tend to exhibit heightened pain sensitivity. Yet despite this link, its ability to forecast longer-term postoperative pain trajectories remains unclear. MethodsSeventeen adults undergoing cervical or lumbar fusion surgery were included. Resting-state, eyes-closed EEG was recorded preoperatively and at multiple visits after surgery. PAF was extracted from central electrodes using the centre-of-mass method. Pain intensity was assessed longitudinally on standardised self-report pain scales. Associations between PAF measures and postoperative pain change were examined using correlation analyses, and receiver operating characteristic (ROC) analyses evaluated discrimination of pain responders ([&ge;]50% improvement). ResultsPreoperative peak alpha frequency (PAF) was positively associated with longer-term pain reduction at the 3-month follow-up, but showed no consistent relationship with early postoperative pain. Across pain measures, a consistent pattern emerged across the Brief Pain Inventory (BPI), visual analogue scale (VAS), and numerical rating scale (NRS), but not the verbal rating scale (VRS) or Short-Form McGill (SF-MPQ). At the 3-month follow-up, associations reached statistical significance for BPI-Worst ({rho} = 0.67, p = 0.017), and BPI-Average Pain ({rho} = 0.62, p = 0.033). VAS and NRS showed moderate-to-strong effects that approached significance in non-parametric analyses and were significant for VAS when treated as an approximately interval measure (Pearson r = 0.63, p = 0.022). ROC analyses using BPI-Worst pain improvement demonstrated good discriminative ability of preoperative PAF for identifying treatment responders at 3 months (AUC = 0.84; 95% CI: 0.61-1.00), with high specificity and moderate sensitivity at the Youden-optimal threshold of 10.11 Hz. By contrast, changes in PAF over time were not reliably related to changes in pain scores, suggesting that PAF functions more as a stable, trait-like predictor than a dynamic biomarker in this context. ConclusionThis study demonstrates the feasibility and potential clinical value of preoperative EEG for characterising individual differences in postoperative pain recovery following spinal fusion. The results identify faster preoperative PAF as a stable neural signal that captures meaningful variability in longer-term pain reduction, with convergent support across multiple patient-reported measures. While replication in a larger cohort is required, these findings establish a clear foundation for evaluating PAF as a candidate neurophysiological marker to inform preoperative risk profiling and potentially personalised perioperative pain-management strategies in spinal fusion patients.

PurposeTo quantify and compare the peak force applied on the glottis during endotracheal intubation across five laryngoscopy techniques, two intubation conditions (standard and simulated laryngospasm), and two operator experience levels, and to assess the effects of stylet use and operator anthropometric characteristics on applied force. MethodsThis prospective, manikin-based experimental study enrolled 50 operators (30 experienced, 20 less experienced). Each performed endotracheal intubation using five techniques: direct laryngoscopy and videolaryngoscopy with a Macintosh blade, each with and without stylet, and videolaryngoscopy with a hyperangulated blade with stylet. A calibrated force sensor positioned at the glottis measured peak forces during standard and simulated laryngospasm conditions. Non-parametric statistical methods were used (Mann-Whitney U, Wilcoxon signed-rank, Friedman tests); effect sizes are reported as rank-biserial correlations. ResultsAcross all techniques, median glottic forces ranged from 4.8 N (IQR: 3.3-6.5) for videolaryngoscopy without stylet to 11.1 N (IQR: 7.5-14.5) for direct laryngoscopy with stylet under standard conditions. No significant differences in applied force were observed between experienced and less experienced operators for any technique-condition combination (all adjusted p = 1.0; |r| [&le;] 0.27). Stylet use significantly increased glottic force across all conditions and groups (median increases 3.4-7.3 N; all p < 0.001; rank-biserial r [&ge;] 0.75). Videolaryngoscopy with a Macintosh blade produced significantly lower forces than hyperangulated videolaryngoscopy under standard conditions (adjusted p = 0.049). Neither grip strength nor hand size correlated with applied force. ConclusionGlottic force during endotracheal intubation is determined primarily by technique and stylet use, not operator experience or anthropometrics. Stylet use is the single largest modifiable contributor to glottic force. These findings have implications for device selection, clinical training, and strategies to minimize airway trauma during intubation. IMPLICATION STATEMENTThis manikin-based study quantifies glottic forces during endotracheal intubation across laryngoscopy techniques, stylet use, and operator experience levels, providing the first comprehensive characterization of right-hand forces transmitted through the tube. Stylet use consistently and substantially increases glottic force regardless of technique or operator experience, informing device selection and training strategies to minimize airway trauma.

Background Social disconnection has emerged as a major public health concern, with health risks comparable to established biomedical factors. At the same time, pain remains the leading cause of years lived with disability worldwide, imposing profound individual and societal costs. Although social factors are increasingly implicated in pain perception and chronification, existing evidence is fragmented across heterogeneous and often conflated constructs of social connectedness. It remains unclear whether subjective experiences such as loneliness or structural factors such as social isolation differentially relate to pain outcomes. A comprehensive synthesis directly comparing these dimensions has been lacking. Methods We conducted a preregistered multivariate meta-analysis (PROSPERO: CRD420250643896) including 239 studies, 520 effect sizes, and 1,407,803 participants from clinical and non-clinical populations. Pain outcomes encompassed sensory, affective, cognitive, and functional domains. Social connectedness was operationalized as loneliness, social isolation, social support, and social exclusion. Multilevel random-effects models accounted for within-study dependency, with extensive sensitivity analyses and correction for small-study bias. Results Across populations and social outcomes, greater social connectedness was associated with lower pain (z = -0.09, 95% CI -0.11 to -0.07). Notably, loneliness emerged as the strongest correlate (z = 0.14, 95% CI 0.11 to 0.17). Associations with social isolation were smaller compared to loneliness but were also significant (z = 0.09, 95% CI 0.05 to 0.13). Social support showed modest, significant inverse associations (z = -0.05, 95% CI -0.08 to -0.03), primarily confined to affective and somatic pain components. No reliable association was observed for social exclusion. Associations were consistent across age, sex, and clinical status, and longitudinal evidence supported temporal links between changes in social connectedness and subsequent pain outcomes. Conclusions This large-scale synthesis identifies subjective social disconnection, particularly loneliness, as a robust correlate of pain across populations and pain dimensions, exceeding the relevance of objective social isolation. Given evidence linking loneliness to increased analgesic and psychotropic medication use, social disconnection may contribute to pharmacological burden and polypharmacy risk in vulnerable populations. Social connectedness emerges as a clinically meaningful, non-pharmacological determinant of pain and a potential target for integrative pain prevention and management strategies.

Background Observational studies have reported an association between inflammation and postoperative complications but it is unclear whether these associations are causal. It is also unknown whether postoperative outcomes share a causal architecture with chronic, all-cause disease. Methods We performed bi-directional two-sample Mendelian randomization to investigate potential causal effects of 19 genetically-proxied inflammatory markers on postoperative acute kidney injury, atrial fibrillation (AF), delirium, myocardial infarction, stroke and surgical site infection, and their all-cause equivalents. Genetic instruments for inflammatory markers were sourced from nine GWAS of up to 204,402 European participants with outcome data derived from UK Biobank. Results The primary postoperative analysis showed a protective effect of down-regulated IL-6 signalling on stroke risk (OR (95% CI) 0.27 (0.11--0.69), p=0.006). However, in the all-cause analysis a causal effect on stroke was not present (OR (95% CI) 1.14 (0.75--1.24), p=0.78), whilst a robust protective effect was seen for down-regulated IL-6 with AF across all three instruments studied (all p<0.009). In postoperative and all-cause analyses, genome-wide variants for CRP showed a protective effect on delirium that was not present in cis-restricted analyses. Conclusions We found evidence supporting a potential causal role for IL-6 signalling in perioperative stroke. However, the divergence in IL-6 effects between postoperative and all-cause outcomes suggests that the inflammatory architecture of acute postoperative complications may differ from chronic disease states. Furthermore, our findings suggest previously reported associations between CRP and delirium likely represent horizontal pleiotropy rather than direct causation. Future work should interrogate local tissue responses and the immediate perioperative period.

Objective: To quantify the effect size of four biopsychosocial amplifier loops on chronic pain outcomes through systematic review and meta-analysis, and to develop a logistic regression-based risk stratification tool for interventional pain medicine. Methods: We searched PubMed, Scopus, and Cochrane Library through March 2026 for studies reporting adjusted odds ratios for associations between (1) sleep disturbance, (2) pain catastrophizing, (3) metabolic/inflammatory markers, (4) preoperative opioid use/polypharmacy, and chronic pain chronification or treatment failure. Random-effects meta-analyses (DerSimonian-Laird) were performed for each loop. Effect sizes were translated into a composite logistic regression model, the Pain Amplifier Loop Framework (PALF), using ln(OR) as first-order coefficient approximations. Results: Forty-four studies with over 500,000 participants were included. Pooled odds ratios were: sleep disturbance OR=1.80 (95% CI 1.65-1.96; k=16), pain catastrophizing OR=2.11 (95% CI 1.71-2.61; k=8), metabolic/fat mass OR=2.02 (95% CI 1.32-3.09; k=7), preoperative opioid use OR=4.48 (95% CI 2.87-6.97; k=6), and opioid-benzodiazepine co-prescription OR=2.62 (95% CI 1.76-3.89; k=7). All four loops converge on TLR4/NF-kB microglial signaling. The PALF model produces a probability of interventional failure enabling stratification into low, moderate, and high risk categories. Conclusions: Four amplifier loops independently increase chronic pain risk. The PALF provides a transparent, clinically actionable risk score requiring prospective validation.

Why some surgical participants experience pain that extends beyond the original site of injury while others do not remains poorly understood. Both pain intensity and widespread pain contribute to recovery and quality of life, yet their psychosocial correlates are often examined separately. Using data from two large pre-surgical cohorts--participants preparing for knee replacement or thoracic surgery--we examined associations between sociodemographic and psychosocial factors, pain intensity at surgical and non-surgical sites, and widespread chronic pain. Across cohorts and outcomes, fatigue showed the strongest and most consistent associations with pain intensity and widespread pain, independent of other measured factors. Fatigue also occupied a central position in statistical association networks and accounted for substantial shared variance among multiple psychosocial variables, including sleep disturbance, depression, stress, and socioeconomic disadvantage. Pain at non-surgical sites was strongly associated with widespread pain and frequently accounted for observed associations between surgical-site pain and widespread pain. Together, these findings highlight robust patterns of association linking fatigue, pain intensity, and widespread pain in pre-surgical populations. One Sentence SummaryFatigue is the strongest and most consistent factor linked to how pain intensifies and spreads before surgery.

IntroductionPatients undergoing anterior cruciate ligament (ACL) reconstruction experience substantial postoperative pain, which delays recovery and leads to both immediate and long-term opioid use. In other knee procedures, infiltration between the popliteal artery and the capsule of the posterior knee (IPACK) has demonstrated analgesic and opioid reducing effects. However, the effect in patients undergoing ACL reconstruction has not been investigated. We aimed to investigate the real-world effect of IPACK in patients undergoing ACL reconstruction on immediate postoperative opioid consumption. ParticipantsIn this single-centre difference-in-differences cohort study, all patients who underwent ACL reconstruction surgery at Bispebjerg Hospital, Denmark, from 1 February 2024 to 30 June 2025 are included. The study further includes a similar reference cohort, comprising all patients who underwent trochleaplasty, Elmslie-Trillat, or medial patellofemoral ligament reconstruction during the same period, and at the same hospital. InterventionThe primary exposure is the implementation of IPACK as part of perioperative management for ACL reconstruction on 1 January 2025. The IPACK was performed under ultrasound guidance, immediately before surgery, administering 20 mL of ropivacaine 0.5% between the popliteal artery and the posterior knee capsule. OutcomesThe primary outcome is the cumulative opioid consumption from surgical incision to 2 hours postoperatively. Secondary outcomes include the cumulative opioid consumption from incision to 24 hours postoperatively, the worst reported pain score at 0-24h postoperatively, occurrence of postoperative nausea or vomiting (PONV) 0-24h postoperatively, length of PACU stay, length of hospital stay, and nerve injuries. As an exploratory outcome, carbon dioxide emissions will be investigated. Statistical analysisThe main analysis will be a standard two-way fixed effects DiD regression assessing the changes occurring at the time of implementation of IPACK in the ACL cohort, with adjustment for the underlying time trend. Continuous outcomes are reported as mean difference (95% confidence interval [CI]), and binary outcomes as absolute and relative risks (95% CI).

BackgroundCesarean section is one of the most commonly performed surgical procedures worldwide and is frequently associated with moderate to severe postoperative pain. While overall pain after cesarean delivery is well described, evidence comparing pain intensity and analgesic use between primary and repeat cesarean sections remains limited. ObjectiveTo compare postoperative pain severity and total analgesic consumption within the first 24 hours among women undergoing primary versus repeat cesarean sections under spinal anesthesia at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia, from January 1 to March 30, 2025. MethodsA prospective cohort study was conducted among 203 women who underwent cesarean delivery under spinal anesthesia. Participants were selected using systematic random sampling and categorized into primary and repeat cesarean groups. Demographic and clinical characteristics were summarized using descriptive statistics. Group comparisons were performed using independent t-tests or Mann-Whitney U tests for continuous variables and Chi-square tests for categorical variables. A p-value < 0.05 was considered statistically significant. ResultsWomen undergoing repeat cesarean sections experienced significantly higher postoperative pain. During movement, 92.1% of women in the repeat group reported moderate to severe pain compared with 66.7% in the primary group (p < 0.001). At rest, moderate to severe pain occurred in 74.3% of the repeat group versus 52.9% of the primary group (p = 0.002). Pain scores within the first 6 hours were also higher in the repeat group (median NRS 7, IQR 7-8) than in the primary group (median NRS 5, IQR 4-7; p < 0.001). Total analgesic consumption was significantly greater among women in the repeat group (243.3 {+/-} 98.4 mg) compared with the primary group (146.3 {+/-} 82.5 mg; p < 0.001). ConclusionsRepeat cesarean sections are associated with higher early postoperative pain and increased analgesic requirements. These findings support the need for individualized and intensified pain management strategies for women undergoing repeat cesarean delivery. Clinical trial numberNot applicable