Randomized Prospective Trial of Epidural Analgesia after Open Hepatectomy.

OBJECTIVE: To evaluate whether patient-controlled epidural analgesia (PCEA) improves postoperative pain during ambulation following elective open hepatectomy. BACKGROUND: Strategies to alleviate postoperative pain are a critical element of recovery after surgery. However, the optimal postoperative pain management strategy following open hepatectomy remains unclear. METHODS: We conducted a prospective, nonblinded, randomized comparison of PCEA (intervention) versus intravenous patient-controlled analgesia (IV PCA; control) for postoperative pain following elective open hepatectomy. The primary end point was pain during ambulation on postoperative day (POD) 2. The study was powered to detect a clinically significant 2-point difference on the pain numeric rating scale (NRS). Secondary end points included pain at rest, morbidity, time to return of bowel function, and length of stay. RESULTS: From 2015 to 2020, 231 patients were randomized (116 patients in the PCEA arm and 115 in the IV PCA arm). The incidence of epidural failure was 3% (n=4/116), with no epidural-related complications. Patients in the PCEA arm had a <2-point difference in NRS pain scores during ambulation on POD 2 vs. IV PCA (median 4.0 vs. 5.0, P <0.001). There was no difference in overall complications between the PCEA and IV PCA arms (33% vs. 40%, P =0.276). Secondary outcomes, including pain scores at rest, were similar between the study arms. CONCLUSIONS: PCEA was safe following open hepatectomy and was associated with a small difference in pain with activity on POD 2 that did not reach our pre-specified definition of clinical significance.

Perioperative Oncology Health Care Providers and Transgender Health: A Single-Institution Survey to Gauge Attitudes, Knowledge, Behaviors, and Education.

Purpose: Patients identifying as transgender report that a lack of access to providers with trans-specific medical knowledge represents one of the largest barriers to equitable health care access. Through an institutional survey, we assessed and analyzed the attitudes, knowledge, behaviors, and education of perioperative clinical staff when caring for transgender patients with cancer. Methods: A web-based survey was distributed to 1100 perioperative clinical staff at the National Cancer Institute (NCI)-Designated Comprehensive Cancer Center in New York City between January 14, 2020, and February 28, 2020, and received 276 responses. The survey instrument consisted of 42 nondemographic questions about attitudes, knowledge, behaviors, and education regarding transgender health care and 14 demographic questions. Questions were presented as a mix of Yes/No, free text response, and a 5-point Likert scale. Results: Certain demographic groups (younger, lesbian, gay, or bisexual [LGB], fewer years employment at the institution) held more favorable attitudes toward the transgender population and were more knowledgeable regarding their health needs. Respondents underreported the rates of mental illness and risk factors for cancer like HIV and substance use among the transgender population. A greater proportion of respondents identifying as LGB endorsed witnessing an interaction wherein a colleague exhibited attitudes/beliefs about the transgender population that were barriers to care. Only 23.2% of respondents were ever trained on the health needs of transgender patients. Conclusion: There is a need for institutions to assess the cultural competency of perioperative clinical staff toward transgender health, especially within certain demographics. This survey may inform quality education initiatives to eliminate biases and knowledge gaps.

Discharge prescribing of enteral opioids in opioid naïve patients following non-surgical intensive care: A retrospective cohort study.

PURPOSE: To estimate the incidence of new prescription of enteral opioids on hospital discharge in opioid naïve, non-surgical, critically ill patients and evaluate the risk factors associated with such occurrence. METHODS: Using hospital-wide and ICU databases, we retrospectively identified all patients (≥ 18 years old) who were admitted to the 20-bed adult ICU of Memorial Sloan Kettering Cancer Center (MSKCC) between July 1, 2015 and April 20, 2020. Patients' electronic medical records (EMR) were retrieved and patient demographics, peri-ICU admission data were captured and analyzed. RESULTS: During the study period, a total of 3755 opioid naïve patients were admitted to the ICU and 848 patients met the inclusion criteria. Among these, 346 (40.8%) patients were discharged with a new opioid prescription. Age at ICU admission, preadmission use of benzodiazepine, and antidepressants, a diagnosis of sepsis, and use of mechanical ventilation, antidepressants or, opioid infusion for greater than 4 h during the ICU stay, hospital length of stay (LOS), and days between ICU discharge and hospital discharge were independently associated with increased odds of a new opioid prescription. CONCLUSIONS: A significant proportion of opioid naïve non-surgical ICU survivors receive a new opioid prescription on hospital discharge.

The adaptive landscape of a metallo-enzyme is shaped by environment-dependent epistasis.

Enzymes can evolve new catalytic activity when environmental changes present them with novel substrates. Despite this seemingly straightforward relationship, factors other than the direct catalytic target can also impact adaptation. Here, we characterize the catalytic activity of a recently evolved bacterial methyl-parathion hydrolase for all possible combinations of the five functionally relevant mutations under eight different laboratory conditions (in which an alternative divalent metal is supplemented). The resultant adaptive landscapes across this historical evolutionary transition vary in terms of both the number of "fitness peaks" as well as the genotype(s) at which they are found as a result of genotype-by-environment interactions and environment-dependent epistasis. This suggests that adaptive landscapes may be fluid and molecular adaptation is highly contingent not only on obvious factors (such as catalytic targets), but also on less obvious secondary environmental factors that can direct it towards distinct outcomes.

Effects of a single bout of short-duration high-intensity and long-duration low-intensity exercise on insulin resistance and adiponectin/leptin ratio.

OBJECTIVES: Moderate-intensity exercise improves insulin sensitivity, which may depend on the intensity, duration, and frequency of exercise. We examined the effects of a single bout of short-duration high-intensity exercise (HIE) and long-duration lowintensity exercise (LIE) on insulin sensitivity and the adiponectin/leptin ratio in individuals with different body mass indices (BMIs) who do not exercise regularly. METHODS: We enrolled 42 healthy volunteers aged 20-64 years and divided them into two groups based on BMI: BMI <24 kg/m2 and BMI ≥27 kg/m2. They were randomly assigned to either the short-duration (20 min) HIE (70%-80% heart rate reserve, HRR) or long-duration (60 min) LIE training groups (30%-40% HRR). Glucose, insulin, adiponectin, and leptin levels were assessed before training and at 0, 30, 60, and 120 min after training. RESULTS: We finally analyzed 27 normal weight and 9 obese individuals. No significant differences were observed in the baseline information of both BMI groups. Homeostatic model assessment for insulin resistance significantly improved for both exercise patterns in the normal weight group and for the HIE pattern in the obese group (P < 0.01), whereas the adiponectin/leptin ratio increased significantly only among normal weight participants with the LIE intervention. CONCLUSION: Both exercise patterns in BMI <24 kg/m2 and BMI ≥27 kg/m2 benefit on insulin resistance. Therefore, people can choose the way they can fit to improve insulin resistance both short-duration high-intensity exercise and long-duration low-intensity exercise.

Institution of Monthly Anesthesia Quality Reports Does Not Reduce Postoperative Complications despite Improved Metric Compliance.

While quality programs have been shown to improve provider compliance, few have demonstrated conclusive improvements in patient outcomes. We hypothesized that there would be increased metric compliance and decreased postoperative complications after initiation of an anesthesiology quality improvement program at our institution. We performed a retrospective study of all adult inpatients having anesthesia for a twelve-month period that spanned six months before and after program implementation. The primary outcome was the rate of complications in the post-implementation period. Secondary outcomes included the change in proportion of complications and compliance with quality metrics. We studied a total of 9620 adult inpatient cases, subdivided into pre- and post-implementation groups (4832 vs 4788.) After multivariate model adjustment, the rate of any complication (our primary outcome) was not significantly changed (32% to 31%; adjusted P = 0.410.) Of the individual complications, only wound infection (2.0% to 1.5%; adjusted P = 0.020) showed a statistically significant decrease. Statistically and clinically significant increases in compliance were seen for the BP-02 Avoiding Monitoring Gaps metric (81% to 93%, P < 0.001), both neuromuscular blockade metrics (NMB-01 76% to 91%, P < 0.001; NMB-02 95% to 97%, P = 0.006), both tidal volume metrics (PUL-01 84% to 93%, P < 0.001; PUL-02 30% to 45%, P < 0.001), and the TEMP-02 Core Temperature Measurement metric (88% to 94%, P < 0.001). Implementation of a comprehensive quality feedback program improved metric compliance but was not associated with a change in postoperative complications.

A mechanistic view of enzyme evolution.

New enzyme functions often evolve through the recruitment and optimization of latent promiscuous activities. How do mutations alter the molecular architecture of enzymes to enhance their activities? Can we infer general mechanisms that are common to most enzymes, or does each enzyme require a unique optimization process? The ability to predict the location and type of mutations necessary to enhance an enzyme's activity is critical to protein engineering and rational design. In this review, via the detailed examination of recent studies that have shed new light on the molecular changes underlying the optimization of enzyme function, we provide a mechanistic perspective of enzyme evolution. We first present a global survey of the prevalence of activity-enhancing mutations and their distribution within protein structures. We then delve into the molecular solutions that mediate functional optimization, specifically highlighting several common mechanisms that have been observed across multiple examples. As distinct protein sequences encounter different evolutionary bottlenecks, different mechanisms are likely to emerge along evolutionary trajectories toward improved function. Identifying the specific mechanism(s) that need to be improved upon, and tailoring our engineering efforts to each sequence, may considerably improve our chances to succeed in generating highly efficient catalysts in the future.

Author Correction: Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The impact of real-time clinical alerts on the compliance of anesthesia documentation: A retrospective observational study.

INTRODUCTION: Clinical alert systems (CAS) have been used to analyze deviations from hospital standards in the electronic medical record to identify missing documentations and send alerts to the appropriate providers to increase adherence to required elements. To improve compliance, an alert system for documentation of the Immediate Preoperative Assessment (IPOA) was implemented at our institution in August 2018 with the goal of improving documentation compliance rates. We hypothesized that implementation of this alert system would increase the compliance of on-time documentation of the IPOA. METHODS: An initial data query in our institutional data warehouse was made for all patients who had a completed anesthetic during our study period. This date range corresponded to 6 months before and after August 2nd, 2018, the date when the IPOA alert was implemented and the anesthesiology department. The following analyses were performed: testing the proportion of cases compliant with on-time documentation of the IPOA pre- versus post-implementation for the full cohort and among subsets of interest, testing the time when the IPOA was completed relative to anesthesia end, and testing whether time of day of when surgery occurred had an impact on the time when the IPOA was completed relative to the drapes off/IPOA alert sent time. The proportion of compliance for pre- versus post-implementation was tested by Chi-square test. RESULTS: Through retrospective chart review of electronic patient records, 47,417 cases matched our inclusion criteria of patients that had a completed anesthetic between February 2nd, 2018 to February 2nd, 2019. In total, we excluded 5132 cases. The compliance rate of IPOA completion increased from 76% to 88% (P < 0.001) before and after the alert implementation date. In the initial month following alert implementation, the compliance rate immediately increased to 83% and stayed in the high 80's for the balance of the study period. CONCLUSION: In summary, we demonstrate that automated Clinical Alert Systems operating via a single page notification can improve the compliance rate for documentation of key anesthesia events and that this observation is sustained six months after the implementation date. Furthermore, improvement in compliance is highest shorter cases and cases that occur early in the day. This study shows promising results in the use of automatic CAS system alerts to help hospitals meet the Center for Medicare and Medicaid Services (CMS) and The Joint Commission (TJC) standards.

Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme.

Characterizing the adaptive landscapes that encompass the emergence of novel enzyme functions can provide molecular insights into both enzymatic and evolutionary mechanisms. Here, we combine ancestral protein reconstruction with biochemical, structural and mutational analyses to characterize the functional evolution of methyl-parathion hydrolase (MPH), an organophosphate-degrading enzyme. We identify five mutations that are necessary and sufficient for the evolution of MPH from an ancestral dihydrocoumarin hydrolase. In-depth analyses of the adaptive landscapes encompassing this evolutionary transition revealed that the mutations form a complex interaction network, defined in part by higher-order epistasis, that constrained the adaptive pathways available. By also characterizing the adaptive landscapes in terms of their functional activities towards three additional organophosphate substrates, we reveal that subtle differences in the polarity of the substrate substituents drastically alter the network of epistatic interactions. Our work suggests that the mutations function collectively to enable substrate recognition via subtle structural repositioning.

Real Time Locating Systems and sustainability of Perioperative Efficiency of Anesthesiologists.

OBJECTIVE: We determine if Real Time Locating Systems (RTLS) paired with automated notifications have a sustained effect on perioperative efficiency in anesthesiologists over a one-year period from the time of implementation. METHODS: A retrospective chart review of all outpatient and short-stay patients, who received general anesthesia at our ambulatory surgery center between July 1st, 2017 and December 31st, 2018 was performed. Patients included were over 18 years of age who presented for non-urgent cases with ASA classification of 1, 2, and 3. Additionally, only first cases of the day for individual anesthesiologists were included.Time was used as a measure of efficiency between three comparison groups: Anesthesiologists who use RTLS prior to implementation of automated notification pairing for the period of 1 July 2017 to 31 December 2017.Anesthesiologists who use RTLS paired with automated notifications for the period of 1 January 2018 to 30 June 2018.Anesthesiologists who use RTLS paired with automated notifications for the period of 1 July 2018 to 31 December 2018.The primary outcome measure duration (DUR) was collected from patient electronic records.DUR was defined as duration of time, in minutes, from patient arrival to the Operating Room (OR) and initiation of induction by the anesthesiologist (exclusively for first cases of the day). RESULTS: During the initial six months, DUR between time of OR admission and time of induction was significantly reduced to 6.0 minutes (5.0,8.0) post-implementation of automated notification pairing with RTLS. DUR then returned to pre-intervention baseline of 7.0 minutes (5.0, 9.0) during the subsequent six-month study period. CONCLUSION: Initial results indicate that implementation of integrated RTLS technology enabled anesthesiologists at our institution to be more efficient during the perioperative period. However, this perceived benefit was not sustained over a 1-year period as our measure of efficiency DUR ultimately returned to the pre-intervention baseline.

The incidence of intraoperative gastric tube malposition verified by Point-of-Care Ultrasound.

BACKGROUND: Over a million gastric tubes are placed yearly for varying medical reasons including gastric decompression. In the operating room (OR), this is performed blindly, and position is confirmed by auscultation, aspiration, or palpation by a surgeon. Despite the known risks of malpositioned gastric tubes, there is limited data in anesthesia literature about the incidence of intraoperative malpositioned gastric tubes. In this study, we use Point-of-Care ultrasonography (POCUS) to confirm gastric tube placement in the OR. METHODS: Prospective observational study with a total of 149 subjects, all over 18 years of age, undergoing surgery with general endotracheal anesthesia and intraoperative blind placement of a gastric tube by an anesthesia provider. The primary objective of this study is to determine the incidence of malposition of blindly placed gastric tubes. RESULTS: In our analysis, we found that out of 149 patients 110 patients were successfully visualized; the incidence of malposition was 0.14 [95% CI: 0.08-0.21]. We did not find age, Body Mass Index, or sex to be associated with predisposing patients to intraoperative malposition of gastric tube. However, increasing years of experience of anesthesia provider correlated with higher malposition rates. CONCLUSIONS: In summary, we demonstrated that the incidence of malposition of blindly gastric tubes was 14%. Given the attendant risks of malpositioned gastric tubes, this data should inform decision algorithms for the blind placement of gastric tubes.

Improved Compliance With Anesthesia Quality Measures After Implementation of Automated Monthly Feedback.

PURPOSE: Minimization of postoperative complications is important in patients with cancer. We wished to improve compliance with anesthesiology quality measures through staff education reinforced with automated monthly feedback. METHODS: The anesthesiology department implemented a program to capture and report quality metrics. After staff education, monthly e-mail reports were sent to each anesthesiology physician and nurse anesthetist to detail individual compliance rates for a set of quality measures. For each measure, the proportion of patient cases that passed the measure before and after implementation of the program was compared using a two-sample proportion test. RESULTS: After exclusions, we analyzed 15 of 23 quality measures. Of the 15 measures, 11 were process measures, and four were outcome measures. Of the 11 process measures, seven demonstrated statistically significant improvements (P < .01). The most improved measure was TEMP-02 (core temperature measurement), which increased from 69.6% to 85.7% (16.1% difference; P < .001). Also improved were PUL-02 (low tidal volume, less than 8 mL/kg ideal body weight; 15.4% difference; P < .001) and NMB-01 (train of four taken; 12.2% difference; P < .001). The outcome measure TEMP-03 (perioperative temperature management) had a statistically significant increase of a small magnitude (0.2% difference; P < .001). No other outcome measures showed statistically significant improvement. CONCLUSION: After implementation of a comprehensive quality improvement program, our group observed significant improvements in anesthesia quality measure compliance for several process measures. Future work is needed to determine if this initial success can be preserved and associated with improved outcomes.

Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes.

Genetic variation among orthologous proteins can cause cryptic phenotypic properties that only manifest in changing environments. Such variation may impact the evolvability of proteins, but the underlying molecular basis remains unclear. Here, we performed comparative directed evolution of four orthologous metallo-ß-lactamases toward a new function and found that different starting genotypes evolved to distinct evolutionary outcomes. Despite a low initial fitness, one ortholog reached a significantly higher fitness plateau than its counterparts, via increasing catalytic activity. By contrast, the ortholog with the highest initial activity evolved to a less-optimal and phenotypically distinct outcome through changes in expression, oligomerization and activity. We show how cryptic molecular properties and conformational variation of active site residues in the initial genotypes cause epistasis, that could lead to distinct evolutionary outcomes. Our work highlights the importance of understanding the molecular details that connect genetic variation to protein function to improve the prediction of protein evolution.

Interrater variability in ASA physical status assignment: an analysis in the pediatric cancer setting.

BACKGROUND: The American Society of Anesthesiologists (ASA) physical status is a universal classification system that helps clinicians to categorize their patients preoperatively. However, there is a lack of both inter-rater and intra-rater reliability among clinicians for the ASA physical status classification. Our study focuses on testing these reliabilities within pediatric anesthesia providers in the cancer setting. METHODS: In our retrospective observational study, a total of 1177 anesthesia records were reviewed. The cohort included all pediatric patients (≤ 18 years old) diagnosed with either retinoblastoma or neuroblastoma who had two or more anesthesia procedure within a 14-day time period. RESULTS: Overall, the ASA physical status score among two different anesthesia providers for the same patient treated at different times had very little inter-rater reliability, κ = - 0.042 (95% CI - 0.17; 0.09). Of the 1177-patient anesthesia records, only 25% had two or more ASA physical status score assigned by the same anesthesiologist within a 14-day time period. There was moderate intra-rater reliability κ = 0.48 (95% CI 0.29; 0.68) for patients who were assigned an ASA physical status score by the identical anesthesia provider at different times points within a 14 day period. CONCLUSION: In contrast to observations in earlier studies, findings indicate poor agreement in inter-rater reliability. Although there was moderate agreement in intra-rater reliability, one would expect to find stronger, even perfect, intra-rater reliability. These findings suggest the need to develop a specific physical status classification system directed toward patients with a systemic illness such as cancer in both young and adult patients.

Does Checklist Implementation Improve Quantity of Data Transfer: An Observation in Postanesthesia Care Unit (PACU).

BACKGROUND: Omission of patient information in perioperative communication is closely linked to adverse events. Use of checklists to standardize the handoff in the post anesthesia care unit (PACU) has been shown to effectively reduce medical errors. OBJECTIVE: Our study investigates the use of a checklist to improve quantity of data transfer during handoffs in the PACU. DESIGN: A cross-sectional observational study. SETTING: PACU at Memorial Sloan Kettering Cancer Center (MSKCC); June 13, 2016 through July 15, 2016. PATIENTS OTHER PARTICIPANTS: We observed the handoff reports between the nurses, PACU midlevel providers, anesthesia staff, and surgical staff. INTERVENTION: A physical checklist was provided to all anesthesia staff and recommended to adhere to the list at all observed PACU handoffs. MAIN OUTCOME MEASURE: Quantity of reported handoff items during 60 pre- and 60 post-implementation of a checklist. RESULTS: Composite value from both surgical and anesthesia reports showed an increase in the mean report of 8.7 items from pre-implementation period to 10.9 post-implementation. Given that surgical staff reported the mean of 5.9 items pre-implementation and 5.5 items post-implementation without intervention, improvements in anesthesia staff report with intervention improved the overall handoff data transfer. CONCLUSIONS: Using a physical 12-item checklist for PACU handoff increased overall data transfer.

Conformational Tinkering Drives Evolution of a Promiscuous Activity through Indirect Mutational Effects.

How remote mutations can lead to changes in enzyme function at a molecular level is a central question in evolutionary biochemistry and biophysics. Here, we combine laboratory evolution with biochemical, structural, genetic, and computational analysis to dissect the molecular basis for the functional optimization of phosphotriesterase activity in a bacterial lactonase (AiiA) from the metallo-ß-lactamase (MBL) superfamily. We show that a 1000-fold increase in phosphotriesterase activity is caused by a more favorable catalytic binding position of the paraoxon substrate in the evolved enzyme that resulted from conformational tinkering of the active site through peripheral mutations. A nonmutated active site residue, Phe68, was displaced by ∼3 Å through the indirect effects of two second-shell trajectory mutations, allowing molecular interactions between the residue and paraoxon. Comparative mutational scanning, i.e., examining the effects of alanine mutagenesis on different genetic backgrounds, revealed significant changes in the functional roles of Phe68 and other nonmutated active site residues caused by the indirect effects of trajectory mutations. Our work provides a quantitative measurement of the impact of second-shell mutations on the catalytic contributions of nonmutated residues and unveils the underlying intramolecular network of strong epistatic mutational relationships between active site residues and more remote residues. Defining these long-range conformational and functional epistatic relationships has allowed us to better understand the subtle, but cumulatively significant, role of second- and third-shell mutations in evolution.

AKR1C1 and SRD5A1 messenger RNA expression at term in the human myometrium and chorioamniotic membranes.

We sought to determine relative mRNA expression of AKR1C1 and SRD5A1, which respectively encode for the key progesterone metabolizing enzymes, 20alpha-hydroxysteroid dehydrogenase and 5alpha-reductase type 1, in the myometrium and chorioamniotic membranes during human spontaneous or induced labor and nonlabor. Quantitative real-time reverse-transcriptase polymerase chain reaction was used to compare relative mRNA expression of AKR1C1 and SRD5A1 in the myometrium and chorioamniotic membranes from 20 subjects during three different states of labor: not in labor ( N = 10), spontaneous labor ( N = 5), or induced labor ( N = 5). Labor was defined as regular uterine contractions that resulted in cervical dilation. Myometrial AKR1C1 mRNA expression was significantly greater in spontaneously laboring subjects compared with those not in labor (2.4-fold [1.97 to 2.98], P = 0.02). There was no difference in myometrial AKR1C1 mRNA expression between those with induced labor compared with those not in labor. Regardless of labor status, no differences were observed in the chorioamniotic membrane AKR1C1 mRNA expression between the groups. SRD5A1 mRNA expression was significantly lower in the membranes of both laboring groups when compared with those not in labor (spontaneous: 0.10-fold [0.06 to 0.18], P = 0.007; induced: 0.09-fold [0.03 to 0.25], P = 0.013). Regardless of labor status, there was no difference in SRD5A1 mRNA expression in the myometrium. Our study demonstrated tissue-specific changes in progesterone metabolizing enzyme mRNA expression in human intrauterine tissue at term associated with labor status. These observed changes in mRNA expression may have important implications for progesterone metabolism at those specific sites and thereby may differentially regulate the tissue-specific progesterone concentration and/or the level of specific progesterone metabolites.