Missouri Baptist Medical Center

Identification and measurement of adverse medical events is central to patient safety, forming a foundation for accountability, prioritizing problems to work on, generating ideas for safer care, and testing which interventions work. We compared three methods to detect adverse events in hospitalized patients, using the same patient sample set from three leading hospitals. We found that the adverse event detection methods commonly used to track patient safety in the United States today-voluntary reporting and the Agency for Healthcare Research and Quality's Patient Safety Indicators-fared very poorly compared to other methods and missed 90 percent of the adverse events. The Institute for Healthcare Improvement's Global Trigger Tool found at least ten times more confirmed, serious events than these other methods. Overall, adverse events occurred in one-third of hospital admissions. Reliance on voluntary reporting and the Patient Safety Indicators could produce misleading conclusions about the current safety of care in the US health care system and misdirect efforts to improve patient safety.

OBJECTIVE: To determine the attributable cost of ventilator-associated pneumonia from a hospital-based cost perspective, after adjusting for potential confounders. DESIGN: Patients admitted between January 19, 1998, and December 31, 1999, were followed prospectively for the occurrence of ventilator-associated pneumonia. Hospital costs were defined by using the hospital cost accounting database. SETTING: The medical and surgical intensive care units at a suburban, tertiary care hospital. PATIENTS: Patients requiring >24 hrs of mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured occurrence of ventilator-associated pneumonia, in-hospital mortality rate, total intensive care unit (ICU) and hospital lengths of stay (LOS), and total hospital cost per patient. Ventilator-associated pneumonia occurred in 127 of 819 patients (15.5%). Compared with uninfected, ventilated patients, patients with ventilator-associated pneumonia had a higher Acute Physiology and Chronic Health Evaluation II score on admission (p <.001) and were more likely to require multiple intubations (p <.001), hemodialysis (p <.001), tracheostomy (p <.001), central venous catheters (p <.001), and corticosteroids (p <.001). Patients with ventilator-associated pneumonia were more likely to be bacteremic during their ICU stay (36 [28%] vs. 22 [3%]; p <.001). Patients with ventilator-associated pneumonia had significantly higher unadjusted ICU LOS (26 vs. 4 days; p <.001), hospital LOS (38 vs. 13 days; p <.001), mortality rate (64 [50%] vs. 237 [34%]; p <.001), and hospital costs (70,568 dollars vs. 21,620 dollars, p <.001). Multiple linear regression, controlling for other factors that may affect costs, estimated the attributable cost of ventilator-associated pneumonia to be 11,897 dollars (95% confidence interval = 5,265 dollars-26,214 dollars; p <.001). CONCLUSIONS: Patients with ventilator-associated pneumonia had significantly longer ICU and hospital LOS, with higher crude hospital cost and mortality rate compared with uninfected patients. After we adjusted for underlying severity of illness, the attributable cost of ventilator-associated pneumonia was approximately 11,897 dollars.

The modern surgical treatment of disorders of the thoracic aorta began in the early 1950s when Gross, Swan, Lam, and DeBakey and their associates14 reported successful treatment of coarctation and aneurysms of the descending thoracic aorta using segmental resection and replacement with several types of grafts. In 1956, Cooley and DeBakey5 reported the first successful operation for resection and graft replacement of the ascending aorta using cardiopulmonary bypass. In 1957, DeBakey and colleagues,6 also using cardiopulmonary bypass, reported the first successful resection and graft replacement of an aneurysm of the aortic arch. Since then, important advances in the diagnosis . . .

BACKGROUND: Vein-graft harvesting with the use of endoscopy (endoscopic harvesting) is a technique that is widely used to reduce postoperative wound complications after coronary-artery bypass grafting (CABG), but the long-term effects on the rate of vein-graft failure and on clinical outcomes are unknown. METHODS: We studied the outcomes in patients who underwent endoscopic harvesting (1753 patients) as compared with those who underwent graft harvesting under direct vision, termed open harvesting (1247 patients), in a secondary analysis of 3000 patients undergoing CABG. The method of graft harvesting was determined by the surgeon. Vein-graft failure was defined as stenosis of at least 75% of the diameter of the graft on angiography 12 to 18 months after surgery (data were available in an angiographic subgroup of 1817 patients and 4290 grafts). Clinical outcomes included death, myocardial infarction, and repeat revascularization. Generalized estimating equations were used to adjust for baseline covariates associated with vein-graft failure and to account for the potential correlation between grafts within a patient. Cox proportional-hazards modeling was used to assess long-term clinical outcomes. RESULTS: The baseline characteristics were similar between patients who underwent endoscopic harvesting and those who underwent open harvesting. Patients who underwent endoscopic harvesting had higher rates of vein-graft failure at 12 to 18 months than patients who underwent open harvesting (46.7% vs. 38.0%, P<0.001). At 3 years, endoscopic harvesting was also associated with higher rates of death, myocardial infarction, or repeat revascularization (20.2% vs. 17.4%; adjusted hazard ratio, 1.22; 95% confidence interval [CI], 1.01 to 1.47; P=0.04), death or myocardial infarction (9.3% vs. 7.6%; adjusted hazard ratio, 1.38; 95% CI, 1.07 to 1.77; P=0.01), and death (7.4% vs. 5.8%; adjusted hazard ratio, 1.52; 95% CI, 1.13 to 2.04; P=0.005). CONCLUSIONS: Endoscopic vein-graft harvesting is independently associated with vein-graft failure and adverse clinical outcomes. Randomized clinical trials are needed to further evaluate the safety and effectiveness of this harvesting technique.

PURPOSE: Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC). MATERIALS AND METHODS: Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS). RESULTS: PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm. CONCLUSION: Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.

COVID-19-associated morbidity and mortality have been attributed to a pathologic host response. Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury. A key explanation for the inability to address this controversy has been the lack of diagnostic tools to evaluate immune function in COVID-19 infections. ELISpot, a highly sensitive, functional immunoassay, was employed in 27 patients with COVID-19, 51 patients with sepsis, 18 critically ill nonseptic (CINS) patients, and 27 healthy control volunteers to evaluate adaptive and innate immune status by quantitating T cell IFN-ɣ and monocyte TFN-α production. Circulating T cell subsets were profoundly reduced in COVID-19 patients. Additionally, stimulated blood mononuclear cells produced less than 40%-50% of the IFN-ɣ and TNF-α observed in septic and CINS patients, consistent with markedly impaired immune effector cell function. Approximately 25% of COVID-19 patients had increased IL-6 levels that were not associated with elevations in other canonical proinflammatory cytokines. Collectively, these findings support the hypothesis that COVID-19 suppresses host functional adaptive and innate immunity. Importantly, IL-7 administered ex vivo restored T cell IFN-ɣ production in COVID-19 patients. Thus, ELISpot may functionally characterize host immunity in COVID-19 and inform prospective therapies.

Patients in rural areas face limited access to medical and oncology providers, long travel times, and low recruitment to clinical trials, all of which affect quality of care and health outcomes. Rural counties also have high rates of cancer-related mortality and other negative treatment outcomes. On April 10, 2019, ASCO hosted Closing the Rural Cancer Care Gap, the second event in its State of Cancer Care in America series. The event focused on two aspects of rural cancer care: a review of the major issues and concerns in delivering rural cancer care and a discussion of creative solutions to address rural-nonrural disparities. This article draws from the event and supporting literature to summarize the challenges to delivering high-quality care in rural communities, update ASCO's workforce data on the geographic distribution of oncologists, and highlight 3 institutional approaches to addressing these challenges in diverse rural settings. The experience of the 3 institutions featured in the article suggests that increasing rural patients' access to care requires expanding services and decreasing travel distances, mitigating financial burdens when insurance coverage is limited, opening avenues to clinical trial participation, and creating partnerships between providers and community leaders to address local gaps in care. Because the characteristics of rural communities, health care resources, and patient populations are not homogeneous, rural health disparities require local solutions that are based on community needs, available resources, and trusting and collaborative partnerships.

UNLABELLED: This prospective, multicenter, community-based and academic-based, open-label, investigator-initiated, U.S. study evaluated efficacy and safety of pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in adults with chronic hepatitis C. Patients (n = 5027) were randomly assigned to receive PEG-IFN alfa-2b 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (genotype 2/3 patients). Primary end point was sustained virologic response (undetectable [<125 IU/mL] serum hepatitis C virus RNA at 24-week follow-up). Sustained virologic response, but not end-of-treatment, rates were significantly higher with weight-based than with flat-dose RBV (44.2% versus 40.5%; P = 0.008). Sustained virologic response rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in genotype 1 patients (P = 0.005) and 31.2% and 26.7%, respectively, in genotype 1 patients with high baseline viral load (P = 0.056). In genotype 2/3 patients, rates were not significantly different (61.8% and 59.5%, respectively) regardless of treatment duration. Besides greater hemoglobin reductions with weight-based RBV, safety profiles were similar across RBV dosing groups, including the 1400-mg/day group. CONCLUSION: PEG-IFN alfa-2b plus weight-based RBV is more effective than flat-dose RBV, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups. RBV 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose RBV is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated.

Disasters are tragedies that overwhelm our communities, destroy our property, and harm our populations. The United Nations General Assembly, recognizing the magnitude of the problem, has declared the 1990s the International Decade of Natural Disaster Reduction and has called for a worldwide effort to reduce the loss of life and property. The involvement of the medical community in this effort is crucial.Disasters are the results of natural or man-made events and are routinely described in terms of certain characteristics (Table 1).1 2 3 Yet each is unique, each is of extreme urgency, and each places a tremendous burden on the community . . .

We pursued a study of immune responses in coronavirus disease 2019 (COVID-19) and influenza patients. Compared to patients with influenza, patients with COVID-19 exhibited largely equivalent lymphocyte counts, fewer monocytes, and lower surface human leukocyte antigen (HLA)-class II expression on selected monocyte populations. Furthermore, decreased HLA-DR on intermediate monocytes predicted severe COVID-19 disease. In contrast to prevailing assumptions, very few (7 of 168) patients with COVID-19 exhibited cytokine profiles indicative of cytokine storm syndrome. After controlling for multiple factors including age and sample time point, patients with COVID-19 exhibited lower cytokine levels than patients with influenza. Up-regulation of IL-6, G-CSF, IL-1RA, and MCP1 predicted death in patients with COVID-19 but were not statistically higher than patients with influenza. Single-cell transcriptional profiling revealed profound suppression of interferon signaling among patients with COVID-19. When considered across the spectrum of peripheral immune profiles, patients with COVID-19 are less inflamed than patients with influenza.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that affects approximately 400,000 people in the United States. The etiology of MS is unknown, but it is likely the result of a complex interaction between genetic and environmental factors and the immune system. The clinical manifestations of MS are highly variable, but most patients initially experience a relapsing-remitting course. Patients accumulate disability as a result of incomplete recovery from acute exacerbations and/or gradual disease progression. This article briefly reviews the immunopathology of MS, the symptoms and natural course of the disease, and the recently revised MS diagnostic criteria.

Oral transmucosal fentanyl citrate (OTFC) is a novel opioid formulation in which the potent synthetic mu-agonist fentanyl is embedded in a sweetened matrix that is dissolved in the mouth. It is undergoing investigation as a treatment for cancer-related breakthrough pain, a prevalent phenomenon defined as a transitory flare of moderate to severe pain that interrupts otherwise controlled persistent pain. There have been no controlled trials of other treatments for this condition. To evaluate the safety and efficacy of ascending doses of OTFC, a novel controlled dose titration methodology was developed that applied blinding and randomization procedures to the evaluation of recurrent pains in the home environment. The study was a multicenter, randomized, double-blind dose titration study in ambulatory cancer patients. The sample comprised adult patients receiving a scheduled oral opioid regimen equivalent to 60-1000 mg oral morphine per day, who were experiencing at least one episode per day of breakthrough pain and had achieved at least partial relief of this pain by use of an oral opioid rescue dose. After collection of 2 days of baseline data concerning the efficacy of the usual rescue drug, patients were randomly treated with either 200 or 400 microg OTFC unit doses in double-blind fashion. Up to two breakthrough pains each day could be treated with up to four OTFC unit doses per pain. OTFC in unit doses containing 200, 400, 600, 800, 1200 or 1600 microg of fentanyl citrate were available for the study. The unit dose was titrated upward in steps until the patient had 2 consecutive days on which breakthrough pain could be treated with the single unit dose, titration was ineffective at a 1600 microg unit dose, or 20 days elapsed. To maintain the double-blind, orders to titrate up were ignored one-third of the time according to a pre-defined randomization schedule accessible only to an unblinded study pharmacist. Main outcome measures included, numeric or categorical measures of pain intensity, pain relief, and global assessment of drug performance. Dose response relationships were found suggesting that the methodology was sensitive to opioid effects. Seventy-four percent of patients were successfully titrated. There was no relationship between the total daily dose of the fixed schedule opioid regimen and the dose of OTFC required to manage the breakthrough pain. Although the study was not designed to provide a definitive comparison between OTFC and the usual rescue drug, exploratory analyses found that OTFC provided significantly greater analgesic effect at 15, 30 and 60 min, and a more rapid onset of effect, than the usual rescue drug. Adverse effects of the OTFC were typically opioid-related, specifically somnolence, nausea and dizziness. Very few adverse events were severe or serious. This study demonstrated the feasibility of controlled trial methodology in studies of breakthrough pain. OTFC appears to be a safe and effective therapy for breakthrough pain, and dose titration can usually identify a unit dose capable of providing adequate analgesia. If the lack of a relationship between the effective OTFC dose and fixed schedule opioid regimen is confirmed, dose titration may be needed in the clinical use of this formulation. Further investigation of OTFC as a specific treatment for breakthrough pain is warranted.

OBJECTIVES: This study was performed to test the safety and efficacy of a novel bioabsorbable hemostatic puncture closure device deployed through an arterial sheath. BACKGROUND: Cardiac catheterization procedures are associated with a risk of complications at the arterial access site. Increasing numbers of interventional procedures requiring large sheaths or intense anticoagulation underline the need for secure, rapid methods of obtaining hemostasis at the time of sheath removal. METHODS: We conducted a randomized, multicenter trial in 435 patients undergoing cardiac catheterization or angioplasty at eight participating centers. In 218 patients, hemostasis was achieved using the device (group I); 217 patients were assigned to the manual pressure control group (group II). RESULTS: There were no significant differences in baseline characteristics. Time to hemostasis was considerably shorter in group I (2.5 +/- 15.2 vs. 15.3 +/- 11.7 min [mean +/- SD], p < 0.0001). The deployment success rate for the device was 96%, and 76% of group I patients experienced immediate (within 1 min) hemostasis. Complication rates were lower in group I for bleeding, hematoma and occurrence of any complication. There was no difference in the small incidence of pseudoaneurysm formation. There was no change in either group in the ankle/brachial systolic blood pressure index. Ultrasound follow-up studies 60 days after device deployment revealed complete absorption of the device in all cases. Subgroup analysis revealed particular benefit in patients undergoing interventional procedures. The administration of heparin was associated with a significantly higher complication rate in the manual pressure control group, whereas heparin had no effect on hemostasis time or complication rates in the device group. CONCLUSIONS: This sheath-deployed, bioabsorbable device provides a safe and effective means of obtaining rapid arterial hemostasis after cardiac catheterization procedures. It appears to be particularly useful in those patients most at risk for access site complications.

BACKGROUND: Coronary artery bypass grafting success is limited by vein graft failure (VGF). Understanding the factors associated with VGF may improve patient outcomes. METHODS AND RESULTS: We examined 1828 participants in the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial undergoing protocol-mandated follow-up angiography 12 to 18 months post-coronary artery bypass grafting or earlier clinically driven angiography. Outcomes included patient- and graft-level angiographic VGF (≥75% stenosis or occlusion). Variables were selected by using Fast False Selection Rate methodology. We examined relationships between variables and VGF in patient- and graft-level models by using logistic regression without and with generalized estimating equations. At 12 to 18 months post-coronary artery bypass grafting, 782 of 1828 (42.8%) patients had VGF, and 1096 of 4343 (25.2%) vein grafts had failed. Demographic and clinical characteristics were similar between patients with and without VGF, although VGF patients had longer surgical times, worse target artery quality, longer graft length, and they more frequently underwent endoscopic vein harvesting. After multivariable adjustment, longer surgical duration (odds ratio per 10-minute increase, 1.05; 95% confidence interval, 1.03-1.07), endoscopic vein harvesting (odds ratio, 1.41; 95% confidence interval, 1.16-1.71), poor target artery quality (odds ratio, 1.43; 95% confidence interval, 1.11-1.84), and postoperative use of clopidogrel or ticlopidine (odds ratio, 1.35; 95% confidence interval, 1.07-1.69) were associated with patient-level VGF. The predicted likelihood of VGF in the graft-level model ranged from 12.1% to 63.6%. CONCLUSIONS: VGF is common and associated with patient and surgical factors. These findings may help identify patients with risk factors for VGF and inform the development of interventions to reduce VGF. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00042081.

OBJECTIVE: The study reports the results of treatment of oral tongue cancer with five different treatment modalities with long-term follow-up. STUDY DESIGN: Retrospective study of 332 patients with oral tongue cancer treated in the Departments of Otolaryngology-Head and Neck Surgery and Radiation Therapy at Washington University School of Medicine (St. Louis, MO) from 1957 to 1996. METHODS: Patients with biopsy-proven squamous cell carcinoma of the oral tongue who were previously untreated and were treated with curative intent by one of five modalities and who were eligible for 5-year follow-up were included. The treatment modalities included local resection alone, composite resection alone (with neck dissection), radiation therapy alone, local resection with radiation therapy, and composite resection with radiation therapy. Multiple diagnostic, treatment, and follow-up parameters were studied using standard statistical analysis to determine statistical significance. RESULTS: The overall 5-year disease-specific survival rate (DSS) was 57% with death due to tumor in 43%. The 5-year cumulative disease-specific survival probability (CDSS) was 0.61 (Kaplan-Meier) with a mean of 17.5 years and a median of 30.1 years. The DSS by treatment modality included local resection (73%), composite resection (61%), radiation therapy (46%), local resection and radiation therapy (65%), and composite resection with radiation therapy (CR/RT) (44%). Overall, local resection had a significantly improved DSS and CR/RT had a decreased DSS that was related to the stage of disease being treated. In treating stage IV disease, CR/RT produced a more significantly improved CDSS than the other treatment modalities. Recurrence at the primary site was as common as recurrence in the neck. Eighty-nine percent of recurrences occurred within the first 60 months. Recurrence significantly decreased survival. DSS was significantly improved in patients with clear margins of resection. Metastasis to a distant site occurred in 9.6% of patients. Twenty-one percent of patients had second primary cancers, and 54% of these patients died of their second primary cancer. CONCLUSIONS: Significant improvement in DSS was seen in patients with clear margins, early stage grouping and clinical (pretreatment) tumor stage, and negative nodes. Significant decrease in DSS was seen in patients with close or involved margins, advanced stage grouping and clinical (pretreatment) tumor staging, positive clinical (pretreatment) node staging, and tumor recurrence. Obtaining clear margins of resection is crucial because it significantly affects survival. A minimum of 5 years of close monitoring is recommended because of the high incidence of second primary cancers.

BACKGROUND: The purpose of this study was to evaluate whether women undergoing cardiac surgery are more likely to suffer neurological complications than men and whether these complications could explain, at least in part, their higher perioperative mortality. METHODS AND RESULTS: The Society of Thoracic Surgery National Cardiac Surgery Database was examined for the years 1996 and 1997 to determine the frequency of new neurological events (stroke, transient ischemic attack, or coma) occurring after cardiac surgery. We reviewed clinical information on 416 347 patients (32% women) for whom complete neurological outcome data were available. New neurological events after surgery were higher for women than for men (3.8% versus 2.4%, P=0.001). For the whole group, the 30-day mortality was higher for women than for men (5.7% versus 3.5%, P=0.001), and among those patients who suffered a perioperative neurological event, mortality was also significantly higher for women than men (32% versus 28%, P=0.001). After adjustment for other risk factors (eg, age, history of hypertension and/or diabetes, duration of cardiopulmonary bypass, and other comorbid conditions) by multivariable logistic regression, female sex was independently associated with significantly higher risk of suffering new neurological events after cardiac surgery (OR 1.21, 95% CI 1.14 to 1.28, P=0.001). CONCLUSIONS: Women undergoing cardiac surgery are more likely than men to suffer new perioperative neurological events, and they have higher 30-day mortality when these complications occur. The higher incidence of perioperative neurological complications in women cannot be explained by currently known risk factors.

IMPORTANCE: Total neoadjuvant therapy (TNT) is often used to downstage locally advanced rectal cancer (LARC) and decrease locoregional relapse; however, more than one-third of patients develop recurrent metastatic disease. As such, novel combinations are needed. OBJECTIVE: To assess whether the addition of pembrolizumab during and after neoadjuvant chemoradiotherapy can lead to an improvement in the neoadjuvant rectal (NAR) score compared with treatment with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and chemoradiotherapy alone. DESIGN, SETTING, AND PARTICIPANTS: In this open-label, phase 2, randomized clinical trial (NRG-GI002), patients in academic and private practice settings were enrolled. Patients with stage II/III LARC with distal location (cT3-4 ≤ 5 cm from anal verge, any N), with bulky disease (any cT4 or tumor within 3 mm of mesorectal fascia), at high risk for metastatic disease (cN2), and/or who were not candidates for sphincter-sparing surgery (SSS) were stratified based on clinical tumor and nodal stages. Trial accrual opened on August 1, 2018, and ended on May 31, 2019. This intent-to-treat analysis is based on data as of August 2020. INTERVENTIONS: Patients were randomized (1:1) to neoadjuvant FOLFOX for 4 months and then underwent chemoradiotherapy (capecitabine with 50.4 Gy) with or without intravenous pembrolizumab administered at a dosage of 200 mg every 3 weeks for up to 6 doses before surgery. MAIN OUTCOMES AND MEASURES: The primary end point was the NAR score. Secondary end points included pathologic complete response (pCR) rate, SSS, disease-free survival, and overall survival. This report focuses on end points available after definitive surgery (NAR score, pCR, SSS, clinical complete response rate, margin involvement, and safety). RESULTS: A total of 185 patients (126 [68.1%] male; mean [SD] age, 55.7 [11.1] years) were randomized to the control arm (CA) (n = 95) or the pembrolizumab arm (PA) (n = 90). Of these patients, 137 were evaluable for NAR score (68 CA patients and 69 PA patients). The mean (SD) NAR score was 11.53 (12.43) for the PA patients (95% CI, 8.54-14.51) vs 14.08 (13.82) for the CA patients (95% CI, 10.74-17.43) (P = .26). The pCR rate was 31.9% in the PA vs 29.4% in the CA (P = .75). The clinical complete response rate was 13.9% in the PA vs 13.6% in the CA (P = .95). The percentage of patients who underwent SSS was 59.4% in the PA vs 71.0% in the CA (P = .15). Grade 3 to 4 adverse events were slightly increased in the PA (48.2%) vs the CA (37.3%) during chemoradiotherapy. Two deaths occurred during FOLFOX: sepsis (CA) and pneumonia (PA). No differences in radiotherapy fractions, FOLFOX, or capecitabine doses were found. CONCLUSIONS AND RELEVANCE: Pembrolizumab added to chemoradiotherapy as part of total neoadjuvant therapy was suggested to be safe; however, the NAR score difference does not support further study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02921256.

OBJECTIVES: Hyper-inflammation caused by COVID-19 may be mediated by mast cell activation (MCA) which has also been hypothesized to cause Long-COVID (LC) symptoms. We determined prevalence/severity of MCA symptoms in LC. METHODS: Adults in LC-focused Facebook support groups were recruited for online assessment of symptoms before and after COVID-19. Questions included presence and severity of known MCA and LC symptoms and validated assessments of fatigue and quality of life. General population controls and mast cell activation syndrome (MCAS) patients were recruited for comparison if they were ≥18 years of age and never had overt COVID-19 symptoms. RESULTS: There were 136 LC subjects (89.7% females, age 46.9 ±12.9 years), 136 controls (65.4% females, age 49.2 ±15.5), and 80 MCAS patients (85.0% females, age 47.7 ±16.4). Pre-COVID-19 LC subjects and controls had virtually identical MCA symptom and severity analysis. Post-COVID-19 LC subjects and MCAS patients prior to treatment had virtually identical MCA symptom and severity analysis. CONCLUSIONS: MCA symptoms were increased in LC and mimicked the symptoms and severity reported by patients who have MCAS. Increased activation of aberrant mast cells induced by SARS-CoV-2 infection by various mechanisms may underlie part of the pathophysiology of LC, possibly suggesting routes to effective therapy.

BACKGROUND: Vein graft failure (VGF) is common after coronary artery bypass graft surgery, but its relationship with long-term clinical outcomes is unknown. In this retrospective analysis, we examined the relationship between VGF, assessed by coronary angiography 12 to 18 months after coronary artery bypass graft surgery, and subsequent clinical outcomes. METHODS AND RESULTS: Using the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial database, we studied data from 1829 patients who underwent coronary artery bypass graft surgery and had an angiogram performed up to 18 months after surgery. The main outcome measure was death, myocardial infarction, and repeat revascularization through 4 years after angiography. VGF occurred in 787 of 1829 patients (43%). Clinical follow-up was completed in 97% of patients with angiographic follow-up. The composite of death, myocardial infarction, or revascularization occurred more frequently among patients who had any VGF compared with those who had none (adjusted hazard ratio, 1.58; 95% confidence interval, 1.21-2.06; P=0.008). This was due mainly to more frequent revascularization with no differences in death (adjusted hazard ratio, 1.04; 95% confidence interval, 0.71-1.52; P=0.85) or death or myocardial infarction (adjusted hazard ratio, 1.08; 95% confidence interval, 0.77-1.53; P=0.65). CONCLUSIONS: VGF is common after coronary artery bypass graft surgery and is associated with repeat revascularization but not with death and/or myocardial infarction. Further investigations are needed to evaluate therapies and strategies for decreasing VGF to improve outcomes in patients undergoing coronary artery bypass graft surgery.

BACKGROUND: Nonischemic cardiomyopathy is a leading cause of reduced left ventricular ejection fraction (LVEF) and is associated with high mortality risk from progressive heart failure and arrhythmias. Myocardial scar on cardiovascular magnetic resonance imaging is increasingly recognized as a risk marker for adverse outcomes; however, left ventricular dysfunction remains the basis for determining a patient's eligibility for primary prophylaxis with implantable cardioverter-defibrillator. We investigated the relationship of LVEF and scar with long-term mortality and mode of death in a large cohort of patients with nonischemic cardiomyopathy. METHODS: This study is a prospective, longitudinal outcomes registry of 1020 consecutive patients with nonischemic cardiomyopathy who underwent clinical cardiovascular magnetic resonance imaging for the assessment of LVEF and scar at 3 centers. RESULTS: =0.57). On multivariable analysis including established clinical factors, LVEF and scar are independent risk markers of all-cause and cardiac death. The addition of LVEF provided incremental prognostic value but insignificant discrimination improvement by C-statistic for all-cause and cardiac death, but no incremental prognostic value for SCD. Conversely, scar extent demonstrated significant incremental prognostic value and discrimination improvement for all 3 end points. On net reclassification analysis, the addition of LVEF resulted in no significant improvement for all-cause death (11.0%; 95% CI, -6.2% to 25.9%), cardiac death (9.8%; 95% CI, -5.7% to 29.3%), or SCD (7.5%; 95% CI, -41.2% to 42.9%). Conversely, the addition of scar extent resulted in significant reclassification improvement of 25.5% (95% CI, 11.7% to 41.0%) for all-cause death, 27.0% (95% CI, 11.6% to 45.2%) for cardiac death, and 40.6% (95% CI, 10.5% to 71.8%) for SCD. CONCLUSIONS: Myocardial scar and LVEF are both risk markers for all-cause and cardiac death in patients with nonischemic cardiomyopathy. However, whereas myocardial scar has strong and incremental prognostic value for SCD risk stratification, LVEF has no incremental prognostic value over clinical measures. Scar assessment should be incorporated into patient selection criteria for primary prevention implantable cardioverter-defibrillator placement.