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Objective: Burnout syndrome, characterised by emotional exhaustion, depersonalisation and decreased personal accomplishment, is well documented in the medical workforce. This study aimed to investigate the prevalence of burnout in New Zealand resident doctors (doctors who have yet to complete their specialty training)., Design: Cross-sectional survey study of resident doctors in New Zealand., Setting: Distributed by email., Participants: 509 resident doctors currently working in New Zealand. Doctors not currently working or those who have completed their specialty training (consultants) were excluded., Primary and Secondary Outcome Measures: Participants were asked about a number of demographic and work-related factors and to complete the Maslach Burnout Inventory, which measures the three dimensions of burnout: 'Emotional Exhaustion', 'Depersonalisation' and low 'Personal Accomplishment'., Results: 409/509 (80%) of respondents had scores indicating high burnout on at least one dimension. 163 (32%) had high burnout on one dimension, 111 (22%) on two dimensions and 135 (26%) on all three dimensions. Feeling well supported protected against burnout in all three dimensions: emotional exhaustion (OR 0.34, CI 0.19 to 0.60), depersonalisation (OR 0.52, CI 0.31 to 0.86) and decreased personal accomplishment (OR 0.51, CI 0.29 to 0.78). Having a manageable workload protected against emotional exhaustion (OR 0.23, CI 0.13 to 0.37) and depersonalisation (OR 0.39, CI 0.24 to 0.61). Increasing weekly exercise was protective for personal accomplishment (OR 0.846, CI 0.73 to 0.98). Having children was protective for depersonalisation (OR 0.7, CI 0.53 to 0.90). A personal history of depression or anxiety was associated with burnout on all three dimensions: emotional exhaustion (OR 2.86, CI 1.67 to 5.00), depersonalisation (OR 1.66, CI 1.01 to 2.73) and decreased personal accomplishment (OR 1.71, CI 1.05 to 2.80). Alcohol misuse was associated with an increased risk of depersonalisation (OR 1.68, CI 1.08 to 2.62), and feeling inadequately remunerated was associated with emotional exhaustion (OR 2.27, CI 1.28 to 4.17). Qualitative data revealed concerns about poor staffing, inadequate remuneration, a focus on service provision over education, slow career progression and difficulty balancing work and specialty examinations., Conclusions: Burnout has a high prevalence in New Zealand's resident doctor workforce. Several associations and qualitative themes were identified. These findings may aid in the development of interventions to mitigate burnout in the medical workforce., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Dental Age Estimation (DAE) is an effective instrument of the rule of law for verifying dubious age claims in living individuals. Once tooth development is complete, only degenerative dental characteristics can be used for this purpose. The influence of ethnicity on these degenerative dental characteristics has not been clarified.Degenerative changes were examined using modified Gustafson's criteria including secondary dentin formation, cementum apposition, periodontal recession and attrition using the Olze et al. (2012) staging scales. Orthopantomograms of 1882 black South Africans, consisting of 934 females and 948 males, from 12.00 to 40.96 years of chronological age were utilized. Two independent examiners performed the evaluations, with one of the two evaluating all radiographs twice.The relationship between individual characteristics and chronological age was analyzed using multiple regression analysis with chronological age as the dependent variable. The resulting R 2 values ranged from 0.22 to 0.35, and the standard error of estimate were between 6.6 and 7.3 years. The correlation with age was consistently lower for females compared to males. The characteristic of cementum apposition emerged as critical in this population, due to a particularly low correlation with age and observer agreements partly in the "slight" range. The formula's values for the correlation with age were in general below the literature values for other populations. Overall, the limited precision of the age estimation by the formulae presented, especially for females, must be emphasized. The question of whether ethnicity per se exerts an influence on the characteristics in question, or whether the different socio-economic status, which encompasses factors such as nutrition and healthcare, is the determining factor, needs to be assessed in future studies., Competing Interests: Declarations. Compliance with ethical standards: All examinations were performed with the approval of the responsible ethics committee of the Medical Association Westfalen-Lippe and the University of Münster (AZ 2020-038-f-S), and in accordance with national law. This study was also approved by the University of Pretoria, Faculty of Health Sciences Research Ethics Committee (Reference no.: 587/2021). All procedures followed the ethical standards of the Helsinki Declaration of 1975, as revised in 2008. Conflict of interest: The authors have no conflict of interest to declare., (© 2024. The Author(s).)

Background Context: Venture capital (VC) plays a vital role in advancing spinal surgery technologies, driven by the growing burden of spinal disorders and high healthcare costs. Despite increasing interest, trends in VC funding for spinal surgery remain understudied., Purpose: This study aimed to examine temporal and thematic trends in VC investments in spinal surgery companies from 2000 to 2023., Study Design/setting: A retrospective cross-sectional study analyzing VC investment trends in privately held US-based spinal surgery companies., Methods: Using the PitchBook database, we analyzed 1001 VC investments in 227 spinal surgery companies between 2000 and 2023. Investments were categorized into surgical devices, noninvasive devices, biotechnology, surgical software, and clinical services. Total and annual investments were quantified in USD., Results: From 2000 to 2023, $5.37 billion was invested in spine surgery, with nonsurgical devices receiving the largest share (42.6%), followed by surgical devices (26.3%) and biotechnology (22.2%). Annual investment increased by 1782%, with a decline in 2023 likely due to macroeconomic factors., Conclusions: VC funding in spinal surgery has grown significantly, especially in noninvasive technologies. Further research is needed to assess the long-term impact of these investments and explore alternative financing models., 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 Elsevier Inc. All rights reserved.)

The U.S. COVID-19 vaccination program, which commenced in December 2020, has been instrumental in preventing morbidity and mortality from COVID-19 disease. Safety monitoring has been an essential component of the program. The federal government undertook a comprehensive and coordinated approach to implement complementary safety monitoring systems and to communicate findings in a timely and transparent way to healthcare providers, policymakers, and the public. Monitoring involved both well-established and newly developed systems that relied on both spontaneous (passive) and active surveillance methods. Clinical consultation for individual cases of adverse events following vaccination was performed, and monitoring of special populations, such as pregnant persons, was conducted. This report describes the U.S. government's COVID-19 vaccine safety monitoring systems and programs used by the Centers for Disease Control and Prevention, the U.S. Food and Drug Administration, the Department of Defense, the Department of Veterans Affairs, and the Indian Health Service. Using the adverse event of myocarditis following mRNA COVID-19 vaccination as a model, we demonstrate how the multiple, complementary monitoring systems worked to rapidly detect, assess, and verify a vaccine safety signal. In addition, longer-term follow-up was conducted to evaluate the recovery status of myocarditis cases following vaccination. Finally, the process for timely and transparent communication and dissemination of COVID-19 vaccine safety data is described, highlighting the responsiveness and robustness of the U.S. vaccine safety monitoring infrastructure during the national COVID-19 vaccination program., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Katherine Edwards serves as an advisor to Bionet, Dynavax, and IBM, and is on DSMBs Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, Roche, Novavax, and Brighton Collaboration. KM Edwards also reports grants from CDC and NIH. C. Buddy Creech serves as a consults for Pfizer, GSK, Moderna, CommenseBio, and TDCowen. CB Creedch also serves on a DSMB for GSK. Nicola P. Klein reports research support from Pfizer for COVID-19 vaccine clinical trials and from Sanofi Pastuer, Merck, GSK, and Sequirus. unrelated to the work in this manuscript. Matthew Oster serves as the Emory Principal Investigator for a Pfizer-funded NIH study. All other authors have declared that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Previous studies suggested that surgeon sex is associated with differential patient outcomes. Whether this also applies to anaesthesia providers is unclear. We hypothesised that female sex of the primary anaesthesia provider is associated with lower risk of perioperative complications., Methods: The first case for all adult patients undergoing anaesthesia care between 2008 and 2022 at two academic healthcare networks in the USA was included in this retrospective cohort study. The primary exposure was the sex of the anaesthesia provider who spent the most time in the operating theatre during the case. The primary outcome was intraoperative complications, defined as hypotension (mean arterial blood pressure <55 mm Hg for ≥5 cumulative minutes) or hypoxaemia (oxygen saturation <90% for >2 consecutive minutes). The co-primary outcome was 30-day adverse postoperative events (including complications, readmission, and mortality). Analyses were adjusted for a priori defined confounders., Results: Among 364,429 included patients, 57,550 (15.8%) experienced intraoperative complications and 55,168 (15.1%) experienced adverse postoperative events. Care by female compared with male anaesthesia providers was associated with lower risk of intraoperative complications (adjusted odds ratio [aOR] 0.95, 95% confidence interval [CI] 0.94-0.97, P<0.001), which was magnified among non-trainees (aOR 0.84, 95% CI 0.82-0.87, P-for-interaction<0.001). Anaesthesia provider sex was not associated with the composite of adverse postoperative events (aOR 1.00, 95% CI 0.98-1.02, P=0.88)., Conclusions: Care by a female anaesthesia provider was associated with a lower risk of intraoperative complications, which was magnified among non-trainees. Future studies should investigate underlying mechanisms., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Plastic surgery sector has experienced significant growth, driven by an aging population's demand for minimally invasive procedures and technological innovation. Despite this, the role of venture capital (VC) in driving innovation within this sector remains underexplored. This study aimed to analyze the trends in VC investments in plastic surgery over the last 20 years, providing insights into the financial landscape of the sector. A retrospective cross-sectional analysis was conducted on VC investments in plastic and aesthetic surgery companies worldwide from January 1, 2003 to December 31, 2023, utilizing PitchBook (Seattle, WA). Companies were categorized into therapeutic and thematic areas, with investment trends analyzed by deal and company values, average investment size, and total capital invested. The study found 543 VC firms made 402 investments in 163 companies, totaling $1.98 billion, increasing by 15,143% over the study period, and focused on general plastic surgery and facial cosmetic procedures. Significant investments were also made in surgical software (25.3%), biotechnology and drug discovery (22.8%), and clinic and outpatient services (20.3%). Geographically, most investments were made in companies registered in Asia (45%) and North America (33.2%). VC investments have contributed to the growth and innovation in the plastic surgery sector, particularly in minimally invasive devices. The focus on general and facial cosmetic surgery aligns with market demand trends for aesthetic procedures. These findings underscore the importance of VC in shaping the future of plastic surgery and suggest the potential for strategic investments to further drive innovation., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Aesthetic Society.)

Background: Acetaminophen and 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are administered as standard prophylaxes for postoperative pain, nausea, and vomiting. Preclinical studies, however, suggest that 5-HT3 antagonists may compromise acetaminophen's analgesic effect. This hospital registry study investigates whether 5-HT3 antagonists mitigate the analgesic effect of prophylactic acetaminophen in a perioperative setting., Methods: This study included 55,016 adult patients undergoing general anesthesia for ambulatory procedures at a tertiary healthcare center in Massachusetts from 2015 to 2022. Using binary exposure variables and a comprehensive selection of preplanned patient- and procedure-related covariates for confounder control, the authors investigated whether intraoperative 5-HT3 antagonists affected the association between pre- or intraoperative acetaminophen and postoperative opioid consumption, gauged by opioid dose in milligram oral morphine equivalents (OME) administered in the postanesthesia care unit. A multivariable, zero-inflated negative binomial regression model was applied., Results: A total of 3,166 patients (5.8%) received only acetaminophen, 15,438 (28.1%) only 5-HT3 antagonists, 31,850 (57.9%) both drugs, and 4,562 (8.3%) neither drug. The median postanesthesia care unit opioid dose was 7.5 mg OME (interquartile range, 7.5 to 14.3 mg OME) among 16,640 of 55,016 (30.2%) patients who received opioids, and the mean opioid dose was 3.2 mg OME across all patients (maximum cumulative dose, 20.4 mg OME). Acetaminophen administration was associated with a -5.5% (95% CI, -9.6 to -1.4%; P = 0.009; adjusted absolute difference, -0.19 mg OME; 95% CI, -0.33 to -0.05; P = 0.009) reduction in opioid consumption among patients who did not receive a 5-HT3 antagonist, while there was no effect in patients who received a 5-HT3 antagonist (adjusted absolute difference, 0.00 mg OME; 95% CI, -0.06 to 0.05; P = 0.93; P for interaction = 0.013)., Conclusions: A dose-dependent association of pre- or intraoperative acetaminophen with decreased postoperative opioid consumption was not observed when 5-HT3 antagonists were coadministered, suggesting that physicians might consider reserving 5-HT3 antagonists as rescue medication for postoperative nausea or vomiting when acetaminophen is administered for pain prophylaxis., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Competing Interests: Ravi Dhawan (R.D.) reports owning stock/equity in Microsoft Corporation and Adobe Inc. The authors report no other financial, commercial, or research-related conflicts of interest.

Declining estrogen (E2) leads to physical inactivity and adipose tissue (AT) dysfunction. Mechanisms are not fully understood, but E2's effects on dopamine (DA) activity in the nucleus accumbens (NAc) brain region may mediate changes in mood and voluntary physical activity (PA). Our prior work revealed that loss of E2 robustly affected NAc DA-related gene expression, and the pattern correlated with sedentary behavior and visceral fat. The current study used a new transgenic mouse model (D1ERKO) to determine whether the abolishment of E2 receptor alpha (ERα) signaling within DA-rich brain regions affects PA and AT metabolism. Adult male and female wild-type (WT) and D1ERKO (KD) mice were assessed for body composition, energy intake (EE), spontaneous PA (SPA), and energy expenditure (EE); underwent glucose tolerance testing; and were assessed for blood biochemistry. Perigonadal white AT (PGAT), brown AT (BAT), and NAc brain regions were assessed for genes and proteins associated with DA, E2 signaling, and metabolism; AT sections were also assessed for uncoupling protein (UCP1). KD mice had greater lean mass and EE (genotype effects) and a visible change in BAT phenotype characterized by increased UCP1 staining and lipid depletion, an effect seen only among females. Female KD had higher NAc Oprm1 transcript levels and greater PGAT UCP1. This group tended to have improved glucose tolerance ( p = 0.07). NAc suppression of Esr1 does not appear to affect PA, yet it may directly affect metabolism. This work may lead to novel targets to improve metabolic dysfunction following E2 loss, possibly by targeting the NAc.

Background: The treatment of intraoperative hypotension with phenylephrine may impair cerebral perfusion through vasoconstriction, which has been linked to postoperative delirium. The hypothesis was that intraoperative administration of phenylephrine, compared to ephedrine, is associated with higher odds of postoperative delirium., Methods: A total of 103,094 hospitalized adults undergoing general anesthesia for noncardiac, non-neurosurgical procedures between 2008 and 2020 at two tertiary academic healthcare networks in Massachusetts were included in this multicenter hospital registry study. The primary exposure was the administration of phenylephrine versus ephedrine during surgery, and the primary outcome was postoperative delirium within 7 days. Multivariable logistic regression analyses adjusted for a priori defined confounding variables including patient demographics, comorbidities, and procedural factors including magnitude of intraoperative hypotension were applied., Results: Between the two healthcare networks, 78,982 (76.6%) patients received phenylephrine, and 24,112 (23.4%) patients received ephedrine during surgery; 770 patients (0.8%) developed delirium within 7 days. The median (interquartile range) total intraoperative dose of phenylephrine was 1.0 (0.2 to 3.3) mg and 10.0 (10.0 to 20.0) mg for ephedrine. In adjusted analyses, the administration of phenylephrine, compared to ephedrine, was associated with higher odds of developing postoperative delirium within 7 days (adjusted odds ratio, 1.35; 95% CI, 1.06 to 1.71; and adjusted absolute risk difference, 0.2%; 95% CI, 0.1 to 0.3%; P = 0.015). A keyword and manual chart review-based approach in a subset of 45,465 patients further validated these findings (delirium incidence, 3.2%; adjusted odds ratio, 1.88; 95% CI, 1.49 to 2.37; P < 0.001). Fractional polynomial regression analysis further indicated a dose-dependent effect of phenylephrine (adjusted coefficient, 0.08; 95% CI, 0.02 to 0.14; P = 0.013, per each μg/kg increase in the cumulative phenylephrine dose)., Conclusions: The administration of phenylephrine compared to ephedrine during general anesthesia was associated with higher odds of developing postoperative delirium. Based on these data, clinical trials are warranted to determine whether favoring ephedrine over phenylephrine for treatment of intraoperative hypotension can reduce delirium after surgery., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Background: Patients suffering from obstructive sleep apnea (OSA) experience chronic sleep disturbances and desaturation, factors that have been associated with postoperative delirium and that can be aggravated after anesthesia for complex procedures. We investigated whether OSA is associated with delirium after anesthesia, and whether this association is modified by procedural complexity., Methods: Hospitalized patients ≥60 years who underwent general anesthesia or procedural sedation for procedures of moderate-to-high complexity between 2009 and 2020 at a tertiary health care network in Massachusetts were included. The primary exposure was OSA, defined based on International Classification of Diseases ( Ninth/Tenth Revision, Clinical Modification ) ( ICD-9 / 10-CM ) diagnostic codes, structured nursing interviews, anesthesia alert notes, and a validated risk score (BOSTN [body mass index, observed apnea, snoring, tiredness, and neck circumference]). The primary end point was delirium within 7 days after the procedure. Multivariable logistic regression and effect modification analyses adjusted for patient demographics, comorbidities, and procedural factors were applied., Results: A total of 46,352 patients were included, of which 1694 patients (3.7%) developed delirium, 537 (3.2%) with OSA, and 1,157 (4.0%) without OSA. In adjusted analyses, OSA was not associated with postprocedural delirium in the overall cohort (adjusted odds ratio [OR adj ], 1.06; 95% confidence interval [CI], 0.94-1.20; P = .35). However, a high procedural complexity modified the primary association ( P value for interaction = .002). OSA patients had a higher risk of delirium after high-complexity procedures (≥40 work relative value units) such as cardiac (OR adj , 1.33; 95% CI, 1.08-1.64; P = .007, P value for interaction = .005) or thoracic surgery (OR adj , 1.89; 95% CI, 1.19-3.00; P = .007, P value for interaction = .009), but no increased risk after moderate complexity procedures, including general surgery (OR adj , 0.86; 95% CI, 0.55-1.35; P = .52)., Conclusions: Compared to non-OSA patients, a history of OSA is associated with a higher risk after high-complexity procedures such as cardiac or thoracic surgery but not after procedures of moderate complexity., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2023 International Anesthesia Research Society.)

Importance: Laboratory testing for the presence of tuberculosis, hepatitis, and other conditions before starting most systemic immunomodulatory agents is recommended in patients with chronic inflammatory skin diseases (CISD) but current testing patterns in the US are unclear., Objective: To determine the prevalence of pretreatment testing that is recommended for patients with CISD (psoriasis, hidradenitis suppurativa, or atopic dermatitis)., Design, Setting, and Participants: This descriptive analysis of US commercial insurance claims databases from December 31, 2002, to December 31, 2020, included adult patients with CISD (psoriasis, hidradenitis suppurativa, or atopic dermatitis) who started an immunomodulatory agent, including methotrexate, tumor necrosis factor α inhibitors, interleukin (IL)-17Ai, ustekinumab, IL-23i, dupilumab, or apremilast., Main Outcomes and Measures: The proportion of patients who underwent the screening tests as suggested by professional societies-including for tuberculosis, hepatitis, and liver function; complete blood cell counts; and lipid panels-were determined within 6 months before and during 2 years after treatment start., Results: A total of 122 308 patients with CISDs (median [IQR] age, 49 [38-58] years; 63 663 [52.1%] male) starting systemic immunomodulatory treatment in the US were included. Treatment for patients with CISDs comprised methotrexate (28 684), tumor necrosis factor α inhibitors (40 965), ustekinumab (12 841), IL-23i (6116), IL-17Ai (9799), dupilumab (7787), or apremilast (16 116). Complete blood cell count was the most common test, performed in 41% (3161/7787) to 69% (19 659/28 684) of individuals before initiation across treatments. Between 11% (889/7787) and 59% (3613/6116) of patients had tuberculosis screening within 6 months before treatment, and 3% (149/4577) to 26% (1559/6097) had updated tests 1 year later. Between 13% (1006/7787) and 41% (16 728/40 965) had hepatitis panels before treatment. Low pretreatment testing levels before apremilast (15% [2331/16 116] to 45% [7253/16 116]) persisted a year into treatment (9% [816/8496] to 36% [2999/8496]) and were similar to dupilumab (11% [850/7787] to 41% [3161/7787] vs 3% [149/4577] to 25% [1160/4577])., Conclusions and Relevance: In this descriptive analysis of patients with CISDs starting systemic immunomodulatory treatment in the US, less than 60% received the recommended pretreatment testing. Additional research is required to understand whether variations in testing affect patient outcomes.

Rationale: Lung-protective mechanical ventilation strategies have been proven beneficial in the operating room (OR) and the ICU. However, differential practices in ventilator management persist, often resulting in adjustments of ventilator parameters when transitioning patients from the OR to the ICU. Objectives: To characterize patterns of ventilator adjustments during the transition of mechanically ventilated surgical patients from the OR to the ICU and assess their impact on 28-day mortality. Methods: Hospital registry study including patients undergoing general anesthesia with continued, controlled mechanical ventilation in the ICU between 2008 and 2022. Ventilator parameters were assessed 1 hour before and 6 hours after the transition. Measurements and Main Results: Of 2,103 patients, 212 (10.1%) died within 28 days. Upon OR-to-ICU transition, V T and driving pressure decreased (-1.1 ml/kg predicted body weight [IQR, -2.0 to -0.2]; P  < 0.001; and -4.3 cm H 2 O [-8.2 to -1.2]; P  < 0.001). Concomitantly, respiratory rates increased (+5.0 breaths/min [2.0 to 7.5]; P  < 0.001), resulting overall in slightly higher mechanical power (MP) in the ICU (+0.7 J/min [-1.9 to 3.0]; P  < 0.001). In adjusted analysis, increases in MP were associated with a higher 28-day mortality rate (adjusted odds ratio, 1.10; 95% confidence interval, 1.06-1.14; P  < 0.001; adjusted risk difference, 0.7%; 95% confidence interval, 0.4-1.0, both per 1 J/min). Conclusion: During transition of mechanically ventilated patients from the OR to the ICU, ventilator adjustments resulting in higher MP were associated with a greater risk of 28-day mortality.

The evaluation of third molar eruption in dental panoramic radiographs (DPRs) constitutes an evidence-based approach for forensic age assessment in living individuals. Existing methodologies involve staging morphological radiographic findings and comparing them to reference populations. Conversely, the existing literature presents an alternative method where the distance between third molars and the occlusal plane is measured on dental plaster models. The aim of this study was to adapt this measurement principle for DPRs and to determine correlation between eruption and chronological age. A total of 423 DPRs, encompassing 220 females and 203 males aged 15 to 25 years, were examined, including teeth 38 [FDI] and 48. Two independent examiners conducted the measurements, with one examiner providing dual assessments. Ultimately, a quotient was derived by comparing orthogonal distances from the mesial cementoenamel junctions of the second and third molars to a simplified radiological occlusal plane. This quotient was subsequently correlated with the individual's age. We estimated correlations between age and quotients, as well as inter- and intra-rater reliability. Correlation coefficients (Spearman's rho) between measurements and individuals' ages ranged from 0.555 to 0.597, conditional on sex and tooth. Intra-rater agreement (Krippendorf's alpha) ranged from 0.932 to 0.991, varying according to the tooth and sex. Inter-rater agreement ranged from 0.984 to 0.992, with distinctions drawn for different teeth and sex. Notably, all observer agreement values fell within the "very good" range. In summary, assessing the distance of third molars from a simplified occlusal plane in DPRs emerges as a new and promising method for evaluating eruption status in forensic age assessment. Subsequent reference studies should validate these findings.

Background: Bile salt export pump (ABCB11) deficiency [Progressive familial intrahepatic cholestasis (PFIC2)] is the most common genetic cause of PFIC and is associated with pruritus and progressive liver disease. Surgical biliary diversion or pharmacological [ileal bile acid transporter inhibitor (IBATi)] approaches can be used to block the recirculation of bile acids to the liver. There is a paucity of detailed data on the natural history and, in particular, the longitudinal evolution of bile acid levels to predict treatment response. Cross-sectional data from large international consortia suggested a maximum cutoff value of bile acids after the intervention to predict a successful outcome., Methods: This retrospective, single-center, cohort study included all patients with confirmed biallelic pathogenic ABCB11 genotype PFIC2 treated at our institution with ≥2 years follow-up. The outcomes of interventions and predictors of long-term health were analyzed., Results: Forty-eight cases were identified with PFIC2. Eighteen received partial external biliary diversion (PEBD) surgery, and 22 patients underwent liver transplantation. Two patients developed HCC and 2 died. Improved survival with native liver was closely associated with genotype, complete normalization of serum bile acids following PEBD, and alleviation of pruritus. Persistence of mild-to-moderate elevation of bile acids or a secondary rise following normalization was associated with liver disease progression and led to transplantation, suggesting that any prolonged elevation of bile acids worsens the chance of native liver survival. Higher-grade fibrosis at the time of PEBD was not associated with reduced long-term native liver survival. Patients with PFIC2 benefit from PEBD even at a stage of advanced fibrosis., Conclusion: Serum bile acid levels are an early predictor of treatment response and might serve as the gold standard in the evaluation of novel therapies including IBATi., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Reversing neuromuscular blockade with sugammadex can eliminate residual paralysis, which has been associated with postoperative respiratory complications. There are equivocal data on whether sugammadex reduces these when compared with neostigmine. We investigated the association of the choice of reversal drug with postoperative respiratory complications and advanced healthcare utilisation. We included adult patients who underwent surgery and received general anaesthesia with sugammadex or neostigmine reversal at two academic healthcare networks between January 2016 and June 2021. The primary outcome was postoperative respiratory complications, defined as post-extubation oxygen saturation < 90%, respiratory failure requiring non-invasive ventilation, or tracheal re-intubation within 7 days. Our main secondary outcome was advanced healthcare utilisation, a composite outcome including: 7-day unplanned intensive care unit admission; 30-day hospital readmission; or non-home discharge. In total, 5746 (6.9%) of 83,250 included patients experienced postoperative respiratory complications. This was not associated with the reversal drug (adjusted OR (95%CI) 1.01 (0.94-1.08); p = 0.76). After excluding patients admitted from skilled nursing facilities, 8372 (10.5%) patients required advanced healthcare utilisation, which was not associated with the choice of reversal (adjusted OR (95%CI) 0.95 (0.89-1.01); p = 0.11). Equivalence testing supported an equivalent effect size of sugammadex and neostigmine on both outcomes, and neostigmine was non-inferior to sugammadex with regard to postoperative respiratory complications or advanced healthcare utilisation. Finally, there was no association between the reversal drug and major adverse cardiovascular events (adjusted OR 1.07 (0.94-1.21); p = 0.32). Compared with neostigmine, reversal of neuromuscular blockade with sugammadex was not associated with a reduction in postoperative respiratory complications or post-procedural advanced healthcare utilisation., (© 2022 Association of Anaesthetists.)

Background: There is paucity of data regarding prevalence and key harms of non-medical cannabis use in surgical patients. We investigated whether cannabis use in patients undergoing surgery or interventional procedures patients was associated with a higher degree of post-procedural healthcare utilisation., Methods: 210,639 adults undergoing non-cardiac surgery between January 2008 and June 2020 at an academic healthcare network in Massachusetts, USA, were included. The primary exposure was use of cannabis, differentiated by reported ongoing non-medical use, self-identified during structured, preoperative nursing/physician interviews, or diagnosis of cannabis use disorder based on International Classification of Diseases, 9th/10th Revision, diagnostic codes. The main outcome measure was the requirement of advanced post-procedural healthcare utilisation (unplanned intensive care unit admission, hospital re-admission or non-home discharge)., Findings: 16,211 patients (7.7%) were identified as cannabis users. The prevalence of cannabis use increased from 4.9% in 2008 to 14.3% by 2020 (p < 0.001). Patients who consumed cannabis had higher rates of psychiatric comorbidities (25.3 versus 16.8%; p < 0.001) and concomitant non-tobacco substance abuse (30.2 versus 7.0%; p < 0.001). Compared to non-users, patients with a diagnosis of cannabis use disorder had higher odds of requiring advanced post-procedural healthcare utilisation after adjusting for patient characteristics, concomitant substance use and socioeconomic factors (aOR [adjusted odds ratio] 1.16; 95% CI 1.02-1.32). By contrast, patients with ongoing non-medical cannabis use had lower odds of advanced post-procedural healthcare utilisation (aOR 0.87; 95% CI 0.81-0.92, compared to non-users)., Interpretation: One in seven patients undergoing surgery or interventional procedures in 2020 reported cannabis consumption. Differential effects on post-procedural healthcare utilisation were observed between patients with non-medical cannabis use and cannabis use disorder., Funding: This work was supported by an unrestricted philantropic grant from Jeff and Judy Buzen to Maximilian S. Schaefer., Competing Interests: Haobo Ma received a SEAd Grant from the Society for Education in Anesthesia not related to this manuscript. Matthias Eikermann has received unrestricted funds from philanthropic donors Jeffrey and Judy Buzen and grants from Merck & Co. not related to this study. He is an Associate Editor of the British Journal of Anaesthesia. Kevin Hill has served as a consultant to for Greenwich Biosciences and has received an honorarium from Wolters-Kluwer as an author. Maximilian S. Schaefer received funding for investigator-initiated studies from Merck & Co., which do not pertain to this manuscript. He is an associate editor for BMC Anesthesiology. Maximilian S. Schaefer received honoraria for presentations from Fisher & Paykel Healthcare and Mindray Medical International Limited. Maximilian S. Schaefer has received an unrestricted grant from Jeff and Judy Buzen. All other authors declare no competing interests., (© 2023 The Author(s).)

Objective: The objective of this study was to identify undertreated subgroups of patients with heart failure who would benefit from better perioperative optimization., Summary of Background Data: Patients with heart failure have increased risks of postoperative cardiac complications after noncardiac surgery., Methods: In this analysis of hospital registry data of 130,677 patients undergoing noncardiac surgery, the exposure was preoperative history of heart failure. The outcome, cardiac complications, was defined as a composite of myocardial infarction, cardiac arrest, acute heart failure, and mortality within 30 postoperative days., Results: History of heart failure (n = 10,256; 7.9%) was associated with increased risk of cardiac complications [8.1% vs 1.1%; adjusted odds ratio, 2.28 (95% CI, 2.02-2.56); P < 0.001). Patients with heart failure and who carried a lower risk profile had increased risks of postoperative cardiac complications secondary to heart failure [adjusted absolute risk difference, 1.7% (95% CI, 1.4%-2.0%, lower risk); P < 0.001 vs 0.5% (95% CI, -0.6% to 1.6%, higher risk); P = 0.38]. Patients with heart failure and lower risk received a lower level of health care utilization preoperatively, and less frequently received anti-heart failure medications (59% vs 72% and 61% vs 82%; both P < 0.001). These preventive therapies significantly decreased the risk of cardiac complications in patients with heart failure., Conclusions: In patients with heart failure who have a lower preoperative risk profile, clinicians often make insufficient attempts to optimize their clinical condition preoperatively. Preoperative preventive treatment reduces the risk of postoperative cardiac complications in these lower-risk patients with heart failure., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Intensive care units (ICU) are often overflooded with alarms from monitoring devices which constitutes a hazard to both staff and patients. To date, the suggested solutions to excessive monitoring alarms have remained on a research level. We aimed to identify patient characteristics that affect the ICU alarm rate with the goal of proposing a straightforward solution that can easily be implemented in ICUs. Alarm logs from eight adult ICUs of a tertiary care university-hospital in Berlin, Germany were retrospectively collected between September 2019 and March 2021. Adult patients admitted to the ICU with at least 24 h of continuous alarm logs were included in the study. The sum of alarms per patient per day was calculated. The median was 119. A total of 26,890 observations from 3205 patients were included. 23 variables were extracted from patients' electronic health records (EHR) and a multivariable logistic regression was performed to evaluate the association of patient characteristics and alarm rates. Invasive blood pressure monitoring (adjusted odds ratio (aOR) 4.68, 95%CI 4.15-5.29, p < 0.001), invasive mechanical ventilation (aOR 1.24, 95%CI 1.16-1.32, p < 0.001), heart failure (aOR 1.26, 95%CI 1.19-1.35, p < 0.001), chronic renal failure (aOR 1.18, 95%CI 1.10-1.27, p < 0.001), hypertension (aOR 1.19, 95%CI 1.13-1.26, p < 0.001), high RASS (aOR 1.22, 95%CI 1.18-1.25, p < 0.001) and scheduled surgical admission (aOR 1.22, 95%CI 1.13-1.32, p < 0.001) were significantly associated with a high alarm rate. Our study suggests that patient-specific alarm management should be integrated in the clinical routine of ICUs. To reduce the overall alarm load, particular attention regarding alarm management should be paid to patients with invasive blood pressure monitoring, invasive mechanical ventilation, heart failure, chronic renal failure, hypertension, high RASS or scheduled surgical admission since they are more likely to have a high contribution to noise pollution, alarm fatigue and hence compromised patient safety in ICUs., (© 2022. The Author(s).)

Glioblastoma (GBM) is the most common type of glioma and is uniformly fatal. Currently, tumour heterogeneity and mutation acquisition are major impedances for tailoring personalized therapy. We collected blood and tumour tissue samples from 25 GBM patients and 25 blood samples from healthy controls. Cell-free DNA (cfDNA) was extracted from the plasma of GBM patients and from healthy controls. Tumour DNA was extracted from fresh tumour samples. Extracted DNA was sequenced using a whole-genome sequencing procedure. We also collected 180 tumour DNA datasets from GBM patients publicly available at the TCGA/PANCANCER project. These data were analysed for mutations and gene-gene fusions that could be potential druggable targets. We found that plasma cfDNA concentrations in GBM patients were significantly elevated (22.6 ± 5 ng·mL -1 ), as compared to healthy controls (1.4 ± 0.4 ng·mL -1 ) of the same average age. We identified unique mutations in the cfDNA and tumour DNA of each GBM patient, including some of the most frequently mutated genes in GBM according to the COSMIC database (TP53, 18.75%; EGFR, 37.5%; NF1, 12.5%; LRP1B, 25%; IRS4, 25%). Using our gene-gene fusion database, ChiTaRS 5.0, we identified gene-gene fusions in cfDNA and tumour DNA, such as KDR-PDGFRA and NCDN-PDGFRA, which correspond to previously reported alterations of PDGFRA in GBM (44% of all samples). Interestingly, the PDGFRA protein fusions can be targeted by tyrosine kinase inhibitors such as imatinib, sunitinib, and sorafenib. Moreover, we identified BCR-ABL1 (in 8% of patients), COL1A1-PDGFB (8%), NIN-PDGFRB (8%), and FGFR1-BCR (4%) in cfDNA of patients, which can be targeted by analogues of imatinib. ROS1 fusions (CEP85L-ROS1 and GOPC-ROS1), identified in 8% of patient cfDNA, might be targeted by crizotinib, entrectinib, or larotrectinib. Thus, our study suggests that integrated analysis of cfDNA plasma concentration, gene mutations, and gene-gene fusions can serve as a diagnostic modality for distinguishing GBM patients who may benefit from targeted therapy. These results open new avenues for precision medicine in GBM, using noninvasive liquid biopsy diagnostics to assess personalized patient profiles. Moreover, repeated detection of druggable targets over the course of the disease may provide real-time information on the evolving molecular landscape of the tumour., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Individuals with type 2 diabetes mellitus experience high rates of influenza virus infection and complications. We compared the magnitude and duration of serologic response to trivalent influenza vaccine in adults aged 50-80 with and without type 2 diabetes mellitus. Serologic response to influenza vaccination was similar in both groups: greater fold-increases in antibody titer occurred among participants with lower pre-vaccination antibody titers. Waning of antibody titers was not influenced by diabetes status., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Residual neuromuscular blockade is associated with an increased incidence of postoperative respiratory complications. The REsidual neuromuscular block Prediction Score (REPS) identifies patients at high risk for residual neuromuscular blockade after surgery., Methods: A total of 101,510 adults undergoing noncardiac surgery under general anesthesia from October 2005 to December 2018 at a tertiary care center in Massachusetts were analyzed for the primary outcome of postoperative respiratory complications (invasive mechanical ventilation requirement within 7 postoperative days or immediate postextubation desaturation [oxygen saturation {Spo2} <90%] within 10 minutes). The primary objective was to assess the association between the REPS and respiratory complications. The secondary objective was to compare REPS and train-of-four (TOF) ratio <0.90 on the strength of their association with respiratory complications., Results: A high REPS (≥4) was associated with an increase in odds of respiratory complications (adjusted odds ratio [OR], 1.13 [95% confidence interval {CI}, 1.06-1.21]; P < .001). In 6224 cases with available TOF ratio measurements, a low TOF ratio (<0.9) was associated with respiratory complications (adjusted OR, 1.43 [95% CI, 1.11-1.85]; P = .006), whereas a high REPS was not (adjusted OR, 0.96 [95% CI, 0.74-1.23]; P = .73) (P = .018 for comparison between ORs)., Conclusions: The REPS may be implemented as a screening tool to encourage clinicians to use quantitative neuromuscular monitoring in patients at risk of residual neuromuscular blockade. A positive REPS should be followed by a quantitative assessment of the TOF ratio., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2021 International Anesthesia Research Society.)

Objective: To assess variability in the intraoperative use of non-depolarising neuromuscular blocking agents (NMBAs) across individual anaesthesia providers, surgeons and hospitals., Design: Retrospective observational cohort study., Setting: Two major tertiary referral centres, Boston, Massachusetts, USA., Participants: 265 537 adult participants undergoing non-cardiac surgery between October 2005 and September 2017., Main Outcome Measures: We analysed the variances in NMBA use across 958 anaesthesia and 623 surgical providers, across anaesthesia provider types (anaesthesia residents, certified registered nurse anaesthetists, attendings) and across hospitals using multivariable-adjusted mixed effects logistic regression. Intraclass correlations (ICC) were calculated to further quantify the variability in NMBA use that was unexplained by other covariates. Procedure-specific subgroup analyses were performed., Results: NMBAs were used in 183 242 (69%) surgical cases. Variances in NMBA use were significantly higher among individual surgeons than among anaesthesia providers (variance 1.32 (95% CI 1.06 to 1.60) vs 0.24 (95% CI 0.19 to 0.28), p<0.001). Procedure-specific subgroup analysis of hernia repairs, spine surgeries and mastectomies confirmed our findings: the total variance in NMBA use that was unexplained by the covariate model was higher for surgeons versus anaesthesia providers (ICC 37.0% vs 13.0%, 69.7% vs 25.5%, 69.8% vs 19.5%, respectively; p<0.001). Variances in NMBA use were also partially explained by the anaesthesia provider's hospital network (Massachusetts General Hospital: variance 0.35 (95% CI 0.27 to 0.43) vs Beth Israel Deaconess Medical Center: 0.15 (95% CI 0.12 to 0.19); p<0.001). Across provider types, surgeons showed the highest variance, and anaesthesia residents showed the lowest variance in NMBA use., Conclusions: There is wide variability across individual surgeons and anaesthesia providers and institutions in the use of NMBAs, which could not sufficiently be explained by a large number of patient-related and procedure-related characteristics, but may instead be driven by preference. Surgeons may have a stronger influence on a key aspect of anaesthesia management than anticipated., Competing Interests: Competing interests: TTH reports grants from NINDS (PI), grants from NIGMS, personal fees from Headache, personal fees from Anesthesiology, personal fees from Cephalalgia, outside the submitted work. ME received honorarium for giving advice to Merck, holds equity of Calabash Bioscience and is an Associate Editor of the British Journal of Anaesthesia., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: ICU discharge is often delayed by a requirement for intravenous vasopressor medications to maintain normotension. We hypothesised that the administration of midodrine, an oral α 1 -adrenergic agonist, as adjunct to standard treatment shortens the duration of intravenous vasopressor requirement., Methods: In this multicentre, randomised, controlled trial including three tertiary referral hospitals in the US and Australia, we enrolled adult patients with hypotension requiring a single-agent intravenous vasopressor for ≥ 24 h. Subjects received oral midodrine (20 mg) or placebo every 8 h in addition to standard care until cessation of intravenous vasopressors, ICU discharge, or occurrence of adverse events. The primary outcome was time to vasopressor discontinuation. Secondary outcomes included time to ICU discharge readiness, ICU and hospital lengths of stay, and ICU readmission rates., Results: Between October 2012 and June 2019, 136 participants were randomised, of whom 132 received the allocated intervention and were included in the analysis (modified intention-to-treat approach). Time to vasopressor discontinuation was not different between midodrine and placebo groups (median [IQR], 23.5 [10-54] vs 22.5 [10.4-40] h; difference, 1 h; 95% CI - 10.4 to 12.3 h; p = 0.62). No differences in secondary endpoints were observed. Bradycardia occurred more often after midodrine administration (5 [7.6%] vs 0 [0%], p = 0.02)., Conclusion: Midodrine did not accelerate liberation from intravenous vasopressors and was not effective for the treatment of hypotension in critically ill patients.

In contrast to fossorial and above-ground organisms, subterranean species have adapted to the extreme stresses of living underground. We analyzed the predicted protein-protein interactions (PPIs) of all gene products, including those of stress-response genes, among nine subterranean, ten fossorial, and 13 aboveground species. We considered 10,314 unique orthologous protein families and constructed 5,879,879 PPIs in all organisms using ChiPPI. We found strong association between PPI network modulation and adaptation to specific habitats, noting that mutations in genes and changes in protein sequences were not linked directly with niche adaptation in the organisms sampled. Thus, orthologous hypoxia, heat-shock, and circadian clock proteins were found to cluster according to habitat, based on PPIs rather than on sequence similarities. Curiously, "ordered" domains were preserved in aboveground species, while "disordered" domains were conserved in subterranean organisms, and confirmed for proteins in DistProt database. Furthermore, proteins with disordered regions were found to adopt significantly less optimal codon usage in subterranean species than in fossorial and above-ground species. These findings reveal design principles of protein networks by means of alterations in protein domains, thus providing insight into deep mechanisms of evolutionary adaptation, generally, and particularly of species to underground living and other confined habitats.

Identifying mutations in tumors of cancer patients is a very important step in disease management. These mutations serve as biomarkers for tumor diagnosis as well as for the treatment selection and its response in cancer patients. The current gold standard method for detecting tumor mutations involves a genetic test of tumor DNA by means of tumor biopsies. However, this invasive method is difficult to be performed repeatedly as a follow-up test of the tumor mutational repertoire. Liquid biopsy is a new and emerging technique for detecting tumor mutations as an easy-to-use and non-invasive biopsy approach. Cancer cells multiply rapidly. In parallel, numerous cancer cells undergo apoptosis. Debris from these cells are released into a patient's circulatory system, together with finely fragmented DNA pieces, called cell-free DNA (cfDNA) fragments, which carry tumor DNA mutations. Therefore, for identifying cfDNA based biomarkers using liquid biopsy technique, blood samples are collected from the cancer patients, followed by the separation of plasma and buffy coat. Next, plasma is processed for the isolation of cfDNA, and the respective buffy coat is processed for the isolation of a patient's genomic DNA. Both nucleic acid samples are then checked for their quantity and quality; and analyzed for mutations using next-generation sequencing (NGS) techniques. In this manuscript, we present a detailed protocol for liquid biopsy, including blood collection, plasma, and buffy coat separation, cfDNA and germline DNA extraction, quantification of cfDNA or germline DNA, and cfDNA fragment enrichment analysis.

In forensic age assessment of living individuals, developmental stages of skeletal maturation and tooth mineralization are examined and compared with a reference population. It is of interest which factors can affect the development of these features. We investigated the effect of body mass index (BMI) on the developmental stages of the medial epiphysis of the clavicle, the distal epiphysis of the radius, the distal epiphysis of the femur, the proximal epiphysis of the tibia, and the left lower third molar in a total of 581 volunteers, 294 females and 287 males aged 12-24 years, using 3 T MRI. BMI values in the cohort ranged from 13.71 kg/m 2 in a 12-year-old female to 35.15 kg/m 2 in an 18-year-old female. The effect of BMI on the development of the characteristics was investigated using linear regression models with multivariable fractional polynomials. In the univariable analysis, BMI was associated with all feature systems (beta between 0.10 and 0.44; p < 0.001). When accounting for the physiological increase of BMI with increasing age, the effect of BMI was lower and in the majority of the models no longer clinically relevant. Betas decreased to values between 0.00 and 0.05. When adding feature variables to a model already including age, r 2 values increased only minimally. For an overall bone ossification score combining all characteristics, the adjusted ß was 0.11 (p = 0.021) and 0.08 (p = 0.23) for females and males, respectively. Low ß and r 2 values (0.00 (adjusted)-0.16 (crude)) were present in both models for third molar development already in the unadjusted analyses. In conclusion, our study found no to little effect of BMI on osseous development in young adults. Teeth development in both sexes was completely independent of BMI. Therefore, dental methods should be part of every age assessment.

Non-depolarizing neuromuscular blocking agents are used during general anesthesia to facilitate intubation and optimize surgical conditions. When patients leave the operating room after surgery, postoperative residual neuromuscular block occurs frequently, increasing vulnerability to respiratory complications such as hypoxemia and unplanned postoperative mechanical ventilation. To restore neuromuscular transmission and skeletal muscle strength, anesthesiologists typically administer peripherally acting acetylcholinesterase inhibitors such as neostigmine. However, neostigmine's desirable effects have a narrow therapeutic range. Even at recommended dose (15-50 μg/kg), neostigmine induces nicotinic (upper airway muscle weakness leading to dysphagia and upper airway obstruction, and decreased maximum inspiratory airflow) and muscarinic (blurred vision, bronchial constriction, abdominal cramping and nausea) side effects. Recent data have questioned as to whether neostigmine reversal of neuromuscular blockade improves relevant patient outcomes such as postoperative respiratory and perioperative cardiovascular complications. A central strategy to avoid side effects of neuromuscular blocking agents is their judicious use based on quantitative monitoring of neuromuscular transmission using repetitive peripheral nerve stimulation (train-of-four ratio). Peripherally acting acetylcholinesterase inhibitors such as neostigmine should then only be administered when indicated and dosed based on results of the train-of-four ratio., Competing Interests: Declaration of competing interest All other authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The anticholinesterase neostigmine and the muscarinic inhibitor glycopyrrolate are frequently coadministered for the reversal of neuromuscular blockade. This practice can precipitate severe bradycardia or tachycardia, but whether it affects the incidence of cardiovascular complications remains unclear. We hypothesized that anticholinesterase reversal with neostigmine and glycopyrrolate versus no anticholinesterase reversal increases the risk of postoperative cardiovascular complications among adult patients undergoing noncardiac surgery with general anesthesia., Methods: We conducted a prespecified retrospective analysis of hospital registry data from a major health care network for patients undergoing surgery with general anesthesia from January 2007 to December 2015. The primary outcome was a composite of cardiac dysrhythmia, acute heart failure, transient ischemic attack, ischemic stroke, and acute myocardial infarction within 30 days after surgery. We performed sensitivity analyses in subgroups and propensity score adjustment and explored the association between exposure and outcome in subgroups of patients with high risk of cardiovascular complications., Results: Of the 98,147 cases receiving neuromuscular blockade, 73,181 (74.6%) received neostigmine and glycopyrrolate, while 24,966 (25.4%) did not. A total of 5612 patients (7.7%) in the anticholinesterase reversal group and 1651 (6.6%) in the control group (P < .001) experienced the primary outcome. After adjustment for clinical covariates, neostigmine and glycopyrrolate exposure was significantly associated in a dose-dependent fashion (P for trend <.001, respectively) with tachycardia (adjusted odds ratio = 2.1 [95% CI, 1.97-2.23]; P < .001) and bradycardia (adjusted odds ratio = 2.84 [95% CI, 2.49-3.24]; P < .001) but not with postoperative cardiovascular complications (adjusted odds ratio = 1.03 [95% CI, 0.97-1.1]; P = .33). We identified a significant effect modification of anticholinesterase reversal by high age, high-risk surgery, and history of atrial fibrillation (P for interaction = .002, .001, and .02, respectively). By using linear combinations of main effect and exposure-risk interaction terms, we detected significant associations between anticholinesterase reversal and cardiovascular complications toward a higher vulnerability in these patient subgroups., Conclusions: Neuromuscular blockade reversal with neostigmine and glycopyrrolate was associated with an increased incidence of intraoperative tachycardia and bradycardia but not with 30-day postoperative cardiovascular complications. Exploratory analyses suggest that a high postoperative cardiovascular complication risk profile may modify the effects of anticholinesterase reversal toward clinical relevance.

Background: Preclinical data suggest suppression of cancer proliferation by propofol, and retrospective studies suggest improved survival after cancer surgery with propofol-based anaesthesia., Methods: To determine whether propofol dose administered for anaesthesia is associated with 1-yr mortality in patients with and without a diagnosis of solid cancer, we analysed adult patients undergoing monitored anaesthesia care or general anaesthesia at two academic medical centres in Boston, MA, USA. Logistic regression with interaction term analysis was applied with propofol dose (mg kg -1 ) as primary and diagnosis of solid cancer as co-primary exposure, and 1-yr mortality as the primary outcome., Results: Of 280 081 patient cases, 10 744 (3.8%) died within 1 yr. Increasing propofol dose was associated with reduced odds of 1-yr mortality (adjusted odds ratio [aOR] 0.93 per 10 mg kg -1 ; 95% confidence interval [CI]: 0.89-0.98; absolute risk reduction fifth vs first quintile 0.5%; 95% CI: 0.2-0.7). This association was modified by a diagnosis of solid cancer (P<0.001 for interaction). Increasing propofol dose was associated with reduced odds of 1-yr mortality in patients without solid cancer (aOR: 0.78; 95% CI: 0.71-0.85), but not in patients with solid cancer (0.99; 0.94-1.04), a finding that was replicated when examining 5-yr mortality., Conclusions: Increasing propofol dose is associated with lower 1-yr mortality in patients without, but not in patients with, a diagnosis of solid cancer. We found evidence for competing effects, modifying the association between propofol dose and mortality., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Chimeric RNA transcripts are formed when exons from two genes fuse together, often due to chromosomal translocations, transcriptional errors or trans-splicing effect. While these chimeric RNAs produce functional proteins only in certain cases, they play a significant role in disease phenotyping and progression. ChiTaRS 5.0 (http://chitars.md.biu.ac.il/) is the latest and most comprehensive chimeric transcript repository, with 111 582 annotated entries from eight species, including 23 167 known human cancer breakpoints. The database includes unique information correlating chimeric breakpoints with 3D chromatin contact maps, generated from public datasets of chromosome conformation capture techniques (Hi-C). In this update, we have added curated information on druggable fusion targets matched with chimeric breakpoints, which are applicable to precision medicine in cancers. The introduction of a new section that lists chimeric RNAs in various cell-lines is another salient feature. Finally, using text-mining techniques, novel chimeras in Alzheimer's disease, schizophrenia, dyslexia and other diseases were collected in ChiTaRS. Thus, this improved version is an extensive catalogue of chimeras from multiple species. It extends our understanding of the evolution of chimeric transcripts in eukaryotes and contributes to the analysis of 3D genome conformational changes and the functional role of chimeras in the etiopathogenesis of cancers and other complex diseases., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Metabolic disease risk escalates following menopause. The mechanism is not fully known, but likely involves reduced signaling through estrogen receptor alpha (ERα), which is highly expressed in brown and white adipose tissue (BAT and WAT). Objective: Test the hypothesis that uncoupling protein (UCP1) activation mitigates metabolic dysfunction caused by loss of signaling through ERα. Methods: At 8 weeks of age, female ERα knock out (KO) and wild-type mice were housed at 28°C and fed a Western-style high-fat, high sucrose diet (HFD) or a normal low-fat chow diet (NC) for 10 weeks. During the final 2 weeks, they received daily injections of CL 316,256 (CL), a selective β3 adrenergic agonist, or vehicle control (CTRL), creating eight groups: WT-CTRL, WT-CL, KO-CTRL, and KO-CL on HFD or NC; n = 4-10/group. Results: ERαKO demonstrated exacerbated HFD-induced adiposity gain ( P < 0.001) and insulin resistance ( P = 0.006). CL treatment improved insulin sensitivity ( P < 0.05) and normalized ERαKO-induced adiposity increase ( P < 0.05). In both genotypes, CL increased resting energy expenditure ( P < 0.05) and induced WAT beiging indicated by increased UCP1 protein in both perigonadal (PGAT) and subcutaneous (SQAT) depots. These effects were attenuated under HFD conditions ( P < 0.05). In KO, CL reduced HFD energy consumption compared to CTRL ( P < 0.05). Remarkably, CL increased WAT ERβ protein levels of both WT and KO ( P < 0.001), revealing CL-mediated changes in estrogen signaling may have protective metabolic effects. Conclusion: CL completely restored metabolic dysfunction in ERαKO mice. Thus, UCP1 may be a therapeutic target for treating metabolic dysfunction following loss of estrogen receptor signaling.

Dilated cardiomyopathy (DCM) is a life-threatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab Christian infants, aged 4-30 months from four families, were diagnosed with DCM associated with mild skin, teeth, and hair abnormalities. All passed away before age 3. A homozygous sequence variation creating a premature stop codon at  PPP1R13L encoding the iASPP protein was identified in three infants and in the mother of the other two. Patients' fibroblasts and PPP1R13L -knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to lipopolysaccharide, as well as Ppp1r13l -knocked down murine cardiomyocytes and hearts of Ppp1r13l -deficient mice. The hypersensitivity to lipopolysaccharide was NF-κB-dependent, and its inducible binding activity to promoters of pro-inflammatory cytokine genes was elevated in patients' fibroblasts. RNA sequencing of Ppp1r13l -knocked down murine cardiomyocytes and of hearts derived from different stages of DCM development in Ppp1r13l -deficient mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Our results determined  PPP1R13L as the gene underlying a novel autosomal-recessive cardio-cutaneous syndrome in humans and strongly suggest that the fatal DCM during infancy is a consequence of failure to regulate transcriptional pathways necessary for tuning cardiac threshold response to common inflammatory stressors., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)

Discovery of chimeric RNAs, which are produced by chromosomal translocations as well as the joining of exons from different genes by trans-splicing, has added a new level of complexity to our study and understanding of the transcriptome. The enhanced ChiTaRS-3.1 database (http://chitars.md.biu.ac.il) is designed to make widely accessible a wealth of mined data on chimeric RNAs, with easy-to-use analytical tools built-in. The database comprises 34 922: chimeric transcripts along with 11 714: cancer breakpoints. In this latest version, we have included multiple cross-references to GeneCards, iHop, PubMed, NCBI, Ensembl, OMIM, RefSeq and the Mitelman collection for every entry in the 'Full Collection'. In addition, for every chimera, we have added a predicted Chimeric Protein-Protein Interaction (ChiPPI) network, which allows for easy visualization of protein partners of both parental and fusion proteins for all human chimeras. The database contains a comprehensive annotation for 34 922: chimeric transcripts from eight organisms, and includes the manual annotation of 200 sense-antiSense (SaS) chimeras. The current improvements in the content and functionality to the ChiTaRS database make it a central resource for the study of chimeric transcripts and fusion proteins., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

We conducted prospective, community-wide surveillance for acute respiratory illnesses (ARIs) in Rochester, NY and Marshfield, WI during a 3-month period in winter 2011. We estimated the incidence of ARIs in each community, tested for viruses, and determined the proportion of ARIs associated with healthcare visits. We used a rolling cross-sectional design to sample participants, conducted telephone interviews to assess ARI symptoms (defined as a current illness with feverishness or cough within the past 7 days), collected nasal/throat swabs to identify viruses, and extracted healthcare utilization from outpatient/inpatient records. Of 6492 individuals, 321 reported an ARI within 7 days (4·9% total, 5·7% in Rochester, 4·4% in Marshfield); swabs were collected from 208 subjects. The cumulative ARI incidence for the entire 3-month period was 52% in Rochester [95% confidence interval (CI) 42-63] and 35% in Marshfield (95% CI 28-42). A specific virus was identified in 39% of specimens: human coronavirus (13% of samples), rhinovirus (12%), RSV (7%), influenza virus (4%), human metapneumovirus (4%), and adenovirus (1%). Only 39/200 (20%) had a healthcare visit (2/9 individuals with influenza). ARI incidence was ~5% per week during winter.

As influenza vaccination is now widely recommended, randomized clinical trials are no longer ethical in many populations. Therefore, observational studies on patients seeking medical care for acute respiratory illnesses (ARIs) are a popular option for estimating influenza vaccine effectiveness (VE). We developed a probability model for evaluating and comparing bias and precision of estimates of VE against symptomatic influenza from two commonly used case-control study designs: the test-negative design and the traditional case-control design. We show that when vaccination does not affect the probability of developing non-influenza ARI then VE estimates from test-negative design studies are unbiased even if vaccinees and non-vaccinees have different probabilities of seeking medical care against ARI, as long as the ratio of these probabilities is the same for illnesses resulting from influenza and non-influenza infections. Our numerical results suggest that in general, estimates from the test-negative design have smaller bias compared to estimates from the traditional case-control design as long as the probability of non-influenza ARI is similar among vaccinated and unvaccinated individuals. We did not find consistent differences between the standard errors of the estimates from the two study designs.

In order to estimate influenza-associated excess mortality in southern Brazil, we applied Serfling regression models to monthly mortality data from 1980 to 2008 for pneumonia/influenza- and respiratory/circulatory-coded deaths for all ages and for those aged ≥60 years. According to viral data, 73∙5% of influenza viruses were detected between April and August in southern Brazil. There was no clear influenza season for northern Brazil. In southern Brazil, influenza-associated excess mortality was 1∙4/100,000 for all ages and 9∙2/100,000 person-years for persons aged ≥60 years using underlying pneumonia/influenza-coded deaths and 10∙0/100,000 for all ages and 86∙6/100,000 person-years for persons aged ≥60 years using underlying respiratory/circulatory-coded deaths. Influenza-associated excess mortality rates for southern Brazil are similar to those published for other countries. Our data support the need for continued influenza surveillance to guide vaccination campaigns to age groups most affected by this virus in Brazil.