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Purpose:In multiple myeloma, drug-resistant cells underlie relapse or progression following chemotherapy. Cell adhesion–mediated drug resistance (CAM-DR) is an established mechanism used by myeloma cells (MMC) to survive chemotherapy and its markers are upregulated in residual disease. The integrin very late antigen 4 (VLA4; α4β1) is a key mediator of CAM-DR and its expression affects drug sensitivity of MMCs. Rather than trying to inhibit its function, here, we hypothesized that upregulation of VLA4 by resistant MMCs could be exploited for targeted delivery of drugs, which would improve safety and efficacy of treatments.Experimental Design:We synthetized 20 nm VLA4-targeted micellar nanoparticles (V-NP) carrying DiI for tracing or a novel camptothecin prodrug (V-CP). Human or murine MMCs, alone or with stroma, and immunocompetent mice with orthotopic multiple myeloma were used to track delivery of NPs and response to treatments.Results:V-NPs selectively delivered their payload to MMCs in vitro and in vivo, and chemotherapy increased their uptake by surviving MMCs. V-CP, alone or in combination with melphalan, was well tolerated and prolonged survival in myeloma-bearing mice. V-CP also reduced the dose requirement for melphalan, reducing tumor burden in association with suboptimal dosing without increasing overall toxicity.Conclusions:V-CP may be a safe and effective strategy to prevent or treat relapsing or refractory myeloma. V-NP targeting of resistant cells may suggest a new approach to environment-induced resistance in cancer.

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Introduction: The effective delivery of patient care is a complex venture, often requiring efficient collaboration among varied healthcare professions. Not surprisingly, research continues to indicate collaboration between these diverse professionals can be challenging. Early exposure of health professions students to interprofessional education (IPE) offers a promising way to improve this collaboration and, in turn, improve patient care and service delivery. Objectives: This study examines the impact of an innovative IPE cocurricular event on knowledge, understanding, and attitudes, regarding future healthcare delivery between medical and pharmacy students. Method: Students developed and conducted an IPE cocurricular event involving medical students of a dermatology-interest club, and pharmacy students of a compounding-interest club. Medical students introduced a patient case, delivered in a standardized-patient format. This was followed by a pharmacy student presentation representing compounding the prescriptions needed for the patient case and writing accurate prescriptions. Following both presentations, students from each program were paired. Each interprofessional pair then communicated and compounded two medications for the case, working collaboratively. Pre- and post-questionnaires were designed with rating scales and open-ended questions for data collection. Results: Both parametric and nonparametric tests revealed significant differences between the pretests and posttests. There was no significant difference in responding between the groups. Inspection of the open-ended questions revealed changes in attitudes regarding collaboration and learning. Conclusions: This study found students of both professions reported significant improvements in their level of knowledge, understanding, and interest in interprofessional collaboration. The open-ended questions revealed both groups of students began the event with different expectations regarding cooperation and interprofessional activities but left the session with very similar perspectives. By including similar IPE activities in early healthcare education, medical students will gain an understanding of the knowledge, skills, and services that a compounding pharmacist can offer in personalized patient care, and pharmacy students will acquire clinical reasoning based on patient presentations. Both factors promote collaboration between professions and ultimately show promise in improving outcomes in patient care.

In a large health system in the United States, investigators examined whether mortality, receipt of mechanical ventilation, and patient acuity changed over time among adult patients with COVID-19–related critical illness admitted to intensive care units., Visual Abstract. COVID-19–Related Critical Illness In a large health system in the United States, investigators examined whether mortality, receipt of mechanical ventilation, and patient acuity changed over time among adult patients with COVID-19–related critical illness admitted to intensive care units. Visual Abstract. COVID-19–Related Critical Illness In a large health system in the United States, investigators examined whether mortality, receipt of mechanical ventilation, and patient acuity changed over time among adult patients with COVID-19–related critical illness admitted to intensive care units., Background: The coronavirus disease 2019 (COVID-19) pandemic continues to surge in the United States and globally. Objective: To describe the epidemiology of COVID-19–related critical illness, including trends in outcomes and care delivery. Design: Single–health system, multihospital retrospective cohort study. Setting: 5 hospitals within the University of Pennsylvania Health System. Patients: Adults with COVID-19–related critical illness who were admitted to an intensive care unit (ICU) with acute respiratory failure or shock during the initial surge of the pandemic. Measurements: The primary exposure for outcomes and care delivery trend analyses was longitudinal time during the pandemic. The primary outcome was all-cause 28-day in-hospital mortality. Secondary outcomes were all-cause death at any time, receipt of mechanical ventilation (MV), and readmissions. Results: Among 468 patients with COVID-19–related critical illness, 319 (68.2%) were treated with MV and 121 (25.9%) with vasopressors. Outcomes were notable for an all-cause 28-day in-hospital mortality rate of 29.9%, a median ICU stay of 8 days (interquartile range [IQR], 3 to 17 days), a median hospital stay of 13 days (IQR, 7 to 25 days), and an all-cause 30-day readmission rate (among nonhospice survivors) of 10.8%. Mortality decreased over time, from 43.5% (95% CI, 31.3% to 53.8%) to 19.2% (CI, 11.6% to 26.7%) between the first and last 15-day periods in the core adjusted model, whereas patient acuity and other factors did not change. Limitation: Single–health system study; use of, or highly dynamic trends in, other clinical interventions were not evaluated, nor were complications. Conclusion: Among patients with COVID-19–related critical illness admitted to ICUs of a learning health system in the United States, mortality seemed to decrease over time despite stable patient characteristics. Further studies are necessary to confirm this result and to investigate causal mechanisms. Primary Funding Source: Agency for Healthcare Research and Quality.

Background Enhanced Recovery After Surgery (ERAS) protocols reduce length of stay, complications and costs for a large number of elective surgical procedures. A similar, structured approach appears to improve outcomes, including mortality, for patients undergoing high-risk emergency general surgery, and specifically emergency laparotomy. These are the first consensus guidelines for optimal care of these patients using an ERAS approach. Methods Experts in aspects of management of the high-risk and emergency general surgical patient were invited to contribute by the International ERAS® Society. Pubmed, Cochrane, Embase, and MEDLINE database searches on English language publications were performed for ERAS elements and relevant specific topics. Studies on each item were selected with particular attention to randomized controlled trials, systematic reviews, meta-analyses and large cohort studies, and reviewed and graded using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Recommendations were made on the best level of evidence, or extrapolation from studies on non-emergency patients when appropriate. The Delphi method was used to validate final recommendations. The guideline has been divided into two parts: Part 1—Preoperative Care and Part 2—Intraoperative and Postoperative management. This paper provides guidelines for Part 1. Results Twelve components of preoperative care were considered. Consensus was reached after three rounds. Conclusions These guidelines are based on the best available evidence for an ERAS approach to patients undergoing emergency laparotomy. Initial management is particularly important for patients with sepsis and physiological derangement. These guidelines should be used to improve outcomes for these high-risk patients.

Purpose: In multiple myeloma, drug-resistant cells underlie relapse or progression following chemotherapy. Cell adhesion–mediated drug resistance (CAM-DR) is an established mechanism used by myeloma cells (MMC) to survive chemotherapy and its markers are upregulated in residual disease. The integrin very late antigen 4 (VLA4; α4β1) is a key mediator of CAM-DR and its expression affects drug sensitivity of MMCs. Rather than trying to inhibit its function, here, we hypothesized that upregulation of VLA4 by resistant MMCs could be exploited for targeted delivery of drugs, which would improve safety and efficacy of treatments. Experimental Design: We synthetized 20 nm VLA4-targeted micellar nanoparticles (V-NP) carrying DiI for tracing or a novel camptothecin prodrug (V-CP). Human or murine MMCs, alone or with stroma, and immunocompetent mice with orthotopic multiple myeloma were used to track delivery of NPs and response to treatments. Results: V-NPs selectively delivered their payload to MMCs in vitro and in vivo, and chemotherapy increased their uptake by surviving MMCs. V-CP, alone or in combination with melphalan, was well tolerated and prolonged survival in myeloma-bearing mice. V-CP also reduced the dose requirement for melphalan, reducing tumor burden in association with suboptimal dosing without increasing overall toxicity. Conclusions: V-CP may be a safe and effective strategy to prevent or treat relapsing or refractory myeloma. V-NP targeting of resistant cells may suggest a new approach to environment-induced resistance in cancer.

Abdominal and peritoneal pain after surgery is common and burdensome, yet the lack of standardized diagnostic criteria for this type of acute pain impedes basic, translational, and clinical investigations. The collaborative effort among the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, American Pain Society, and American Academy of Pain Medicine Pain Taxonomy (AAAPT) provides a systematic framework to classify acute painful conditions. Using this framework, a multidisciplinary working group reviewed the literature and developed core diagnostic criteria for acute abdominal and peritoneal pain after surgery. In this report, we apply the proposed AAAPT framework to 4 prototypical surgical procedures resulting in abdominal and peritoneal pain as examples: cesarean delivery, cholecystectomy, colorectal surgical procedures, and pancreas resection. These diagnostic criteria address the 3 most common surgical procedures performed in the United States, capture diverse surgical approaches, and may also be applied to other surgical procedures resulting in abdominal and peritoneal pain. Additional investigation regarding the validity and reliability of this framework will facilitate its adoption in research that advances our comprehension of mechanisms, deliver better treatments, and help prevent the transition of acute to chronic pain after surgery in the abdominal and peritoneal region. Perspective Using AAAPT, we present key diagnostic criteria for acute abdominal and peritoneal pain after surgery. We provide a systematic classification using 5 dimensions for abdominal and peritoneal pain that occurs after surgery, in addition to 4 specific surgical procedures: cesarean delivery, cholecystectomy, colorectal surgical procedures, and pancreas resection.

Preoperative optimization protocols targeting potentially modifiable risk factors could prove beneficial in reducing the rate of complications in lower extremity total joint arthroplasty (LE-TJA). We aimed to summarize the evidence on preoperative screening protocols targeting modifiable risk factors to assess their effect on postoperative outcomes following primary LE-TJA.A literature search of MEDLINE, EMBASE, CINAHL, and Cochrane Library databases was performed in August 2019. The bibliographies of relevant publications were searched for further applicable studies. Included studies were required to report at least one outcome including prosthetic joint infection/surgical site infection (PJI/SSI), hospital length of stay (LOS), disposition, 90-day emergency department visits, or hospital readmissions after implementation of an evidence-based preoperative optimization protocol targeting modifiable risk factors. Methodological quality of included studies was assessed using the methodological index for non-randomized studies (MINORS) criteria.A total of 8 retrospective cohort studies including 9915 patients were reviewed. Implementation of preoperative optimization protocols were associated with reductions in SSI (0.56% vs. 2.60%; RR 0.21 [95% CI 0.12 to 0.37]; P.00001), hospital LOS, mean cost of care, and hospital readmission rates. The mean MINORS score for comparative studies was 16.285.Implementation and compliance with evidence-based preoperative protocols for optimization of modifiable risk factors is associated with overall improved outcomes following LE-TJA. SSI, hospital LOS, average total cost of care, and hospital readmission rates were favorable in those cohorts subjected to a preoperative intervention protocol. Future prospective studies are necessary for further refinement of preoperative optimization protocols and referral algorithms, without compromising patients' access to surgery.III, Systematic Review.

Background: Enhanced recovery after surgery (ERAS) pathways are now implemented worldwide with strong evidence that adhesion to such protocol reduces medical complications, costs and hospital stay. This concept has been applied for pancreatic surgery since the first published guidelines in 2012. This study presents the updated ERAS recommendations for pancreatoduodenectomy (PD) based on the best available evidence and on expert consensus. Methods: A systematic literature search was conducted in three databases (Embase, Medline Ovid and Cochrane Library Wiley) for the 27 developed ERAS items. Quality of randomized trials was assessed using the Consolidated Standards of Reporting Trials statement checklist. The level of evidence for each item was determined using the Grading of Recommendations Assessment Development and Evaluation system. The Delphi method was used to validate the final recommendations. Results: A total of 314 articles were included in the systematic review. Consensus among experts was reached after three rounds. A well-implemented ERAS protocol with good compliance is associated with a reduction in medical complications and length of hospital stay. The highest level of evidence was available for five items: avoiding hypothermia, use of wound catheters as an alternative to epidural analgesia, antimicrobial and thromboprophylaxis protocols and preoperative nutritional interventions for patients with severe weight loss (> 15%). Conclusions: The current updated ERAS recommendations for PD are based on the best available evidence and processed by the Delphi method. Prospective studies of high quality are encouraged to confirm the benefit of current updated recommendations.

BACKGROUND There has recently been increasing interest in the use of peri-operative intravenous lidocaine (IVL) due to its analgesic, anti-inflammatory and opioid-sparing effects. However, these potential benefits are not well established in elective colorectal surgery. OBJECTIVES To examine the effect of peri-operative IVL infusion on postoperative outcome in patients undergoing elective colorectal surgery. DESIGN A meta-analysis of randomised controlled trials (RCTs) comparing peri-operative IVL with placebo infusion in elective colorectal surgery. The primary outcome measure was postoperative pain scores up to 48 h. The secondary outcome measures included time to return of gastrointestinal function, postoperative morphine requirement, anastomotic leak, local anaesthetic toxicity and hospital length of stay. DATA SOURCES PubMed, Scopus and the Cochrane Library databases were searched on 5 November 2018. ELIGIBILITY CRITERIA Studies were included if they were RCTs evaluating the role of peri-operative IVL vs. placebo in adult patients undergoing elective colorectal surgery. Exclusion criteria were paediatric patients, noncolorectal or emergency procedures, non-RCT methodology or lack of relevant outcome measures. RESULTS A total of 10 studies were included (n = 508 patients; 265 who had undergone IVL infusion, 243 who had undergone placebo infusion). IVL infusion was associated with a significant reduction in time to defecation (mean difference −12.06 h, 95% CI −17.83 to −6.29, I2 = 93%, P = 0.0001), hospital length of stay (mean difference −0.76 days, 95% CI −1.32 to −0.19, I2 = 45%, P = 0.009) and postoperative pain scores at early time points, although this difference does not meet the threshold for a clinically relevant difference. There was no difference in time to pass flatus (mean difference −5.33 h, 95% CI −11.53 to 0.88, I2 = 90%, P = 0.09), nor in rates of surgical site infection or anastomotic leakage. CONCLUSION This meta-analysis provides some support for the administration of peri-operative IVL infusion in elective colorectal surgery. However, further evidence is necessary to fully elucidate its potential benefits in light of the high levels of study heterogeneity and mixed quality of methodology.