Facets of physical function assessed by patient-reported outcome measures in oncology research.

PURPOSE: The U.S. Food & Drug Administration has identified physical functioning (PF) as a core patient-reported outcome (PRO) in cancer clinical trials. The purpose of this study was to identify PF PRO measures (PROMs) in adult cancer populations and classify the PROMs by content covered (facets of PF) in each measure. METHODS: As part of the Patient Reports of Physical Functioning Study (PROPS) research program, we conducted a targeted literature review to identify PROMs that could be used in clinical trials to evaluate PF from the patient perspective. Next, we convened an advisory panel to conduct a modified, reactive, Delphi study to reach consensus on which PF facets are assessed by PROMs identified in the review. The panel engaged in a "card sort" activity to classify PROM items by PF facets. Consensus was reached when 80% of panel members agreed that at least one facet was being measured by each PROM item. RESULTS: The literature review identified 13 PROMs that met inclusion criteria. Eight facets of PF were identified for classification in the Delphi study: ability, completion, difficulty, limitation, quality, frequency, bother, and satisfaction. Through two rounds, the panel documented and classified conceptual approaches for each PRO item presented. The most prevalent PF facets were ability, difficulty, and limitation. CONCLUSION: Classifying PF PROMs by PF facets will promote more consistent communication regarding the aspects of PF represented in each PROM, helping researchers prioritize measures for inclusion in cancer clinical trials.

What facets of physical function are most important to adults diagnosed with cancer?

PURPOSE: Successful patient-focused drug development involves selecting and measuring outcomes in clinical trials that are important to patients. The U.S. Food & Drug Administration's definition of clinical benefit includes how patients feel, function, or survive. Patients are considered the experts in describing how they feel and function. In cancer trials, patient-reported measures of physical function provide insight into how patients function at baseline, benefit from the interventions being studied, and the impact of treatment side effects. We conducted a qualitative study with adults diagnosed with cancer to describe facets of physical function from their perspective and to identify which facets are most important to this patient population. METHODS: Using concept elicitation and cognitive interviewing techniques, we conducted semi-structured interviews with 72 adults ≥ 22 years of age with cancer who received treatment with an anticancer drug or biologic within six months of the interview. We selected participants using purposive sampling with the aim to elicit diverse experiences regarding how they may interpret and respond to questions related to physical function. Participants were presented with patient-reported outcome (PRO) items representative of PRO measures used in cancer and general populations. RESULTS: Five facets of how physical function relates to activities were defined from the patient perspective: ability, difficulty, limitation, satisfaction, and completion. More than half of the participants indicated that ability was the most important facet of physical function. The next most important were satisfaction (18.3%), limitation (14.1%), difficulty (5.6%), and completion (2.8%). CONCLUSION: This study demonstrates that we must be more specific about the facets of physical function that we set out to assess when we use PRO measures to describe the patient experience. These results have implications for the specificity of physical function facets when measured in cancer clinical trials.

Immune Phenotype and Postoperative Complications After Elective Surgery.

OBJECTIVES: To characterize and quantify accumulating immunologic alterations, pre and postoperatively in patients undergoing elective surgical procedures. BACKGROUND: Elective surgery is an anticipatable, controlled human injury. Although the human response to injury is generally stereotyped, individual variability exists. This makes surgical outcomes less predictable, even after standardized procedures, and may provoke complications in patients unable to compensate for their injury. One potential source of variation is found in immune cell maturation, with phenotypic changes dependent on an individual's unique, lifelong response to environmental antigens. METHODS: We enrolled 248 patients in a prospective trial facilitating comprehensive biospecimen and clinical data collection in patients scheduled to undergo elective surgery. Peripheral blood was collected preoperatively, and immediately on return to the postanesthesia care unit. Postoperative complications that occurred within 30 days after surgery were captured. RESULTS: As this was an elective surgical cohort, outcomes were generally favorable. With a median follow-up of 6 months, the overall survival at 30 days was 100%. However, 20.5% of the cohort experienced a postoperative complication (infection, readmission, or system dysfunction). We identified substantial heterogeneity of immune senescence and terminal differentiation phenotypes in surgical patients. More importantly, phenotypes indicating increased T-cell maturation and senescence were associated with postoperative complications and were evident preoperatively. CONCLUSIONS: The baseline immune repertoire may define an immune signature of resilience to surgical injury and help predict risk for surgical complications.

A Multidimensional Bioinformatic Platform for the Study of Human Response to Surgery.

OBJECTIVE: To design and establish a prospective biospecimen repository that integrates multi-omics assays with clinical data to study mechanisms of controlled injury and healing. BACKGROUND: Elective surgery is an opportunity to understand both the systemic and focal responses accompanying controlled and well-characterized injury to the human body. The overarching goal of this ongoing project is to define stereotypical responses to surgical injury, with the translational purpose of identifying targetable pathways involved in healing and resilience, and variations indicative of aberrant peri-operative outcomes. METHODS: Clinical data from the electronic medical record combined with large-scale biological data sets derived from blood, urine, fecal matter, and tissue samples are collected prospectively through the peri-operative period on patients undergoing 14 surgeries chosen to represent a range of injury locations and intensities. Specimens are subjected to genomic, transcriptomic, proteomic, and metabolomic assays to describe their genetic, metabolic, immunologic, and microbiome profiles, providing a multidimensional landscape of the human response to injury. RESULTS: The highly multiplexed data generated includes changes in over 28,000 mRNA transcripts, 100 plasma metabolites, 200 urine metabolites, and 400 proteins over the longitudinal course of surgery and recovery. In our initial pilot dataset, we demonstrate the feasibility of collecting high quality multi-omic data at pre- and postoperative time points and are already seeing evidence of physiologic perturbation between timepoints. CONCLUSIONS: This repository allows for longitudinal, state-of-the-art geno-mic, transcriptomic, proteomic, metabolomic, immunologic, and clinical data collection and provides a rich and stable infrastructure on which to fuel further biomedical discovery.

Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn.

BACKGROUND: Heartburn that persists despite proton-pump inhibitor (PPI) treatment is a frequent clinical problem with multiple potential causes. Treatments for PPI-refractory heartburn are of unproven efficacy and focus on controlling gastroesophageal reflux with reflux-reducing medication (e.g., baclofen) or antireflux surgery or on dampening visceral hypersensitivity with neuromodulators (e.g., desipramine). METHODS: Patients who were referred to Veterans Affairs (VA) gastroenterology clinics for PPI-refractory heartburn received 20 mg of omeprazole twice daily for 2 weeks, and those with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance-pH monitoring. If patients were found to have reflux-related heartburn, we randomly assigned them to receive surgical treatment (laparoscopic Nissen fundoplication), active medical treatment (omeprazole plus baclofen, with desipramine added depending on symptoms), or control medical treatment (omeprazole plus placebo). The primary outcome was treatment success, defined as a decrease of 50% or more in the Gastroesophageal Reflux Disease (GERD)-Health Related Quality of Life score (range, 0 to 50, with higher scores indicating worse symptoms) at 1 year. RESULTS: A total of 366 patients (mean age, 48.5 years; 280 men) were enrolled. Prerandomization procedures excluded 288 patients: 42 had relief of their heartburn during the 2-week omeprazole trial, 70 did not complete trial procedures, 54 were excluded for other reasons, 23 had non-GERD esophageal disorders, and 99 had functional heartburn (not due to GERD or other histopathologic, motility, or structural abnormality). The remaining 78 patients underwent randomization. The incidence of treatment success with surgery (18 of 27 patients, 67%) was significantly superior to that with active medical treatment (7 of 25 patients, 28%; P = 0.007) or control medical treatment (3 of 26 patients, 12%; P<0.001). The difference in the incidence of treatment success between the active medical group and the control medical group was 16 percentage points (95% confidence interval, -5 to 38; P = 0.17). CONCLUSIONS: Among patients referred to VA gastroenterology clinics for PPI-refractory heartburn, systematic workup revealed truly PPI-refractory and reflux-related heartburn in a minority of patients. For that highly selected subgroup, surgery was superior to medical treatment. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT01265550.).

Perioperative Optimization of Senior Health (POSH): A Descriptive Analysis of Cancelled Surgery.

BACKGROUND: Geriatric collaborative care models improve postoperative outcomes for older adults. However, there are limited data exploring how preoperative geriatric assessment may affect surgical cancellations. METHODS: This is a single-center retrospective cohort analysis. Patients enrolled in the Perioperative Optimization of Senior Health (POSH) program from 2011 to 2016 were included. POSH is a collaborative care model between geriatrics, surgery, and anesthesiology. Baseline demographic and medical data were collected during the POSH pre-op appointment. Patients who attended a POSH pre-op visit but did not have surgery were identified, and a chart review was performed to identify reasons for surgical cancellation. Baseline characteristics of patients who did and did not undergo surgery were compared. RESULTS: Of 449 eligible POSH referrals within the study period, 33 (7.3%) did not proceed to surgery; cancellation rates within the POSH program were lower than institutional cancellation rates for adults over age 65 who did not participate in POSH. Patients who did not have surgery were significantly older, more likely to have functional limitations, and had higher rates of several comorbidities compared with those who proceeded to surgery (P < 0.05). Reasons for surgical cancellations included a similar number of patient- and provider-driven causes. CONCLUSIONS: Many reasons for surgical cancellation were related to potentially modifiable factors, such as changes in goals of care or concerns about rehabilitation, emphasizing the importance of shared decision-making in elective surgery for older adults. These results highlight the important role geriatric collaborative care can offer to older adults with complex needs.

Delaying Elective Surgery in Geriatric Patients: An Opportunity for Preoperative Optimization.

Deciding whether to pursue elective surgery is a complex process for older adults. Comprehensive geriatric assessment (CGA) can help refine estimates of benefits and risks, at times leading to a delay of surgery to optimize surgical readiness. We describe a cohort of geriatric patients who were evaluated in anticipation of elective abdominal surgery and whose procedures were delayed for any reason. Themes behind the reasons for delay are described, and a holistic framework to guide preoperative discussion is suggested.

Roadmap for Transforming Preoperative Assessment to Preoperative Optimization.

Preoperative assessment typically equates to evaluating and accepting the presenting condition of the patient (unless extreme) and commonly occurs only a few days before the planned surgery. While this timing enables a preoperative history and examination and mitigates unexpected findings on the day of surgery that may delay throughput, it does not allow for meaningful preoperative management of modifiable medical conditions. Evidence is limited regarding how best to balance efforts to mitigate modifiable risk factors versus the timing of surgery. Furthermore, while the concept of preoperative risk modification is not novel, evidence is lacking for successful and sustained implementation of such an interdisciplinary, collaborative program. A better understanding of perioperative care coordination and, specifically, implementing a preoperative preparation process can enhance the value of surgery and surgical population health. In this article, we describe the implementation of a collaborative preoperative clinic with the primary goal of improving patient outcomes.

The importance of the STOP- BANG questionnaire as a preoperative assessment tool for the elderly population.

Undiagnosed obstructive sleep apnea (OSA) may adversely impact surgical patients and can lead to increased morbidity and mortality during the perioperative period, especially among the geriatric patient population (Chung et al. 2008, 2012, 2014; McDonald et al., 2018; Zietlow et al., 2018; Singh et al., 2012). The setting of this quality improvement project was a preoperative anesthesia and geriatric evaluation clinic housed within a 957-bed tertiary academic affiliated hospital. The sample included 45 patients who met the criteria established for surgery and OSA screening preoperatively. Nine patients (20.0%) were assessed as low risk (Stop-bang [SB] score /= 3 indicative of high-risk for OSA. The retrospective utilization of a modified SB screening on charts that did not receive a clinical OSA evaluation (n = 52) detected 23 (44.2%) patients who were considered high-risk for OSA but were not identified prior to surgery. The SB questionnaire is underutilized, and patients' OSA is often unidentified prior to surgery.

Development and validation of machine learning models to identify high-risk surgical patients using automatically curated electronic health record data (Pythia): A retrospective, single-site study.

BACKGROUND: Pythia is an automated, clinically curated surgical data pipeline and repository housing all surgical patient electronic health record (EHR) data from a large, quaternary, multisite health institute for data science initiatives. In an effort to better identify high-risk surgical patients from complex data, a machine learning project trained on Pythia was built to predict postoperative complication risk. METHODS AND FINDINGS: A curated data repository of surgical outcomes was created using automated SQL and R code that extracted and processed patient clinical and surgical data across 37 million clinical encounters from the EHRs. A total of 194 clinical features including patient demographics (e.g., age, sex, race), smoking status, medications, comorbidities, procedure information, and proxies for surgical complexity were constructed and aggregated. A cohort of 66,370 patients that had undergone 99,755 invasive procedural encounters between January 1, 2014, and January 31, 2017, was studied further for the purpose of predicting postoperative complications. The average complication and 30-day postoperative mortality rates of this cohort were 16.0% and 0.51%, respectively. Least absolute shrinkage and selection operator (lasso) penalized logistic regression, random forest models, and extreme gradient boosted decision trees were trained on this surgical cohort with cross-validation on 14 specific postoperative outcome groupings. Resulting models had area under the receiver operator characteristic curve (AUC) values ranging between 0.747 and 0.924, calculated on an out-of-sample test set from the last 5 months of data. Lasso penalized regression was identified as a high-performing model, providing clinically interpretable actionable insights. Highest and lowest performing lasso models predicted postoperative shock and genitourinary outcomes with AUCs of 0.924 (95% CI: 0.901, 0.946) and 0.780 (95% CI: 0.752, 0.810), respectively. A calculator requiring input of 9 data fields was created to produce a risk assessment for the 14 groupings of postoperative outcomes. A high-risk threshold (15% risk of any complication) was determined to identify high-risk surgical patients. The model sensitivity was 76%, with a specificity of 76%. Compared to heuristics that identify high-risk patients developed by clinical experts and the ACS NSQIP calculator, this tool performed superiorly, providing an improved approach for clinicians to estimate postoperative risk for patients. Limitations of this study include the missingness of data that were removed for analysis. CONCLUSIONS: Extracting and curating a large, local institution's EHR data for machine learning purposes resulted in models with strong predictive performance. These models can be used in clinical settings as decision support tools for identification of high-risk patients as well as patient evaluation and care management. Further work is necessary to evaluate the impact of the Pythia risk calculator within the clinical workflow on postoperative outcomes and to optimize this data flow for future machine learning efforts.

Hospital Standards to Promote Optimal Surgical Care of the Older Adult: A Report From the Coalition for Quality in Geriatric Surgery.

OBJECTIVE: The aim of this study was to establish high-quality, valid standards to improve surgical care of the older adult. BACKGROUND: The aging population increases demand for high-quality surgical care. Building upon prior guidelines, quality indicators, and pilot projects, the Coalition for Quality in Geriatric Surgery (CQGS) includes 58 diverse stakeholder organizations committed to improving geriatric surgery. METHODS: Using a modified RAND-UCLA Appropriateness Methodology, 44 of 58 CQGS Stakeholders twice rated validity (primary outcome) and feasibility for 308 standards, ranging from goals and decision-making, pre-operative assessment and optimization, perioperative and postoperative care, to transitions of care beyond the acute care hospital. RESULTS: Three hundred six of 308 (99%) standards were rated as valid to improve quality of geriatric surgery. There were 4 sections. Section 1 included 157 (57%) standards and focused on goals and decision-making, preoperative optimization, and transitions into and out of the hospital. Section 2 included 84 (27.3%) standards focused on in-hospital care, across the immediate preoperative, intraoperative, and postoperative phases. Section 3 included 59 (19.1%) standards about program management, including personnel and committee structure, credentialing, and education. Section 4 included 8 (2.6%) standards establishing overarching concepts for data collection and patient follow-up. Two hundred ninety of 308 standards (94.2%) were rated as feasible; 18 (5.8%) were rated as uncertain in feasibility. CONCLUSIONS: CQGS Stakeholders rated the vast majority of standards of care as highly valid (99%) and feasible (94%) for improving the quality of surgical care provided to older adults. Future work will focus on a pilot phase to better understand and address challenges to implementation of the standards.

The impact of functional dependency on outcomes after complex general and vascular surgery.

OBJECTIVE: To describe the outcomes of functionally dependent patients who undergo major general or vascular surgery and to determine the relationship between functional health status and early postoperative outcomes. BACKGROUND: In contrast to frailty, functional health status is a relatively easy entity to define and to measure and therefore may be a more practical variable to assess in patients who are being considered for major surgery. To date, few studies have assessed the impact of functional health status on surgical outcomes. METHODS: Patients undergoing 1 of 10 complex general or vascular operations were extracted from the 2005 to 2010 America College of Surgeons National Surgical Quality Improvement Program database. Propensity score techniques were used to match patients with and without preoperative functional dependency on known patient- and procedure-related factors. The postoperative outcomes of this matched cohort were then compared. RESULTS: A total of 10,246 functionally dependent surgical patients were included for analysis. These patients were more acutely and chronically ill than functionally independent patients, and they had higher rates of mortality and morbidity for each of the 10 procedures analyzed. Propensity-matching techniques resulted in the creation of a cohort of functionally independent and dependent patients who were well matched for known patient- and procedure-related variables. Dependent patients from the matched cohort had a 1.75-fold greater odds of postoperative death (95% confidence interval: 1.54-1.98, P < 0.0001) than functionally independent patients. CONCLUSIONS: Preoperative functional dependency is an independent risk factor for mortality after major operation. Functional health status should be routinely assessed in patients who are being considered for complex surgery.

Innovative bridging of the rural-urban divide: comparison of scope, safety, and impact of collaborative rural surgery camps and an urban surgical program.

BACKGROUND: In medically under-resourced regions worldwide, non-permanent surgery programs or camps have been conducted to expand access to surgical services. Surgery camp programs have been reported in rural India, primarily in the ophthalmic and obstetric fields; however, the provision of general surgical services in these settings is largely unknown. METHODS: A 12-month retrospective review of non-ambulatory procedures performed at a rural hospital surgery camp program and at an urban hospital in Maharashtra, India, was completed to characterize relative differences in procedural activity, frequency and severity of perioperative complications, and to evaluate efficacy of care. RESULTS: A total of 449 cases performed in rural hospital surgery camps were compared with 344 cases performed in an urban hospital during the course of the study period. The majority of rural surgical cases were elective and of intermediate complexity. Approximately 4% of rural cases were complex-major compared to 17% of urban cases. Intraoperative complications occurred in 0.2% rural cases compared to 5.5% of urban cases; p = 0.01. Postoperative complications were predominantly low grade in both groups. The postoperative complication rate was higher among rural surgical patients (43.4%; 23.5%; p < 0.01), though the Surgical Risk Score was significantly lower in this group (p < 0. 01). Rural surgery camp activity over 12 months achieved diagnostic and/or therapeutic goals in 92.2% of procedures and rendered 1.74-2.69 disability-adjusted life-years (DALYs) averted per patient. CONCLUSIONS: Rural general surgery camps can safely and effectively provide a wide range of surgical services under appropriate collaborative and clinical conditions. Surgery camps may be a safe, temporizing solution to unmet needs until substantial gains in rural healthcare are realized.

Consensus guidelines for the management of postoperative nausea and vomiting.

The present guidelines are the most recent data on postoperative nausea and vomiting (PONV) and an update on the 2 previous sets of guidelines published in 2003 and 2007. These guidelines were compiled by a multidisciplinary international panel of individuals with interest and expertise in PONV under the auspices of the Society for Ambulatory Anesthesia. The panel members critically and systematically evaluated the current medical literature on PONV to provide an evidence-based reference tool for the management of adults and children who are undergoing surgery and are at increased risk for PONV. These guidelines identify patients at risk for PONV in adults and children; recommend approaches for reducing baseline risks for PONV; identify the most effective antiemetic single therapy and combination therapy regimens for PONV prophylaxis, including nonpharmacologic approaches; recommend strategies for treatment of PONV when it occurs; provide an algorithm for the management of individuals at increased risk for PONV as well as steps to ensure PONV prevention and treatment are implemented in the clinical setting.

Facilitators and barriers to eliciting physical function goals before and after surgery: A qualitative study with clinicians.

OBJECTIVE: Describe clinicians' perspectives of facilitators and barriers to eliciting physical function goals from patients with multiple chronic conditions pre- and post-surgery. METHODS: Semi-structured qualitative interviews were conducted with clinicians, recruited from an academic medical center, who treat adult patients with multiple chronic conditions. Purposive sampling ensured multiple provider types were represented. Interviews were conducted in person or via web conference and were audio recorded. Findings were summarized using descriptive qualitative content analysis. RESULTS: Of the 12 participating clinicians, 92% were female and 83% specialized in geriatrics. Clinicians had a mean of 10.7 (min-max: 1-30) years of experience. Key facilitators to goal-setting conversations were sufficient time, familial support, and patient cognitive ability. Barriers included lack of time, lack of training, patient challenges in choosing realistic and specific actionable goals, emotional barriers, and cognitive challenges. CONCLUSION: Some facilitators and barriers are modifiable, including time, inclusion of family members in the clinical encounter, and clinician training to enable actionable goal setting. These results highlight areas for intervention to facilitate goal elicitation for physical function in clinical care settings. PRACTICE IMPLICATIONS: Clinicians should be aware of the barriers impacting eliciting goals. Healthcare organizations could consider providing effective goal elicitation training and tools to facilitate goal setting conversation.

Multisite Implementation of an American College of Surgeons Geriatric Surgery Quality Improvement Initiative.

BACKGROUND: The American College of Surgeons (ACS) Coalition for Quality in Geriatric Surgery (CQGS) identified standards of surgical care for the growing, vulnerable population of aging adults in the US. The aims of this study were to determine implementation feasibility for 30 selected standards, identify barriers and best practices in their implementation, and further refine these geriatric standards and verification process. STUDY DESIGN: The CQGS requested participation from hospitals involved in the ACS NSQIP Geriatric Surgery Pilot Project, previous CQGS feasibility analyses, and hospitals affiliated with a core development team member. Thirty standards were selected for implementation. After implementation, site visits were conducted, and postvisit surveys were distributed. RESULTS: Eight hospitals were chosen to participate. Program management (55%), immediate preoperative and intraoperative clinical care (62.5%), and postoperative clinical care (58%) had the highest mean percentage of "fully compliant" standards. Goals and decision-making (30%), preoperative optimization (28%), and transitions of care (12.5%) had the lowest mean percentage of fully compliant standards. Best practices and barriers to implementation were identified across 13 of the 30 standards. More than 80% of the institutions reported that participation changed the surgical care provided for older adults. CONCLUSIONS: This study represents the first national implementation assessment undertaken by the ACS for one of its quality programs. The CQGS pilot testing was able to demonstrate implementation feasibility for 30 standards, identify challenges and best practices, and further inform dissemination of the ACS Geriatric Surgery Verification Program.

Failure-to-pursue rescue: explaining excess mortality in elderly emergency general surgical patients with preexisting "do-not-resuscitate" orders.

OBJECTIVE: To describe the outcomes of elderly patients with do-not-resuscitate (DNR) status who undergo emergency general surgery and to improve understanding of the relationship between preoperative DNR status and postoperative mortality. BACKGROUND: Preoperative DNR status has previously been shown to predict increased postoperative mortality, although the reasons for this association are not well understood. METHODS: Patients 65 years or older undergoing emergency operation for 1 of 10 common general surgical diagnoses were extracted from the 2005-2010 National Surgical Quality Improvement database. Propensity score techniques were used to match patients with and without preoperative DNR orders on indication for procedure, patient demographics, comorbid disease burden, acute physical status at the time of operation, and procedure complexity. The postoperative outcomes of this matched cohort were then compared. RESULTS: A total of 25,558 patients were included for analysis (DNR, n =1061; non-DNR, n =24,497). DNR patients seemed to be more acutely and chronically ill than non-DNR patients in the overall study sample but did not seem to be treated less aggressively before or during their operations. Propensity-matching techniques resulted in the creation of a cohort of DNR and non-DNR patients who were well matched for all preoperative and intraoperative variables. DNR patients from the matched cohort had a significantly higher postoperative mortality rate than non-DNR patients (36.9% vs 22.3%, P < 0.0001) despite having a similar rate of major postoperative complications (42.1% vs 40.2%, P = 0.38). DNR patients in the propensity-matched cohort were much less likely to undergo reoperation (8.3% vs 12.0%, P = 0.006) than non-DNR patients and were significantly more likely to die in the setting of a major postoperative complication (56.7% vs 41.4%, P = 0.001). CONCLUSIONS: Emergency general surgery in elderly patients with preoperative DNR orders is associated with significant rates of postoperative morbidity and mortality. One reason for the excess mortality in these patients, relative to otherwise similar patients who do not have preoperative DNR orders, may be their greater reluctance to pursue aggressive management of major complications in the postoperative period.

SMAD4 is required for development of maximal endotoxin tolerance.

Initial exposure of monocytes/macrophages to LPS induces hyporesponsiveness to a second challenge with LPS, a phenomenon termed LPS tolerance. Molecular mechanisms responsible for endotoxin tolerance are not well defined. We and others have shown that IL-1R-associated kinase (IRAK)-M and SHIP-1 proteins, negative regulators of TLR4 signaling, increase in tolerized cells. TGF-beta1, an anti-inflammatory cytokine, is upregulated following LPS stimulation, mediating its effect through SMAD family proteins. Using a monocytic cell line, THP1, we show that LPS activates endogenous SMAD4, inducing its migration into the nucleus and increasing its expression. Secondary challenge with high dose LPS following initial low-dose LPS exposure does not increase IRAK-M or SHIP1 protein expression in small hairpin (sh)SMAD4 THP-1 cells compared with control shLUC THP1 cells. TNF-alpha concentrations in culture supernatants after second LPS challenge are higher in shSMAD4 THP-1 cells than shLUC THP1 cells, indicating failure to induce maximal tolerance in absence of SMAD4 signaling. Identical results are seen in primary murine macrophages and mouse embryonic fibroblasts, demonstrating the biological significance of our findings. TGF-beta1 treatment does not increase IRAK-M or SHIP1 protein expression in shSMAD4 THP-1 cells, whereas it does so in shLUC THP1 cells, indicating that TGF-beta1 regulates IRAK-M and SHIP1 expression through a SMAD4-dependent pathway. Knockdown of endogenous SHIP1 by shSHIP1 RNA decreases native and inducible IRAK-M protein expression and prevents development of endotoxin tolerance in THP1 cells. We conclude that in THP-1 cells and primary murine cells, SMAD4 signaling is required for maximal induction of endotoxin tolerance via modulation of SHIP1 and IRAK-M.

Geriatric Preoperative Optimization: A Review.

This review summarizes best practices for the perioperative care of older adults as recommended by the American Geriatrics Society, American Society of Anesthesiologists, and American College of Surgeons, with practical implementation strategies that can be readily implemented in busy preoperative or primary care clinics. In addition to traditional cardiopulmonary screening, older patients should undergo a comprehensive geriatric assessment. Rapid screening tools such as the Mini-Cog, Patient Health Questionnaire-2, and Frail Non-Disabled Survey and Clinical Frailty Scale, can be performed by multiple provider types and allow for quick, accurate assessments of cognition, functional status, and frailty screening. To assess polypharmacy, online resources can help providers identify and safely taper high-risk medications. Based on preoperative assessment findings, providers can recommend targeted prehabilitation, rehabilitation, medication management, care coordination, and/or delirium prevention interventions to improve postoperative outcomes for older surgical patients. Structured goals of care discussions utilizing the question-prompt list ensures that older patients have a realistic understanding of their surgery, risks, and recovery. This preoperative workup, combined with engaging with family members and interdisciplinary teams, can improve postoperative outcomes.