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Background: Limited data exist to guide oxygen administration during one-lung ventilation for thoracic surgery. We hypothesised that high intraoperative inspired oxygen fraction during lung resection surgery requiring one-lung ventilation is independently associated with postoperative pulmonary complications (PPCs)., Methods: We performed this retrospective multicentre study using two integrated perioperative databases (Multicenter Perioperative Outcomes Group and Society of Thoracic Surgeons General Thoracic Surgery Database) to study adult thoracic surgical procedures using one-lung ventilation. The primary outcome was a composite of PPCs (atelectasis, acute respiratory distress syndrome, pneumonia, respiratory failure, reintubation, and prolonged ventilation >48 h). The exposure of interest was high inspired oxygen fraction (FiO 2 ), defined by area under the curve of a FiO 2 threshold > 80%. Univariate analysis and logistic regression modelling assessed the association between intraoperative FiO 2 and PPCs., Results: Across four US medical centres, 141/2733 (5.2%) procedures conducted in 2716 patients (55% female; mean age 66 yr) resulted in PPCs. FiO 2 was univariately associated with PPCs (adjusted OR [aOR]: 1.17, 95% confidence interval [CI]: 1.04-1.33, P=0.012). Logistic regression modelling showed that duration of one-lung ventilation (aOR: 1.20, 95% CI: 1.03-1.41, P=0.022), but not the time-weighted average FiO 2 (aOR: 1.01, 95% CI: 1.00-1.02, P=0.165), was associated with PPCs., Conclusions: Our results do not support limiting the inspired oxygen fraction for the purpose of reducing postoperative pulmonary complications in thoracic surgery involving one-lung ventilation., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Postoperative nausea and vomiting (PONV) is a key driver of unplanned admission and patient satisfaction following surgery. Because traditional risk factors do not completely explain variability in risk, we hypothesize that genetics may contribute to the overall risk for this complication. The objective of this research is to perform a genome-wide association study of PONV, derive a polygenic risk score for PONV, assess associations between the risk score and PONV in a validation cohort, and compare any genetic contributions to known clinical risks for PONV., Methods: Surgeries with integrated genetic and perioperative data performed under general anesthesia at Michigan Medicine and Vanderbilt University Medical Center were studied. PONV was defined as nausea or emesis occurring and documented in the PACU. In the Discovery Phase, genome-wide association studies were performed on each genetic cohort and the results were meta-analyzed. Next, in the Polygenic Phase, we assessed whether a polygenic score, derived from genome-wide association study in a derivation cohort from Vanderbilt University Medical Center, improved prediction within a validation cohort from Michigan Medicine, as quantified by discrimination (C-statistic) and net reclassification index., Results: Of 64,523 total patients, 5,703 developed PONV (8.8%). We identified 46 genetic variants exceeding P<1x10-5 threshold, occurring with minor allele frequency > 1%, and demonstrating concordant effects in both cohorts. Standardized polygenic score was associated with PONV in a basic model, controlling for age and sex, (aOR 1.027 per standard deviation increase in overall genetic risk, 95% CI 1.001-1.053, P=0.044), a model based on known clinical risks (aOR 1.029, 95% CI 1.003-1.055, P=0.030), and a full clinical regression, controlling for 21 demographic, surgical, and anesthetic factors, (aOR 1.029, 95% CI 1.002-1.056, P=0.033). The addition of polygenic score improved overall discrimination in models based on known clinical risk factors (c-statistic: 0.616 compared to 0.613, P=0.028) and improved net reclassification of 4.6% of cases., Conclusion: Standardized polygenic risk was associated with PONV in all three of our models, but the genetic influence was smaller than exerted by clinical risk factors. Specifically, a patient with a polygenic risk score > 1 standard deviation above the mean, has 2-3% greater odds of developing PONV when compared to the baseline population, which is at least an order of magnitude smaller than the increase associated with having prior PONV/motion sickness (55%), having a history of migraines (17%), or being female (83%), and is not clinically significant. Furthermore, the use of a polygenic risk score does not meaningfully improve discrimination compared to clinical risk factors and is not clinically useful., Competing Interests: Declarations of Interest: CD is a consultant to Exact Sciences and founder of Belay Diagnostics is compensated with income and equity. Exact Sciences is a molecular diagnostics company specializing in the detection of early-stage cancers. Belay Diagnostic is a platform for the detection of brain and spinal cord cancers using cerebrospinal fluid. The companies named above as well as other companies have licensed previously described technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as Johns Hopkins University. The terms of all of these arrangements are being managed by Johns Hopkins in accordance with its conflict-of-interest policies. CD’s involvement with both companies is unrelated to the scope of the research presented in this manuscript. CJW is currently employed by Regeneron Pharmaceuticals Inc and holds stock and options. KHW is currently employed by Regeneron Pharmaceutical Inc. MM received funding paid to the University of Michigan from Chiesi USA for work unrelated to the scope of the research presented in this manuscript., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Background: Pulmonary hypertension (PH) frequently complicates the evaluation of kidney transplantation (KT) candidates, and is associated with increased adverse outcomes [mortality, delayed graft function (DGF), and major adverse cardiovascular event] following KT., Research Question: What is the relationship between cardiopulmonary hemodynamics and post-KT outcomes?, Study Design and Methods: We conducted a multicenter retrospective cohort study of adults undergoing KT between October 1, 2011 and October 1, 2021, who underwent right heart catheterization (RHC) to assess cardiopulmonary hemodynamics within 1 year of transplantation. Frailty models and logistic regression models were used to evaluate the association between cardiopulmonary hemodynamics and outcomes (mortality, DGF, major adverse cardiovascular event) following KT., Results: A total of 117 patients were included in the final analysis, predominantly male (72%), with a median age of 57 years. PH, defined as mean pulmonary artery pressure (mPAP) > 20 mm Hg, was present in most of the cohort (n = 93; 79%). The cohort was monitored for a median of 29.9 months post-KT, during which about one-fourth experienced mortality (23%) or DGF (25%) events, and approximately one-third (34%) experienced major adverse cardiovascular event. Although echocardiographic measures of pulmonary artery pressure failed to identify post-KT outcomes, a mPAP of ≥ 30 mm Hg on RHC was associated with post-KT major adverse cardiovascular event (hazard ratio, 2.60; 95% CI, 1.10-6.10) and more prevalent in those experiencing post-KT mortality (63% vs 32%; P = .001). Precapillary pulmonary hypertension was also associated with post-KT mortality (hazard ratio, 3.71; 95% CI, 1.07-12.90)., Interpretation: Precapillary pulmonary hypertension and an mPAP of ≥ 30 mm Hg on RHC, but not echocardiographic evidence of PH, was associated with mortality and major adverse cardiovascular event following KT. These data suggest that RHC hemodynamics are superior to echocardiographic measures of PH in association with outcomes following KT, and RHC-derived mPAP in particular may have value in predicting major adverse cardiovascular event and mortality post-KT., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. J. reports investigator-initiated research supported by United Therapeutics. S. S. K. has received research grant support from Edwards Life Sciences, Hemosonics, and PCORI. R. G. A. has received research grant support and served on the consultant or advisory board of United Therapeutics. N. M. B. is the site principal investigator for a clinical trial sponsored by Rednvia. J. M. E. has received research grant support from Janssen, United Therapeutics, Liquidia, Phase Bio, Gossamer Bio, Bayer, Merck, Altavant, Aerovate, Tenax, and Pharmosa, and serves on the consultant or advisory board of United Therapeutics, Altavant, Aerovate, Bayer, Gossamer Bio, Liquidia, Merck, and Janssen. None declared (L. G., S. H. F., A. S. F., D. S., M. V., N. J. D., A. P., C. J.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The recent integration of genomic data with electronic health records has enabled large scale genomic studies on a variety of perioperative complications, yet genome-wide association studies on acute kidney injury have been limited in size or confounded by composite outcomes. Genome-wide association studies can be leveraged to create a polygenic risk score which can then be integrated with traditional clinical risk factors to better predict postoperative complications, like acute kidney injury. Methods: Using integrated genetic data from two academic biorepositories, we conduct a genome-wide association study on cardiac surgery-associated acute kidney injury. Next, we develop a polygenic risk score and test the predictive utility within regressions controlling for age, gender, principal components, preoperative serum creatinine, and a range of patient, clinical, and procedural risk factors. Finally, we estimate additive variant heritability using genetic mixed models. Results: Among 1,014 qualifying procedures at Vanderbilt University Medical Center and 478 at Michigan Medicine, 348 (34.3%) and 121 (25.3%) developed AKI, respectively. No variants exceeded genome-wide significance ( p < 5 × 10 -8 ) threshold, however, six previously unreported variants exceeded the suggestive threshold ( p < 1 × 10 -6 ). Notable variants detected include: 1) rs74637005, located in the exonic region of NFU1 and 2) rs17438465, located between EVX1 and HIBADH . We failed to replicate variants from prior unbiased studies of post-surgical acute kidney injury. Polygenic risk was not significantly associated with post-surgical acute kidney injury in any of the models, however, case duration (aOR = 1.002, 95% CI 1.000-1.003, p = 0.013), diabetes mellitus (aOR = 2.025, 95% CI 1.320-3.103, p = 0.001), and valvular disease (aOR = 0.558, 95% CI 0.372-0.835, p = 0.005) were significant in the full model. Conclusion: Polygenic risk score was not significantly associated with cardiac surgery-associated acute kidney injury and acute kidney injury may have a low heritability in this population. These results suggest that susceptibility is only minimally influenced by baseline genetic predisposition and that clinical risk factors, some of which are modifiable, may play a more influential role in predicting this complication. The overall impact of genetics in overall risk for cardiac surgery-associated acute kidney injury may be small compared to clinical risk factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Douville, Larach, Lewis, Bastarache, Pandit, He, Heung, Mathis, Wanderer, Kheterpal, Surakka and Kertai.)

Background: High airway driving pressure is associated with adverse outcomes in critically ill patients receiving mechanical ventilation, but large multicentre studies investigating airway driving pressure during major surgery are lacking. We hypothesised that increased driving pressure is associated with postoperative pulmonary complications in patients undergoing major abdominal surgery., Methods: In this preregistered multicentre retrospective observational cohort study, the authors reviewed major abdominal surgical procedures in 11 hospitals from 2004 to 2018. The primary outcome was a composite of postoperative pulmonary complications, defined as postoperative pneumonia, unplanned tracheal intubation, or prolonged mechanical ventilation for more than 48 h. Associations between intraoperative dynamic driving pressure and outcomes, adjusted for patient and procedural factors, were evaluated., Results: Among 14 218 qualifying cases, 389 (2.7%) experienced postoperative pulmonary complications. After adjustment, the mean dynamic driving pressure was associated with postoperative pulmonary complications (adjusted odds ratio for every 1 cm H 2 O increase: 1.04; 95% confidence interval [CI], 1.02-1.06; P <0.001). Neither tidal volume nor PEEP was associated with postoperative pulmonary complications. Increased BMI, shorter height, and female sex were predictors for higher dynamic driving pressure (β=0.35, 95% CI 0.32-0.39, P <0.001; β=-0.01, 95% CI -0.02 to 0.00, P =0.005; and β=0.74, 95% CI 0.63-0.86, P <0.001, respectively)., Conclusions: Dynamic airway driving pressure, but not tidal volume or PEEP, is associated with postoperative pulmonary complications in models controlling for a large number of risk predictors and covariates. Such models are capable of risk prediction applicable to individual patients., Competing Interests: Declarations of interest DAC reports research funding (paid to institution) unrelated to the presented work from Merck & Co. Inc. (Rahway, NJ, USA). All other authors declare that they have no conflicts of interest.

Background: Prior studies support a genetic basis for postoperative acute kidney injury (AKI). We conducted a genome-wide association study (GWAS), assessed the clinical utility of a polygenic risk score (PRS), and estimated the heritable component of AKI in patients who underwent noncardiac surgery., Methods: We performed a retrospective large-scale genome-wide association study followed by a meta-analysis of patients who underwent noncardiac surgery at the Vanderbilt University Medical Center ("Vanderbilt" cohort) or Michigan Medicine, the academic medical center of the University of Michigan ("Michigan" cohort). In the Vanderbilt cohort, the relationship between polygenic risk score for estimated glomerular filtration rate and postoperative AKI was also tested to explore the predictive power of aggregating multiple common genetic variants associated with AKI risk. Similarly, in the Vanderbilt cohort genome-wide complex trait analysis was used to estimate the heritable component of AKI due to common genetic variants., Results: The study population included 8248 adults in the Vanderbilt cohort (mean [SD] 58.05 [15.23] years, 50.2% men) and 5998 adults in Michigan cohort (56.24 [14.76] years, 49% men). Incident postoperative AKI events occurred in 959 patients (11.6%) and in 277 patients (4.6%), respectively. No loci met genome-wide significance in the GWAS and meta-analysis. PRS for estimated glomerular filtration rate explained a very small percentage of variance in rates of postoperative AKI and was not significantly associated with AKI (odds ratio 1.050 per 1 SD increase in polygenic risk score [95% CI, 0.971-1.134]). The estimated heritability among common variants for AKI was 4.5% (SE = 4.5%) suggesting low heritability., Conclusion: The findings of this study indicate that common genetic variation minimally contributes to postoperative AKI after noncardiac surgery, and likely has little clinical utility for identifying high-risk patients., (© 2022. The Author(s).)

Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits., Competing Interests: M.J.D. is a founder of Maze Therapeutics. B.M.N. is a member of the scientific advisory board at Deep Genomics and a consultant for Camp4 Therapeutics, Takeda Pharmaceutical, and Biogen. The spouse of C.J.W. works at Regeneron Pharmaceuticals. C.-Y.C. is employed by Biogen. C.R.G. owns stock in 23andMe, Inc. T.R.G. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. E.E.K. has received speaker fees from Regeneron, Illumina, and 23andMe and is a member of the advisory board for Galateo Bio. R.E.M. has received speaker fees from Illumina and is a scientific advisor to the Epigenetic Clock Development Foundation. G.D.S. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. K.S. and U.T. are employed by deCODE Genetics/Amgen, Inc. J.Z. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. S.M. is a co-founder of and holds stock in Seonix Bio., (© 2022.)

Acute kidney injury (AKI) is one of the most common complications of liver transplantation (LT). We examined the impact of intraoperative management on risk for AKI following LT. In this retrospective observational study, we linked data from the electronic health record with standardized transplant outcomes. Our primary outcome was stage 2 or 3 AKI as defined by Kidney Disease Improving Global Outcomes guidelines within the first 7 days of LT. We used logistic regression models to test the hypothesis that the addition of intraoperative variables, including inotropic/vasopressor administration, transfusion requirements, and hemodynamic markers improves our ability to predict AKI following LT. We also examined the impact of postoperative AKI on mortality. Of the 598 adult primary LT recipients included in our study, 43% (n = 255) were diagnosed with AKI within the first 7 postoperative days. Several preoperative and intraoperative variables including (1) electrolyte/acid-base balance disorder (International Classification of Diseases, Ninth Revision codes 253.6 or 276.x and International Classification of Diseases, Tenth Revision codes E22.2 or E87.x, where x is any digit; adjusted odds ratio [aOR], 1.917, 95% confidence interval [CI], 1.280-2.869; p = 0.002); (2) preoperative anemia (aOR, 2.612; 95% CI, 1.405-4.854; p = 0.002); (3) low serum albumin (aOR, 0.576; 95% CI, 0.410-0.808; p = 0.001), increased potassium value during reperfusion (aOR, 1.513; 95% CI, 1.103-2.077; p = 0.01), and lactate during reperfusion (aOR, 1.081; 95% CI, 1.003-1.166; p = 0.04) were associated with posttransplant AKI. New dialysis requirement within the first 7 days postoperatively predicted the posttransplant mortality. Our study identified significant association between several potentially modifiable variables with posttransplant AKI. The addition of intraoperative data did not improve overall model discrimination., (© 2022 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Severe hypocalcaemia is associated with increased transfusion in the trauma population. Furthermore, trauma patients developing severe hypocalcaemia have higher mortality and coagulopathy. Electrolyte abnormalities associated with massive transfusion have been less studied in the surgical population. Here, we tested the primary hypothesis that volume of packed red blood cells and fresh frozen plasma transfused intraoperatively is associated with lower nadir ionised calcium in the surgical population receiving massive resuscitation., Methods: We performed a retrospective observational study at an academic quaternary care centre to characterise hypocalcaemia following large volume (4 or more units packed red blood cells) intraoperative transfusion. We used multivariable linear regression to assess if volume of transfusion with packed red blood cells and fresh frozen plasma were independently associated with a lower ionised calcium. We then used multivariable logistic regressions to assess the association between ionised calcium and transfusion with: (i) mortality, (ii) acute kidney injury, and (iii) postoperative coagulopathy., Results: Hypocalcaemia following large volume resuscitation in the operating room is a very frequent occurrence (70% of cases). After controlling for demographic variables and intraoperative variables, the volume transfused intraoperative was independently associated with hypocalcaemia on multivariable linear regression. Hypocalcaemia, intraoperative transfusion of packed red blood cells, and intraoperative transfusion of fresh frozen plasma were not shown to be associated with clinical outcomes., Conclusions: Hypocalcaemia was associated with increased transfusion volume in this single-centre study. Unlike the trauma population, hypocalcaemia was not associated with increased mortality during surgical care. Our findings suggest that despite improved practice patterns of calcium supplementation, intraoperative hypocalcaemia occurs with relatively high frequency following large volume intraoperative transfusion., (© 2021 British Blood Transfusion Society.)

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes are unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study, and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization, we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population., (© The Author(s) 2021. Published by Oxford University Press.)

Background: Patients with coronavirus disease 2019 (COVID-19) requiring mechanical ventilation have high mortality and resource utilisation. The ability to predict which patients may require mechanical ventilation allows increased acuity of care and targeted interventions to potentially mitigate deterioration., Methods: We included hospitalised patients with COVID-19 in this single-centre retrospective observational study. Our primary outcome was mechanical ventilation or death within 24 h. As clinical decompensation is more recognisable, but less modifiable, as the prediction window shrinks, we also assessed 4, 8, and 48 h prediction windows. Model features included demographic information, laboratory results, comorbidities, medication administration, and vital signs. We created a Random Forest model, and assessed performance using 10-fold cross-validation. The model was compared with models derived from generalised estimating equations using discrimination., Results: Ninety-three (23%) of 398 patients required mechanical ventilation or died within 14 days of admission. The Random Forest model predicted pending mechanical ventilation with good discrimination (C-statistic=0.858; 95% confidence interval, 0.841-0.874), which is comparable with the discrimination of the generalised estimating equation regression. Vitals sign data including SpO 2 /FiO 2 ratio (Random Forest Feature Importance Z-score=8.56), ventilatory frequency (5.97), and heart rate (5.87) had the highest predictive utility. In our highest-risk cohort, the number of patients needed to identify a single new case was 3.2, and for our second quintile it was 5.0., Conclusion: Machine learning techniques can be leveraged to improve the ability to predict which patients with COVID-19 are likely to require mechanical ventilation, identifying unrecognised bellwethers and providing insight into the constellation of accompanying signs of respiratory failure in COVID-19., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Existing genetic information can be leveraged to identify patients with susceptibilities to conditions that might impact their perioperative care, but clinicians generally have limited exposure and are not trained to contextualise this information. We identified patients with genetic susceptibilities to anaesthetic complications using a perioperative biorepository and characterised the concordance with existing diagnoses., Methods: Adult patients undergoing surgery within Michigan Medicine from 2012 to 2017 were consented for genotyping. Genotypes were integrated with the electronic health record (EHR). We retrospectively characterised frequencies of variants associated with butyrylcholinesterase deficiency, factor V Leiden, and malignant hyperthermia, three pharmacogenetic factors with perioperative implications. We calculated the percentage homozygous and heterozygous for each that had been diagnosed previously and searched for EHR findings consistent with a predisposition., Results: Analysis of genetic data revealed that 25 out of 40 769 (0.1%) patients were homozygous and 1918 (4.7%) were heterozygous for mutations associated with butyrylcholinesterase deficiency. Of the homozygous individuals, 14 (56%) carried a pre-existing diagnosis. For factor V Leiden, 29 (0.1%) were homozygous and 2153 (5.3%) heterozygous. Of the homozygous individuals, three (10%) were diagnosed by EHR-derived phenotype and six (21%) by clinician review. Malignant hyperthermia was assessed in a subset of patients. We detected two patients with associated mutations. Neither carried clinical diagnoses., Conclusions: We identified patients with genetic susceptibility to perioperative complications using an open source script designed for clinician use. We validated this application in a retrospective analysis for three conditions with well-characterised inheritance, and showed that not all genetic susceptibilities were documented in the EHR., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: While postoperative myocardial injury remains a major driver of morbidity and mortality, the ability to accurately identify patients at risk remains limited despite decades of clinical research. The role of genetic information in predicting myocardial injury after noncardiac surgery (MINS) remains unknown and requires large scale electronic health record and genomic data sets., Methods: In this retrospective observational study of adult patients undergoing noncardiac surgery, we defined MINS as new troponin elevation within 30 days following surgery. To determine the incremental value of polygenic risk score (PRS) for coronary artery disease, we added the score to 3 models of MINS risk: revised cardiac risk index, a model comprised entirely of preoperative variables, and a model with combined preoperative plus intraoperative variables. We assessed performance without and with PRSs via area under the receiver operating characteristic curve and net reclassification index., Results: Among 90 053 procedures across 40 498 genotyped individuals, we observed 429 cases with MINS (0.5%). PRS for coronary artery disease was independently associated with MINS for each multivariable model created (odds ratio=1.12 [95% CI, 1.02-1.24], P =0.023 in the revised cardiac risk index-based model; odds ratio, 1.19 [95% CI, 1.07-1.31], P =0.001 in the preoperative model; and odds ratio, 1.17 [95% CI, 1.06-1.30], P =0.003 in the preoperative plus intraoperative model). The addition of clinical risk factors improved model discrimination. When PRS was included with preoperative and preoperative plus intraoperative models, up to 3.6% of procedures were shifted into a new outcome classification., Conclusions: The addition of a PRS does not significantly improve discrimination but remains independently associated with MINS and improves goodness of fit. As genetic analysis becomes more common, clinicians will have an opportunity to use polygenic risk to predict perioperative complications. Further studies are necessary to determine if PRSs can inform MINS surveillance.

Background: Heart failure with reduced ejection fraction (HFrEF) is a condition imposing significant health care burden. Given its syndromic nature and often insidious onset, the diagnosis may not be made until clinical manifestations prompt further evaluation. Detecting HFrEF in precursor stages could allow for early initiation of treatments to modify disease progression. Granular data collected during the perioperative period may represent an underutilized method for improving the diagnosis of HFrEF. We hypothesized that patients ultimately diagnosed with HFrEF following surgery can be identified via machine-learning approaches using pre- and intraoperative data., Methods: Perioperative data were reviewed from adult patients undergoing general anesthesia for major surgical procedures at an academic quaternary care center between 2010 and 2016. Patients with known HFrEF, heart failure with preserved ejection fraction, preoperative critical illness, or undergoing cardiac, cardiology, or electrophysiologic procedures were excluded. Patients were classified as healthy controls or undiagnosed HFrEF. Undiagnosed HFrEF was defined as lacking a HFrEF diagnosis preoperatively but establishing a diagnosis within 730 days postoperatively. Undiagnosed HFrEF patients were adjudicated by expert clinician review, excluding cases for which HFrEF was secondary to a perioperative triggering event, or any event not associated with HFrEF natural disease progression. Machine-learning models, including L1 regularized logistic regression, random forest, and extreme gradient boosting were developed to detect undiagnosed HFrEF, using perioperative data including 628 preoperative and 1195 intraoperative features. Training/validation and test datasets were used with parameter tuning. Test set model performance was evaluated using area under the receiver operating characteristic curve (AUROC), positive predictive value, and other standard metrics., Results: Among 67,697 cases analyzed, 279 (0.41%) patients had undiagnosed HFrEF. The AUROC for the logistic regression model was 0.869 (95% confidence interval, 0.829-0.911), 0.872 (0.836-0.909) for the random forest model, and 0.873 (0.833-0.913) for the extreme gradient boosting model. The corresponding positive predictive values were 1.69% (1.06%-2.32%), 1.42% (0.85%-1.98%), and 1.78% (1.15%-2.40%), respectively., Conclusions: Machine-learning models leveraging perioperative data can detect undiagnosed HFrEF with good performance. However, the low prevalence of the disease results in a low positive predictive value, and for clinically meaningful sensitivity thresholds to be actionable, confirmatory testing with high specificity (eg, echocardiography or cardiac biomarkers) would be required following model detection. Future studies are necessary to externally validate algorithm performance at additional centers and explore the feasibility of embedding algorithms into the perioperative electronic health record for clinician use in real time.

Background: "Lung-protective ventilation" describes a ventilation strategy involving low tidal volumes (VTs) and/or low driving pressure/plateau pressure and has been associated with improved outcomes after mechanical ventilation. We evaluated the association between intraoperative ventilation parameters (including positive end-expiratory pressure [PEEP], driving pressure, and VT) and 3 postoperative outcomes: (1) PaO2/fractional inspired oxygen tension (FIO2), (2) postoperative pulmonary complications, and (3) 30-day mortality., Methods: We retrospectively analyzed adult patients who underwent major noncardiac surgery and remained intubated postoperatively from 2006 to 2015 at a single US center. Using multivariable regressions, we studied associations between intraoperative ventilator settings and lowest postoperative PaO2/FIO2 while intubated, pulmonary complications identified from discharge diagnoses, and in-hospital 30-day mortality., Results: Among a cohort of 2096 cases, the median PEEP was 5 cm H2O (interquartile range = 4-6), median delivered VT was 520 mL (interquartile range = 460-580), and median driving pressure was 15 cm H2O (13-19). After multivariable adjustment, intraoperative median PEEP (linear regression estimate [B] = -6.04; 95% CI, -8.22 to -3.87; P < .001), median FIO2 (B = -0.30; 95% CI, -0.50 to -0.10; P = .003), and hours with driving pressure >16 cm H2O (B = -5.40; 95% CI, -7.2 to -4.2; P < .001) were associated with decreased postoperative PaO2/FIO2. Higher postoperative PaO2/FIO2 ratios were associated with a decreased risk of pulmonary complications (adjusted odds ratio for each 100 mm Hg = 0.495; 95% CI, 0.331-0.740; P = .001, model C-statistic of 0.852) and mortality (adjusted odds ratio = 0.495; 95% CI, 0.366-0.606; P < .001, model C-statistic of 0.820). Intraoperative time with VT >500 mL was also associated with an increased likelihood of developing a postoperative pulmonary complication (adjusted odds ratio = 1.06/hour; 95% CI, 1.00-1.20; P = .042)., Conclusions: In patients requiring postoperative intubation after noncardiac surgery, increased median FIO2, increased median PEEP, and increased time duration with elevated driving pressure predict lower postoperative PaO2/FIO2. Intraoperative duration of VT >500 mL was independently associated with increased postoperative pulmonary complications. Lower postoperative PaO2/FIO2 ratios were independently associated with pulmonary complications and mortality. Our findings suggest that postoperative PaO2/FIO2 may be a potential target for future prospective trials investigating the impact of specific ventilation strategies for reducing ventilator-induced pulmonary injury.

Background: Compared with historic ventilation strategies, modern lung-protective ventilation includes lower tidal volumes (VT), lower driving pressures, and application of positive end-expiratory pressure (PEEP). The contributions of each component to an overall intraoperative protective ventilation strategy aimed at reducing postoperative pulmonary complications have neither been adequately resolved, nor comprehensively evaluated within an adult cardiac surgical population. The authors hypothesized that a bundled intraoperative protective ventilation strategy was independently associated with decreased odds of pulmonary complications after cardiac surgery., Methods: In this observational cohort study, the authors reviewed nonemergent cardiac surgical procedures using cardiopulmonary bypass at a tertiary care academic medical center from 2006 to 2017. The authors tested associations between bundled or component intraoperative protective ventilation strategies (VT below 8 ml/kg ideal body weight, modified driving pressure [peak inspiratory pressure - PEEP] below 16 cm H2O, and PEEP greater than or equal to 5 cm H2O) and postoperative outcomes, adjusting for previously identified risk factors. The primary outcome was a composite pulmonary complication; secondary outcomes included individual pulmonary complications, postoperative mortality, as well as durations of mechanical ventilation, intensive care unit stay, and hospital stay., Results: Among 4,694 cases reviewed, 513 (10.9%) experienced pulmonary complications. After adjustment, an intraoperative lung-protective ventilation bundle was associated with decreased pulmonary complications (adjusted odds ratio, 0.56; 95% CI, 0.42-0.75). Via a sensitivity analysis, modified driving pressure below 16 cm H2O was independently associated with decreased pulmonary complications (adjusted odds ratio, 0.51; 95% CI, 0.39-0.66), but VT below 8 ml/kg and PEEP greater than or equal to 5 cm H2O were not., Conclusions: The authors identified an intraoperative lung-protective ventilation bundle as independently associated with pulmonary complications after cardiac surgery. The findings offer insight into components of protective ventilation associated with adverse outcomes and may serve as targets for future prospective interventional studies investigating the impact of specific protective ventilation strategies on postoperative outcomes after cardiac surgery.

Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members., Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity., Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6-19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4-22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4-22.3, siblings: OR, 5.1; 95% CI, 1.1-23.9, children: OR, 6.0; 95% CI, 1.4-26.7)., Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.

Background: Comprehensive molecular profiling led to the recognition of multiple prostate cancer (PCa) molecular subtypes and driving alterations, but translating these findings to clinical practice is challenging., Patients and Methods: We developed a formalin-fixed paraffin-embedded (FFPE) tissue compatible integrative assay for PCa molecular subtyping and interrogation of relevant genetic/transcriptomic alterations (MiPC). We applied MiPC, which combines capture-based next generation sequencing and quantitative reverse transcription PCR (qRT-PCR), to 53 FFPE PCa specimens representing cases not well represented in frozen tissue cohorts, including 8 paired primary tumor and lymph node metastases. Results were validated using multiplexed PCR based NGS and Sanger sequencing., Results: We identified known and novel potential driving, somatic mutations and copy number alterations, including a novel BRAF T599&#95;V600insHT mutation and CYP11B2 amplification in a patient treated with ketoconazole (a potent CYP11B2 inhibitor). qRT-PCR integration enabled comprehensive molecular subtyping and provided complementary information, such as androgen receptor (AR) target gene module assessment in advanced cases and SPINK1 over-expression. MiPC identified highly concordant profiles for all 8 tumor/lymph node metastasis pairs, consistent with limited heterogeneity amongst driving events. MiPC and exome sequencing were performed on separately isolated conventional acinar PCa and prostatic small cell carcinoma (SCC) components from the same FFPE resection specimen to enable direct comparison of histologically distinct components. While both components showed TMPRSS2:ERG fusions, the SCC component exclusively harbored complete TP53 inactivation (frameshift variant and copy loss) and two CREBBP mutations., Conclusions: Our results demonstrate the feasibility of integrative profiling of routine PCa specimens, which may have utility for understanding disease biology and enabling personalized medicine applications., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Ultrasound-guided core biopsy provides many benefits compared with fine-needle aspiration cytology and has begun to emerge as part of the diagnostic work-up for a salivary gland lesion. Although the increased potential for tumor-seeding and capsule rupture has been extensively discussed, the safety of this procedure is widely accepted based on infrequent reports of tumor-seeding. In fact, a review of the literature shows only 2 cases of salivary tumor seeding following biopsy with larger-gauge needle characteristics, with 2 reported cases of salivary tumor seeding following fine-needle aspiration cytology. However, the follow-up interval of such studies (<7 years) is substantially less than the 20-year follow-up typically necessary to detect remote recurrence. Studies on tumor recurrence of pleomorphic adenoma, the most common salivary gland lesion, suggest that as many as 16% of tumor recurrences occur at least 10 years following initial surgery, with average time to recurrence ranging anywhere from 6.1 to 11.8 years postoperatively. Despite the benefits of ultrasound-guided core biopsy over fine-needle aspiration biopsy, which include both improved consistency and diagnostic accuracy, current studies lack adequate patient numbers and follow-up duration to confirm comparable safety profile to currently accepted fine-needle aspiration cytology. In this report we: (1) compare the relative benefits of each procedure, (2) review evidence regarding tumor seeding in each procedure, (3) discuss time course and patient numbers necessary to detect tumor recurrence, and (4) describe how these uncertainties should be factored into clinical considerations., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: Transperineal template prostate biopsy has been proposed to facilitate systematic biopsy in patients undergoing repeat biopsy who are at high risk for cancer. Advocates tout the reliability of the grid to define biopsy location compared to hand-held transrectal ultrasound guided biopsy. However, accuracy of the biopsy needle depends on bevel position, tissue deformity, and technique. Due to this potential for error, we sought to determine whether the use of transperineal template biopsy would assure reproducibly accurate needle placement., Materials and Methods: A standard 0.5 cm brachytherapy grid was utilized for transperineal biopsy. A single grid hole was used to obtain biopsies. The bevel of the needle was rotated to a different position with each biopsy, and the angle of the needle was varied to test the ability of the grid to "map" the prostate., Results: We observed wide variation of needle location through a single brachytherapy grid hole. We are able to show that at 5 cm depth, an area of 2.47 mm(2) is possible to biopsy and at a depth of 25 cm; approximately 7.56 mm(2) is possible to biopsy. This gives a precision of biopsy of at the most shallow depth 22% and at the deepest 7%., Conclusion: There is potential for technical and equipment associated error with transperineal template guided prostate biopsy. The grid alone can account for substantial sources of error, so technique remains critical if the grid coordinates are to be used to predict presence or extent of cancer.

This paper describes a novel nanofluidic phenomenon where untethered DNA and chromatin are linearized by rapidly narrowing an elastomeric nanochannel filled with solutions of the biopolymers. This nanoscale squeezing procedure generates hydrodynamic flows while also confining the biopolymers into smaller and smaller volumes. The unique features of this technique enable full linearization then trapping of biopolymers such as DNA. The versatility of the method is also demonstrated by analysis of chromatin stretchability and mapping of histone states using single strands of chromatin.

Microfluidic devices fabricated using poly(dimethylsiloxane) (PDMS) polymer are routinely used for in vitro cell culture for a wide range of cellular assays. These assays typically involve the incubation of cultured cells with a drug molecule or a fluorescent marker while monitoring a cellular response. The accuracy of these assays depends on achieving a consistent and reproducible concentration of solute molecules in solution. However, hydrophobic therapeutic and fluorescent molecules tend to diffuse into the PDMS walls of the microfluidic devices, which reduce their concentration in solution and consequently affect the accuracy and reliability of these assays. In this paper, we quantitatively investigate the relationship between the partition coefficient (log P) of a series of markers routinely used in in vitro cellular assays including [3H]-dexamethasone, [3H]-diazepam, [14C]-mannitol, [3H]-phenytoin, and rhodamine 6G and their absorption into PDMS microfluidic channels. Our results show that the absorption of a given solute into PDMS depends on the hydrophilic/hydrophobic balance defined by its log P value. Specifically, results demonstrate that molecules with log P less than 2.47 exhibit minimal absorption (<10%) into PDMS channels whereas molecules with log P larger than 2.62 exhibit extensive absorption (>90%) into PDMS channels. Further investigations showed that TiO(2) and glass coatings of PDMS channels reduced the absorption of hydrophobic molecules (log P > 2.62) by 2- and 4.5-folds, respectively.

When a tensile strain is applied to a film supported on a compliant substrate, a pattern of parallel cracks can channel through both the film and substrate. A linear-elastic fracture-mechanics model for the phenomenon is presented to extend earlier analyses in which cracking was limited to the film. It is shown how failure of the substrate reduces the critical strain required to initiate fracture of the film. This effect is more pronounced for relatively tough films. However, there is a critical ratio of the film to substrate toughness above which stable cracks do not form in response to an applied load. Instead, catastrophic failure of the substrate occurs simultaneously with the propagation of a single channel crack. This critical toughness ratio increases with the modulus mismatch between the film and substrate, so that periodic crack patterns are more likely to be observed with relatively stiff films. With relatively low values of modulus mismatch, even a film that is more brittle than the substrate can cause catastrophic failure of the substrate. Below the critical toughness ratio, there is a regime in which stable crack arrays can be formed in the film and substrate. The depth of these arrays increases, while the spacing decreases, as the strain is increased. Eventually, the crack array can become deep enough to cause substrate failure.

Studies using this micro-system demonstrated significant morphological differences between alveolar epithelial cells (transformed human alveolar epithelial cell line, A549 and primary murine alveolar epithelial cells, AECs) exposed to combination of solid mechanical and surface-tension stresses (cyclic propagation of air-liquid interface and wall stretch) compared to cell populations exposed solely to cyclic stretch. We have also measured significant differences in both cell death and cell detachment rates in cell monolayers experiencing combination of stresses. This research describes new tools for studying the combined effects of fluid mechanical and solid mechanical stress on alveolar cells. It also highlights the role that surface tension forces may play in the development of clinical pathology, especially under conditions of surfactant dysfunction. The results support the need for further research and improved understanding on techniques to reduce and eliminate fluid stresses in clinical settings.

This manuscript describes a straightforward fabrication process for embedding Ag/AgCl electrodes within a two-layer poly(dimethylsiloxane) (PDMS) microfluidic chip where an upper and a lower channel are separated by a semiporous membrane. This system allows for the reliable real-time measurement of transendothelial and transepithelial electrical resistance (TEER), an accepted quantification of cell monolayer integrity, across cells cultured on membranes inside the microchannels using impedance spectroscopy. The technique eliminates the need for costly or specialized microelectrode fabrication, enabling commercially available wire electrodes to easily be incorporated into PDMS microsystems for measuring TEER under microfluidic environments. The capability of measuring impedance across a confluent cell monolayer is confirmed using (i) brain-derived endothelial cells (bEND.3), (ii) Madin Darby Canine Kidney Cells (MDCK-2), and mouse myoblast (C2C12) (all from ATCC, Manassas, VA). TEER values as a function of cell type and cell culture time were measured and both agree with previously published values from macroscale culture techniques. This system opens new opportunities for conveniently resolving both transendothelial and transepithelial electrical resistance to monitor cell function in real-time in microfluidic cell cultures.