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Objectives Extracorporeal membrane oxygenation (ECMO) is used to support patients in severe cardiogenic shock. In the absence of recovery, these patients may need to be listed for heart transplant (HT), which offers the best long-term prognosis. However, posttransplantation mortality is significantly elevated in patients who receive ECMO. The objective of the present study was to describe and risk-stratify different profiles of patients listed for HT supported by ECMO. Methods Patients listed for HT in the United Network for Organ Sharing database were analyzed. The primary outcome was 1-year survival and was assessed in patients bridged to transplant with ECMO (ECMOBTT) and patients who were previously supported on ECMO but had it removed before HT (ECMOREMOVED). Results Among 65,636 adult candidates listed for HT (between 2001 and 2017), 712 were supported on ECMO, 292 of whom (41%) underwent HT (ECMOBTT, n = 202; ECMOREMOVED, n = 90). Most of the patients with ECMOREMOVED were transplanted with a ventricular assist device. In ECMOBTT, recipient age (each 10-year increase), time on the waitlist (both defined as minor risk factors), need for dialysis, and need for mechanical ventilation (both defined as major risk factors) were independent predictors of mortality. ECMOREMOVED and ECMOBTT with no risk factors showed 1-year survival comparable to that in patients who were never supported on ECMO. Compared with patients who were never on ECMO, patients in ECMOBTT group with minor risk factors, 1 major risk factor, and 2 major risk factors had ~2-, ~5-, and >10-fold greater 1-year mortality, respectively (P Conclusions The HT recipients in the ECMOREMOVED and ECMOBTT groups with no risk factors showed similar survival as the HT recipients who were never supported on ECMO. In the ECMOBTT group, posttransplantation mortality increased significantly with increasing risk factors.

Kratom, a plant that produces opioid-like effects, has gained popularity in the U.S. for self-treating symptoms of chronic pain, mood disorders, and substance-use disorders (SUDs). Most data on kratom are from surveys into which current kratom-using adults could self-select; such surveys may underrepresent people who have used kratom and chosen to stop. Available data also do not adequately assess important psychosocial factors surrounding kratom use. In this study, U.S. adults who reported past 6-month alcohol, opioid, and/or stimulant use (N = 1,670) were recruited via Amazon Mechanical Turk between September and December 2020. Of the 1,510 evaluable respondents, 202 (13.4%) reported lifetime kratom use. Kratom-using adults, relative to others, were typically younger, male, unpartnered, without children, and had lower income. They had higher rates of chronic pain (31.7% vs. 21.9%, p = .003), childhood adversity, anxiety, and depression (p < .001), and lower perceived social rank (d = .19, .02-.22) and socioeconomic status (d = .37 .16-.26). They also reported higher use rates for most substances (except alcohol); this included medically supervised and unsupervised use of prescription opioids and diverted opioid agonist therapy (OAT) medications. Most (83.2%) met diagnostic criteria for any past-year SUD. Those reporting kratom use were less likely to reside in an urban/suburban area. The strongest predictors of kratom use were use of other drugs: cannabidiol (OR = 3.73), psychedelics (OR = 3.39), and nonmedical prescription opioids (OR = 1.72). Another strong predictor was lifetime OAT utilization (OR = 2.31). Despite seemingly poorer psychosocial functioning and health among respondents reporting lifetime kratom use, use of other substances may be the strongest indicators of kratom use. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Light’s criteria is the standard for determining the etiology of pleural effusions. Test characteristics of Light’s criteria varies in different populations, and Light’s criteria may misclassify effusions in patients with impaired immunity such as in neutropenia. This study evaluates the test characteristics of Light’s criteria and other clinically available pleural fluid tests in a cohort of patients with neutropenia. Cases were defined as a thoracentesis performed with an absolute neutrophil count of less than 1000 cells/µl documented at least 24 hours prior to the procedure. The etiology of the effusion was adjudicated by independent review of the case data and hospital course by two board certified pulmonologists. Categories for final diagnosis included exudate due to infection, exudate due to malignancy, exudate due to other, and transudate. A total of 83 thoracenteses from 80 patients were identified. Comorbidities included hematologic and solid tumor malignancies, recipients of allogeneic stem cell and solid organ transplants, heart failure, chronic kidney disease, and decompensated cirrhosis. Light’s criteria had a sensitivity of 92% and a specificity of 55% for identifying exudates, LR+ 2.07 and LR-0.14. A pleural fluid protein value of >2.9 g/dl had a sensitivity of 42% and a specificity of 96%, LR+11.12 and LR-0.61. When comparing exudative effusions, the percentage of neutrophils in the pleural fluid was significantly higher in infection, despite peripheral neutropenia. Together these results show a reduced specificity of Light’s criteria in neutropenia, and underscore the complexity of pleural effusions in this setting.

BACKGROUND: Mood disorders and suicidal behavior have moderate heritability and are associated with altered corticolimbic serotonin 1A receptor (5-HT1A) binding potential. However, it is unclear whether these alterations reflect heritable risk or epigenetic effects of childhood, compensatory mechanisms, or illness-related changes. We sought to separate effects on 5-HT1A binding due to mood disorder, suicidal behavior, and risk and resilience to both by examining high familial risk individuals (HR) who have passed through the age of greatest risk for psychopathology onset. METHODS: PET imaging quantified 5-HT1A binding potential BPND using [11C]CUMI-101 in healthy volunteers (HV, N=23) and three groups with one or more relatives with early-onset mood disorder and suicide attempt: 1. unaffected HR (N=23); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N=26); and 3. HR-MOOD with previous suicide attempt (HR-MOOD+SA, N=20). Findings were tested in two independent cohorts of low risk individuals (HV, MOOD, and MOOD+SA, total N=185). We tested for regional BPND differences and whether brain-wide patterns distinguished between groups. RESULTS: Low ventral prefrontal 5-HT1A BPND in MOOD+SA was found across three independent cohorts. Brain-wide 5-HT1A BPND patterns distinguished HR-MOOD+SA from HV. An endophenotype associated with familial risk was not observed. CONCLUSIONS: Low ventral prefrontal 5-HT1A BPND may reflect suicide-related pathology. Further studies are needed to determine if higher ventral prefrontal 5-HT1A BPND confers resilience for developing suicidal behavior in the context of mood disorders. If so, it could be a potential suicide prevention target.

Adenosine triphosphate potassium sensitive channels provide endogenous myocardial protection via coupling of cell membrane potential to myocardial metabolism. Adenosine triphosphate potassium sensitive channel openers, such as diazoxide, mimic ischemic preconditioning, prevent cardiomyocyte swelling, preserve myocyte contractility after stress, and provide diastolic protection. We hypothesize that diazoxide combined with hyperkalemic cardioplegia provides superior myocardial protection compared with cardioplegia alone during prolonged global ischemia in a large animal model.Twelve pigs were randomized to global ischemia for 2 hours with a single dose of cold blood (4:1) hyperkalemic cardioplegia alone (n = 6) or with diazoxide (500 μmol/L) (n = 6) and reperfused for 1 hour. Cardiac output, myocardial oxygen consumption, left ventricular developed pressure, left ventricular ejection fraction, diastolic function, myocardial troponin, myoglobin, markers of apoptosis, and left ventricular infarct size were compared.Four pigs in the cardioplegia alone group could not be weaned from cardiopulmonary bypass. There were no differences in myoglobin, troponin, or apoptosis between groups. Diazoxide preserved cardiac output versus control (74.5 vs 18.4 mL/kg/min, P = .01). Linear mixed regression modeling demonstrated that the addition of diazoxide to cardioplegia preserved left ventricular developed pressure by 36% (95% confidence interval, 9.9-61.5; P .01), dP/dt max by 41% (95% confidence interval, 14.5-67.5; P .01), and dP/dt min by 33% (95% confidence interval, 8.9-57.5; P = .01). It was also associated with higher (but not significant) myocardial oxygen consumption (3.7 vs 1.4 mL ODiazoxide preserves systolic and diastolic ventricular function in a large animal model of prolonged global myocardial ischemia. Diazoxide as an adjunct to hyperkalemic cardioplegia may allow safer prolonged ischemic times during increasingly complicated cardiac procedures.

Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.

Background Weight changes during neoadjuvant chemotherapy (NAC) for pancreatic cancer (PDAC) are not well studied. We hypothesized that weight loss may predict poor outcomes. Methods Weight change from NAC initiation to pancreatectomy was grouped: gain (≥5%), stable, and loss (≥5%). Pathologic, postoperative, and survival outcomes were compared. Results 95 patients were included: 31.6% lost weight, 58.9% maintained weight, and 9.5% gained weight. There were no differences in chemotherapeutic regimens. Median recurrence-free survival (RFS) and overall survival (OS) were similar between patients with stable weight and those who lost weight (RFS: 9.6vs14.0months; OS: 25.8vs26.7months). Among those who gained weight, RFS (29.5months) and OS (38.4months) were greater relative to the other weight categories. On multivariable regression, weight gain was associated with improved RFS compared to loss (HR = 0.16). Conclusion Most patients maintain or lose weight during NAC, and weight loss does not predict poor outcomes. Weight gain may predict improved RFS.

OBJECTIVE To explore the association between frailty and history of falls in people living with multiple sclerosis (MS). DESIGN Secondary analysis. SETTING University research laboratories in the United States and Israel. PARTICIPANTS 118 people with relapsing-remitting MS [age=48.9 years (SD=10.0); 74.6% female; expanded disability status scale (EDSS) range=1.0-6.0] were studied in this cross-sectional analysis. INTERVENTION Not applicable. MAIN OUTCOMES A frailty index was calculated from 40 health deficits by following standard validated procedures. The number of falls (12-month history) was recorded. RESULTS Overall, 33.9%, 29.7%, and 36.4% of participants were classified as non-frail, moderately frail, and severely frail, respectively. The frailty index was significantly correlated (ρ=0.37, p

Thermal analysis plays an important role in predicting the overall performance of an electric machine. An accurate Heat Transfer Coefficient (HTC) is required for an accurate and reliable thermal model representing the amount of heat that can be transferred by the system. Analytical calculation of HTC is difficult for sophisticated geometric bodies since the correlations are only available for simple geometries. This paper presents a 2- way numerical multi-physics approach using Finite Element Analysis (FEA) and Computational fluid dynamics (CFD) to determine HTC and evaluate the thermal performance of a liquid-cooled electric machine. The approach presents a convenient, time-efficient, and reliable solution applicable to the optimization process. The numerically obtained HTC for a commonly used coolant channel in liquid-cooled electric machines is verified analytically using correlations. The study uses a 60 kW switched reluctance machine (SRM) as an example model to evaluate the thermal performance of the machine. Results are validated with the experimentally obtained data.

We examined the outcomes of children (18 years) operated on for anomalous left coronary artery from the pulmonary artery (ALCAPA).We linked patients undergoing ALCAPA repair between 1982 and 2003 in the Pediatric Cardiac Care Consortium with the National Death Index and the Organ Procurement and Transplantation Network to examine their outcomes through 2019.We identified 228 children (median age, 6.0 months) operated on for ALCAPA. At the time of repair, 38.6% had severe mitral regurgitation (MR), and 71.4% had severe left ventricular (LV) dysfunction. Repair included primarily coronary reimplantation in 173 and the Takeuchi procedure in 34; concurrently, 18 underwent mitral valve (MV) operation. In-hospital death occurred in 31 (13.6%) and was not associated with MR severity (P = .846); however, among patients with moderate or severe MR, risk of death was 28% lower when undergoing MV operation (P = .033). After adjustment for other risk factors, only infant operation reached statistical significance for in-hospital death (adjusted odds ratio, 12.99; 95% CI, 1.61-104.59; P = .016). Among those discharged alive with long-term data available (n = 155), the 30-year transplant-free survival reached 95.5% (95% CI, 92.3%-98.8%) and was not associated with the degree of preoperative MR or LV dysfunction. Coronary reimplantation was associated with better long-term survival compared with other surgical techniques (adjusted odds ratio, 0.11; 95% CI, 0.02-0.74; P = .023).Favorable long-term outcomes can be expected after coronary artery reimplantation for ALCAPA, even in patients with severe LV dysfunction at presentation. MV operation predicted decreased risk for in-hospital mortality in patients with moderate/severe MR, but MR severity predicted neither in-hospital nor longer-term outcomes.

Most patients with pancreatic adenocarcinoma (PDAC) do not undergo surgical resection. The role of radiotherapy (RT) in non-operatively managed localized pancreatic adenocarcinoma is unclear.The National Cancer Database (2010-2016) was queried for patients with clinical stage II-III PDAC treated with multiagent systemic chemotherapy (CT) +/- RT but not surgery. Factors associated with the receipt of RT and overall survival were compared after adjusting for patient demographics and clinical characteristics.A total of 14,921 patients were included, of whom 9279 received CT and 5382 received CT + RT. Patients treated with CT + RT were more likely to be younger (65vs66yrs), treated at non-academic facilities (48.8%vs46.7%), have private insurance (40.3%vs36.5%), and have clinical T4 tumors (53.6%vs48.7%). Most patients who were treated with RT received external beam radiotherapy (89.3%), and the median dose was 5,000 cGy. Median time to start of RT was 129 days. CT + RT was associated with longer overall survival (15.9vs11.8mos,p 0.001), and remained associated with survival on multivariable analysis (HR 0.74, 95%CI 0.70-0.78). On a 4-month conditional survival analysis, combined CT + RT remained associated with improved survival compared to CT alone (16.0vs13.1mos,p 0.001).In patients with non-operatively managed localized pancreatic adenocarcinoma, combined radiotherapy and multiagent systemic chemotherapy is associated with improved overall survival compared to chemotherapy alone.

PURPOSE The utility of blue light cystoscopy (BLC) in patients receiving bacillus Calmette-Guerin (BCG) during post-treatment cystoscopy is not well understood. Our objective was to determine if BLC improves recurrence detection in patients with nonmuscle-invasive bladder cancer (NMIBC) undergoing BCG. MATERIALS AND METHODS Using the prospective multi-institutional Cysview® Registry (2014-2019), patients with NMIBC who received BCG within 1 year prior to BLC were identified. Primary outcomes were recurrences and whether lesions were detected on white light cystoscopy (WLC), BLC or both. We calculated the percentage of cystoscopies with recurrences that were missed with WLC alone. The cystoscopy-level BLC false-positive rate was the proportion of cystoscopies with biopsies only due to BLC suspicious lesions without recurrence. RESULTS Of 1,703 BLCs, 282 cystoscopies were in the analytic cohort. The overall recurrence rate was 45.0% (127). With only WLC, 13% (16/127) of recurrences would have been missed as 5.7% (16/282) of cystoscopies performed had a recurrence only identified with BLC. Among 16 patients with recurrence missed with WLC, 88% (14) had carcinoma in situ. The cystoscopy-level BLC false-positive rate was 5% (15). CONCLUSIONS BLC helped detect recurrences after recent BCG that would have been missed with WLC alone. Providers should consider BLC for high-risk patients undergoing BCG and should discuss the risk of false-positives with these patients. As clinical trials of novel therapies for BCG-unresponsive disease increase and there are no clear guidelines on BLC use for post-treatment cystoscopies, it is important to consider how variable BLC use could affect enrollment in and comparisons of these studies.

Background The Centers for Medicare and Medicaid Services proposed reimbursement cuts for operations in 2021. Literature examining reimbursement for common operations is scarce. Methods Reimbursement rates were abstracted (2011–2021). Trends in reimbursement rates were analyzed using linear regression. Results From 2011 to 2021, the national inflation rate was 16.3%. Unadjusted reimbursement rates for open and laparoscopic inguinal hernia repairs increased by 6.5% and 7.2%, respectively. There was an increase in unadjusted reimbursement for open appendectomies of 5.1% and 6.1% for laparoscopic. Unadjusted reimbursement for open cholecystectomies increased by 4.4%, but decreased by 6.8% for laparoscopic. When adjusted to 2021 values, reimbursement for all six operations decreased. Laparoscopic and open cholecystectomies experienced the largest decreases (19.8%, 10.2%). Conclusion Since 2011, there have been decreases in adjusted reimbursement for three common operations, independent of operative approach. Awareness of trends in reimbursement rates should be a priority to ensure sustainable general surgical care.

PURPOSE Insertion mutations in Erb-b2 receptor tyrosine kinase 2 gene ( ERBB2 or HER2) exon 20 occur in 2%-5% of non–small-cell lung cancers (NSCLCs) and function as an oncogenic driver. Poziotinib, a tyrosine kinase inhibitor, was evaluated in previously treated patients with NSCLC with HER2 exon 20 insertions. METHODS ZENITH20, a multicenter, multicohort, open-label phase II study, evaluated poziotinib in patients with advanced or metastatic NSCLC. In cohort 2, patients received poziotinib (16 mg) once daily. The primary end point was objective response rate evaluated by independent review committee (RECIST v1.1); secondary outcome measures were disease control rate, duration of response, progression-free survival, and safety and tolerability. Quality of life was assessed. RESULTS Between October 2017 and March 2021, 90 patients with a median of two prior lines of therapy (range, 1-6) were treated. With a median follow-up of 9.0 months, objective response rate was 27.8% (95% CI, 18.9 to 38.2); 25 of 90 patients achieved a partial response. Disease control rate was 70.0% (95% CI, 59.4 to 79.2). Most patients (74%) had tumor reduction (median reduction 22%). Median progression-free survival was 5.5 months (95% CI, 3.9 to 5.8); median duration of response was 5.1 months (95% CI, 4.2 to 5.5). Clinical benefit was seen regardless of lines and types of prior therapy, presence of central nervous system metastasis, and types of HER2 mutations. Grade 3 or higher treatment-related adverse events included rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). Most patients had poziotinib dose reductions (76.7%), with median relative dose intensity of 71.5%. Permanent treatment discontinuation because of treatment-related adverse events occurred in 13.3% of patients. CONCLUSION Poziotinib demonstrates antitumor activity in previously treated patients with HER2 exon 20 insertion NSCLC.

Background: Clostridioides difficile infection (CDI) can result in life-threatening illness requiring surgery. Surgical options for managing severe or fulminant, non-perforated C. difficile colitis include total abdominal colectomy with end ileostomy or creation of a diverting loop ileostomy with antegrade vancomycin lavage. Methods: The Surgical Infection Society's Therapeutics and Guidelines Committee convened to develop guidelines for summarizing the current SIS recommendations for total abdominal colectomy versus diverting loop ileostomy with antegrade lavage for severe or fulminant, non-perforated C. difficile colitis. PubMed, Embase, and the Cochrane database were searched for pertinent studies. Severe infection was defined as laboratory diagnosis of C. difficile infection with leukocytosis (white blood cell count of ≥15,000 cells/mL) or elevated creatinine (serum creatinine level >1.5 mg/dL). Fulminant infection was defined as laboratory diagnosis of C. difficile infection with hypotension or shock, ileus, or megacolon. Perforation was defined as complete disruption of the colon wall. Total abdominal colectomy was defined as resection of the ascending, transverse, descending, and sigmoid colon with end ileostomy. For the purpose of the guideline, the terms subtotal colectomy, total abdominal colectomy, and rectal-sparing total colectomy were used interchangeably. Diverting loop ileostomy with antegrade enema was defined as creation of both a diverting loop ileostomy with intra-operative colonic lavage and post-operative antegrade vancomycin unless otherwise specified. Evaluation of the published evidence was performed using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. Using a process of iterative consensus, all committee members voted to accept or reject each recommendation. Results: We recommend that total abdominal colectomy be the procedure of choice for definitive therapy of severe or fulminant, non-perforated C. difficile colitis. In select patients, colon preservation using diverting loop ileostomy with intra-colonic vancomycin may be associated with higher rates of ostomy reversal and restoration of gastrointestinal continuity but may lead to development of recurrent C. difficile colitis. Conclusions: This guideline summarizes the current Surgical Infection Society recommendations regarding use of total abdominal colectomy versus diverting loop ileostomy with antegrade lavage for adults with severe or fulminant, non-perforated C. difficile infection.

Background Guidelines recommend resection of non-functional neuroendocrine tumors of the pancreas (NF-pNETs) that are ≥2 cm in size. We compared utilization of surgery based on race. Methods We identified non-Hispanic White and Black patients with localized NF-pNETs ≥2 cm and Charlson-Deyo score 0–1 in the NCDB (2004–2016). We compared utilization of surgery by race, adjusting for clinicodemographic variables. Overall survival was compared based on management. Results A total of 3459 patients were included (White = 3005; Black = 454). Black patients were younger (58vs63 years) and more often treated at academic facilities (65.3%vs60.3%). Overall, Black and White patients underwent surgery at similar rates (77.3%vs79.6%). When stratified by primary site, Black patients with body/tail tumors were less likely to undergo surgery (78.5%vs84.7%). On multivariable analysis, Black race was associated with a lower likelihood of surgery overall (OR 0.74,p = 0.034) and in patients with body/tail tumors (OR 0.56,p = 0.001). Non-operative management was associated with a higher risk of death (HR 3.19,p Conclusion In a national cohort of patients with NF-pNETs meeting criteria for resection, Black race is associated with lower frequency of surgery. Operative intervention is associated with prolonged survival. Persistent racial disparities in management of a surgically curable disease should be targeted for improvement.

AIMS: Remote monitoring of pulmonary artery pressure has reduced heart failure (HF) hospitalizations in chronic HF as elevation of pulmonary artery pressure provides information that can guide treatment. The venous system is characterized by high capacitance, thus substantial increases in intravascular volume can occur before filling pressures increase. The inferior vena cava (IVC) is a highly compliant venous conduit and thus a candidate for early detection of change in intravascular volume. We aimed to compare IVC cross-sectional area using a novel sensor with cardiac filling pressures during experimental manipulation of volume status, vascular tone, and cardiac function.METHODS AND RESULTS: Experiments were conducted in sheep to manipulate volume status (colloid infusion), vascular tone (nitroglycerin infusion) and cardiac function (rapid cardiac pacing). A wireless implantable IVC sensor was validated ex-vivo and in-vivo, and then used to measure the cross-sectional area of the IVC. Right- and left-sided cardiac filling pressures were obtained via right heart catheterization. The IVC sensor provided highly accurate and precise measurements of cross-sectional area in ex-vivo and in-vivo validation. IVC area changes were more sensitive than the corresponding changes in cardiac filling pressures during colloid infusion (p CONCLUSIONS: Inferior vena cava area can be remotely and accurately measured in real time with a wireless implantable sensor. Changes in IVC area are more sensitive than corresponding changes in filling pressures following experimental volume loading and fluid redistribution. Additional research is warranted to understand if remote monitoring of the IVC may have advantages over pressure-based monitors in HF.

Key Points Severe bone marrow failure was primarily observed in early childhood in children with biallelic SBDS mutations.Absolute neutrophil counts were positively associated with age (P < .0001) in patients with biallelic SBDS mutations., Visual Abstract, Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.

BACKGROUND: People with HIV (PWH) have a higher hospitalization rate than the general population. The Veterans Aging Cohort Study (VACS) Index at study entry well predicts hospitalization in PWH, but it is unknown if the time-updated parameter improves hospitalization prediction. We assessed the association of parameterizations of the VACS Index 2.0 with the 5-year risk of hospitalization. SETTING: PWH ≥ 30 years old with at least 12 months of antiretroviral therapy (ART) use, and contributing hospitalization data from 2000 to 2016 in North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included. Three parameterizations of the VACS Index 2.0 were assessed and categorized by quartile: 1) “baseline” measurement at study entry, 2) time-updated measurements, and 3) cumulative scores calculated using the trapezoidal rule. METHODS: Discrete-time proportional hazard models estimated the crude and adjusted associations (and 95% confidence intervals [CI]) of the VACS Index parameterizations and all-cause hospitalizations. The Akaike information criterion (AIC) assessed the model fit with each of the VACS Index parameters. RESULTS: Among 7,289 patients, 1,537 were hospitalized. Time-updated VACS Index fitted hospitalization best with a more distinct dose-response relationship (score

Introduction An estimated 116 million American adults (47.3%) have hypertension. Most adults with hypertension do not have it controlled—3 in 4 (92.1 million) U.S. adults with hypertension have a blood pressure ≥130/80 mmHg. The Pharmacists’ Patient Care Process is a standardized patient-centered approach to the provision of pharmacist care that is done in collaboration with other healthcare providers. Through the Michigan Medicine Hypertension Pharmacists’ Program, pharmacists use the Pharmacists’ Patient Care Process to provide hypertension management services in collaboration with physicians in primary care and community pharmacy settings. In 2019, the impact of Michigan Medicine Hypertension Pharmacists’ Program patient participation on blood pressure control was evaluated. Methods Propensity scoring was used to match patients in the intervention group with patients in the comparison group and regression analyses were then conducted to compare the 2 groups on key patient outcomes. Negative binomial regression was used to examine the number of days with blood pressure under control. The findings presented in this brief are part of a larger multimethod evaluation. Results More patients in the intervention group than in the comparison group achieved blood pressure control at 3 months (66.3% vs 42.4%) and 6 months (69.1% vs 56.5%). The intervention group experienced more days with blood pressure under control within a 3-month (18.6 vs 9.5 days) and 6-month period (57.0 vs 37.4 days) than the comparison group did. Conclusions Findings support the effectiveness of the Michigan Medicine Hypertension Pharmacists’ Program approach to implementing the Pharmacists’ Patient Care Process to improve blood pressure control.

OBJECTIVE Obsessive-compulsive disorder (OCD) is among the most debilitating and medically refractory psychiatric disorders. While cingulotomy is an anatomically targeted neurosurgical treatment that has shown significant promise in treating OCD-related symptoms, the precise underlying neuroanatomical basis for its beneficial effects has remained poorly understood. Therefore, the authors sought to determine whether lesion location is related to responder status following cingulotomy. METHODS The authors reviewed the records of 18 patients who had undergone cingulotomy. Responders were defined as patients who had at least a 35% improvement in the Yale-Brown Obsessive Compulsive Scale (YBOCS) score. The authors traced the lesion sites on T1-weighted MRI scans and used an anatomical registration matrix generated by the imaging software FreeSurfer to superimpose these lesions onto a template brain. Lesion placement was compared between responders and nonresponders. The placement of lesions relative to various anatomical regions was also compared. RESULTS A decrease in postoperative YBOCS score was significantly correlated with more superiorly placed lesions (decrease −0.52, p = 0.0012). While all lesions were centered within 6 mm of the cingulate sulcus, responder lesions were placed more superiorly and posteriorly along the cingulate sulcus (1-way ANOVA, p = 0.003). The proportions of the cingulum bundle, cingulate gyrus, and paracingulate cortex affected by the lesions were the same between responders and nonresponders. However, all responders had lesions covering a larger subregion of Brodmann area (BA) 32. In particular, responder lesions covered a significantly greater proportion of the posterior BA32 (1-way ANOVA, p = 0.0064). CONCLUSIONS Lesions in patients responsive to cingulotomy tended to be located more superiorly and posteriorly and share greater coverage of a posterior subregion of BA32 than lesions in patients not responsive to this treatment.

Background: Inhalational anesthetics were associated with reduced incidence of angiographic vasospasm and delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (SAH). Whether intravenous anesthetics provide similar level of protection is not known. Methods: Anesthetic data were collected retrospectively for patients with SAH who received general anesthesia for aneurysm repair between January 1, 2014 and May 31, 2018, at 2 academic centers in the United States (one employing primarily inhalational and the other primarily intravenous anesthesia with propofol). We compared the outcomes of angiographic vasospasm, DCI, and neurological outcome (measured by disposition at hospital discharge), between the 2 sites, adjusting for potential confounders. Results: We compared 179 patients with SAH receiving inhalational anesthetics at one institution to 206 patients with SAH receiving intravenous anesthetics at the second institution. The rates of angiographic vasospasm between inhalational versus intravenous anesthetic groups were 32% versus 52% (odds ratio, 0.49 [CI, 0.32–0.75]; P =0.001) and DCI were 21% versus 40% (odds ratio, 0.47 [CI, 0.29–0.74]; P =0.001), adjusting for imbalances between sites/groups, Hunt-Hess and Fisher grades, type of aneurysm treatment, and American Society of Anesthesiology status. No impact of anesthetics on neurological outcome at time of discharge was noted with rates of good discharge outcome between inhalational versus intravenous anesthetic groups at (78% versus 72%, P =0.23). ConclusionS: Our data suggest that those who received inhalational versus intravenous anesthetic for ruptured aneurysm repair had significant protection against SAH-induced angiographic vasospasm and DCI. Although we cannot fully disentangle site-specific versus anesthetic effects in this comparative study, these results, when coupled with preclinical data demonstrating a similar protective effect of inhalational anesthetics on vasospasm and DCI, suggest that inhalational anesthetics may be preferable for patients with SAH undergoing aneurysm repair. Additional investigations examining the effect of inhalational anesthetics on other SAH outcomes such as early brain injury and long-term neurological outcomes are warranted.

Access to high-quality health care, including mental health care, remains a high priority for the Department of Veterans Affairs and civilian health care systems. Increased access to mental health care is associated with improved outcomes, including decreased suicidal behavior. Multiple policy changes and interventions are being developed and implemented to improve access to mental health care. The Perceived Access Inventory (PAI) is a patient-centered questionnaire developed to understand the veteran perspective about access to mental health services. The PAI is a self-report measure that includes 43 items across 5 domains: Logistics (6 items), Culture (4 items), Digital (9 items), Systems of Care (13 items), and Experiences of Care (11 items). This article is a preliminary examination of the concurrent and convergent validity of the PAI with respect to the Hoge Perceived Barriers to Seeking Mental Health Services scale (concurrent) and the Client Satisfaction Questionnaire (CSQ; convergent). Telephone interviews were conducted with veterans from 3 geographic regions. Eligibility criteria included screening positive for posttraumatic stress disorder, alcohol use disorder, or depression in the past 12 months. Data from 92 veterans were analyzed using correlation matrices. PAI scores were significantly correlated with the Hoge total score (concurrent validity) and CSQ scores (convergent validity). The PAI items with the strongest correlation with CSQ were in the Systems of Care domain and the weakest were in the Logistics domain. Future efforts will evaluate validity using larger data sets and utilize the PAI to develop and test interventions to improve access to care. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Objectives: Routine screening for HIV and hepatitis C virus (HCV) among specified age cohorts is recommended. New York State requires consent before screening for HIV but not HCV. We sought to estimate the effect of the consent requirement on screening rates for HIV. Methods: We performed a retrospective study of patients hospitalized in 2015-2016 at a tertiary care hospital in the Bronx, New York, during a period when prompts in the electronic health record facilitated screening for HIV and HCV among specified age cohorts. We compared proportions of patients eligible for screening for HIV and/or HCV who underwent screening and used generalized estimating equations and a meta-analytic weighted average to estimate an adjusted risk difference between undergoing HIV screening and undergoing HCV screening. Results: Among 11 938 hospitalized patients eligible for HIV and/or HCV screening, 38.5% underwent screening for HIV and 59.1% underwent screening for HCV. The difference in screening rates persisted after adjusting for patient and admission characteristics (adjusted risk difference = 22.0%; 95% CI, 20.6%-23.4%). Conclusions: Whereas the requirement for consent was the only difference in the processes of screening for HIV compared with screening for HCV, differences in how the 2 viruses are perceived may also have contributed to the difference in screening rates. Nevertheless, our findings suggest that requiring consent continues to impede progress toward the public health goal of routine HIV screening.

Background Most acute decompensated heart failure admissions are driven by congestion. However, residual congestion is common and often driven by the lack of reliable tools to titrate diuretic therapy. The authors previously developed a natriuretic response prediction equation (NRPE), which predicts sodium output using a spot urine sample collected 2 h after loop diuretic administration. Objectives The purpose of this study was to validate the NRPE and describe proof-of-concept that the NRPE can be used to guide diuretic therapy. Methods Two cohorts were assembled: 1) the Diagnosing and Targeting Mechanisms of Diuretic Resistance (MDR) cohort was used to validate the NRPE to predict 6-h sodium output after a loop diuretic, which was defined as poor ( 150 mmol); and 2) the Yale Diuretic Pathway (YDP) cohort, which used the NRPE to guide loop diuretic titration via a nurse-driven automated protocol. Results Evaluating 638 loop diuretic administrations, the NRPE showed excellent discrimination with areas under the curve ≥0.90 to predict poor, suboptimal, and excellent natriuretic response, and outperformed clinically obtained net fluid loss (p Conclusions Natriuretic response can be rapidly and accurately predicted by the NRPE, and this information can be used to guide diuretic therapy during acute decompensated heart failure. Additional study of diuresis guided by the NRPE is warranted.

Background: Detailed understanding of the immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2, the cause of coronavirus disease 2019 (CO­VID-19) has been hampered by a lack of quantitative antibody assays. Objective: The objective was to develop a quantitative assay for IgG to SARS-CoV-2 proteins that could be implemented in clinical and research laboratories. Methods: The biotin-streptavidin technique was used to conjugate SARS-CoV-2 spike receptor-binding domain (RBD) or nucleocapsid protein to the solid phase of the ImmunoCAP. Plasma and serum samples from patients hospitalized with COVID-19 (n = 60) and samples from donors banked before the emergence of COVID-19 (n = 109) were used in the assay. SARS-CoV-2 IgG levels were followed longitudinally in a subset of samples and were related to total IgG and IgG to reference antigens using an ImmunoCAP 250 platform. Results: At a cutoff of 2.5 μg/mL, the assay demonstrated sensitivity and specificity exceeding 95% for IgG to both SARS-CoV-2 proteins. Among 36 patients evaluated in a post-hospital follow-up clinic, median levels of IgG to spike-RBD and nucleocapsid were 34.7 μg/mL (IQR 18–52) and 24.5 μg/mL (IQR 9–59), respectively. Among 17 patients with longitudinal samples, there was a wide variation in the magnitude of IgG responses, but generally the response to spike-RBD and to nucleocapsid occurred in parallel, with peak levels approaching 100 μg/mL, or 1% of total IgG. Conclusions: We have described a quantitative assay to measure IgG to SARS-CoV-2 that could be used in clinical and research laboratories and implemented at scale. The assay can easily be adapted to measure IgG to mutated COVID-19 proteins, has good performance characteristics, and has a readout in standardized units.

BACKGROUND: Nutrition is a modifiable risk factor for patients undergoing multimodal oncologic interventions and plays a major supportive role in the setting of bladder cancer. For patients undergoing radical cystectomy (RC), malnutrition is associated with increased postoperative complications and mortality. OBJECTIVES: The purpose of this scoping review is to characterize the role of nutritional interventions for patients undergoing RC for bladder cancer. METHODS: A multi-database systematic scoping review based on the Preferred Reporting Items for Systematic Reviews extension for Scoping Reviews (PRISMA-ScR) guidelines was performed. Search terms were developed a priori to identify clinical trials that focused on nutritional interventions for patients with bladder cancer undergoing RC. Eligible articles were original research articles or abstracts from clinical trials evaluating nutritional interventions in adult patients undergoing RC. Articles were excluded if they did not focus on a nutritional intervention, if patients did not carry a diagnosis of bladder cancer, or if RC was not performed. Articles were reviewed independently by the authors, and inclusion/exclusion were based on consensus agreement. RESULTS: A total of 83 articles were identified, of which 17 were included in the final analysis. A total of 49 articles were excluded during abstract screening. An additional 17 articles were excluded based on the review of full-text articles. Results of the scoping review suggest that data on the use of nutritional screening, assessment, and intervention for patients undergoing RC are scarce. Although parenteral nutrition (PN) appears to be associated with greater complications after RC, early introduction of food postoperatively or feeding enterally offers benefit and immunonutrition supplements with a focus on a high protein diet have the potential to better optimize surgical outcomes. CONCLUSIONS: Although the prevalence and consequences of malnutrition among patients undergoing RC are well-established, there are limited data evaluating the use of nutritional screening, assessment, and interventions for this population. The pursuit of future clinical trials in this space is critical.

Monitoring wound progression over time is a critical aspect for studies focused on in-depth molecular analysis or on evaluating the efficacy of potential novel therapies. Histopathological analysis of wound biopsies can provide significant insight into healing dynamics, yet there is no standardized and reproducible scoring system currently available. The purpose of this study was to develop and statistically validate a scoring system based on parameters in each phase of healing that can be easily and accurately assessed using either Hematoxylin & Eosin (H&E) or Masson's Trichrome (MT) staining. These parameters included re-epithelization, epithelial thickness index, keratinization, granulation tissue thickness, remodeling, and the scar elevation index. The initial phase of the study was to (1) optimize and clarify healing parameters to limit investigator bias and variability; (2) compare the consistency of parameters assessed using H&E versus MT staining. During the validation phase of this study, the accuracy and reproducibility of this scoring system was independently iterated upon and validated in four different types of murine skin wound models (Excisional; punch biopsy; pressure ulcers; burn wounds). A total of n = 54 histology sections were randomized, blinded, and assigned to two groups of independent investigators (n = 5 per group) for analysis. The sensitivity of each parameter (ranging between 80% and 95%) is reported with illustrations on the appropriate assessment method using ImageJ software. In the validated scoring system, the lowest score (score:0) is associated with an open/unhealed wound as is evident immediately and within the first day postinjury, whereas the highest score (score:12) is associated with a completely closed and healed wound without excessive scarring. This study defines and describes the minimum recommended criteria for assessing wound healing dynamics using the SPOT skin wound score. The acronym SPOT refers to the academic and scientific institutions that were involved in the development of the scoring system, namely, Stellenbosch University, Polish Academy of Sciences, Obatala Sciences, and the University of Texas Southwestern.

Extracorporeal membrane oxygenation (ECMO) is used to support patients with refractory cardiopulmonary failure. Given ECMO's increased use in adults and the fact that many ECMO patients are cared for by anesthesiologists, the Society of Cardiovascular Anesthesiologists ECMO working group created an expert consensus statement that is intended to help anesthesiologists manage adult ECMO patients who are cared for in the operating room. In the first part of this 2-part series, technical aspects of ECMO are discussed, and related expert consensus statements are provided.

Objective To determine the incidence of hospital readmission in a geriatric hip fracture population within 90 days. Methods Analysis of patients aged ≥60 years presenting with a fragility fracture of the hip from a prospective geriatric hip fracture program registry was performed. Demographics, diagnoses, treatments, complications, hospital events, and readmission for any cause within 30 and 90 days were collected. Readmission events were categorized as defined by Bundled Care Payment Initiative (BCPI)/Care for Joint Replacement payment model. Results The population included 305 patients. All-cause readmission at 30 and 90 days was 11.5% and 19.7%, respectively. Surgical site infection or prosthesis failure accounted for 2.6% of 90 days readmissions. Application of the BCPI rules identified 44 of 60 readmitted patients (73.3%) with causes attributable to the surgical event: medical (0.7%), hospital (12.1%), and mechanical (2.6%). Death within 30 days was the largest contributor to hospital-related events. Conclusions This study identified a 90-day readmission rate of nearly 20% in patients with geriatric fragility fractures. Application of the BCPI definitions currently used in the Care for Joint Replacement payment model will result in more readmissions being attributed to the index surgical event than classically considered. If bundled payment models remain the future, further investigation of this population's risk factors for readmission is needed in light of these findings. Level of evidence Prognostic and Epidemiological Level II. See Instructions for Authors for a complete description of levels of evidence.

Background Tumor mutational burden (TMB) measurements aid in identifying patients who are likely to benefit from immunotherapy; however, there is empirical variability across panel assays and factors contributing to this variability have not been comprehensively investigated. Identifying sources of variability can help facilitate comparability across different panel assays, which may aid in broader adoption of panel assays and development of clinical applications. Materials and methods Twenty-nine tumor samples and 10 human-derived cell lines were processed and distributed to 16 laboratories; each used their own bioinformatics pipelines to calculate TMB and compare to whole exome results. Additionally, theoretical positive percent agreement (PPA) and negative percent agreement (NPA) of TMB were estimated. The impact of filtering pathogenic and germline variants on TMB estimates was assessed. Calibration curves specific to each panel assay were developed to facilitate translation of panel TMB values to whole exome sequencing (WES) TMB values. Results Panel sizes >667 Kb are necessary to maintain adequate PPA and NPA for calling TMB high versus TMB low across the range of cut-offs used in practice. Failure to filter out pathogenic variants when estimating panel TMB resulted in overestimating TMB relative to WES for all assays. Filtering out potential germline variants at >0% population minor allele frequency resulted in the strongest correlation to WES TMB. Application of a calibration approach derived from The Cancer Genome Atlas data, tailored to each panel assay, reduced the spread of panel TMB values around the WES TMB as reflected in lower root mean squared error (RMSE) for 26/29 (90%) of the clinical samples. Conclusions Estimation of TMB varies across different panels, with panel size, gene content, and bioinformatics pipelines contributing to empirical variability. Statistical calibration can achieve more consistent results across panels and allows for comparison of TMB values across various panel assays. To promote reproducibility and comparability across assays, a software tool was developed and made publicly available.

Implantation is a critical step in human reproduction. The success of this step is dependent on a competent blastocyst, receptive endometrium, and successful cross talk between the embryonic and maternal interfaces. Recurrent implantation failure is the lack of implantation after the transfer of several embryo transfers. As the success of in vitro fertilization has increased and failures have become more unacceptable for patients and providers, the literature on recurrent implantation failure has increased. While this clinical phenomenon is often encountered, there is not a universally agreed-on definition—something addressed in an earlier portion of this Views and Reviews. Implantation failure can result from several different factors. In this review, we discuss factors including the maternal immune system, genetics of the embryo and parents, anatomic factors, hematologic factors, reproductive tract microbiome, and endocrine milieu, which factors into embryo and endometrial synchrony. These potential causes are at various stages of research and not all have clear implications or immediately apparent treatment.

INTRODUCTION: The postural instability gait difficulty motor subtype of patients with Parkinson's disease (PIGD-PD) has been associated with more severe cognitive pathology and a higher risk on dementia compared to the tremor-dominant subtype (TD-PD). Here, we investigated whether the microstructural integrity of the cholinergic projections from the nucleus basalis of Meynert (NBM) was different between these clinical subtypes.METHODS: Diffusion-weighted imaging data of 98 newly-diagnosed unmedicated PD patients (44 TD-PD and 54 PIGD-PD subjects) and 10 healthy controls, were analysed using diffusion tensor imaging, focusing on the white matter tracts associated with cholinergic projections from the NBM (NBM-WM) as the tract-of-interest. Quantitative tract-based and voxel-based analyses were performed using FA and MD as the estimates of white matter integrity.RESULTS: Voxel-based analyses indicated significantly lower FA in the frontal part of the medial and lateral NBM-WM tract of both hemispheres of PIGD-PD compared to TD-PD. Relative to healthy control, several clusters with significantly lower FA were observed in the frontolateral NBM-WM tract of both disease groups. Furthermore, significant correlations between the severity of the axial and gait impairment and NBM-WM FA and MD were found, which were partially mediated by NBM-WM state on subjects' attentional performance.CONCLUSIONS: The PIGD-PD subtype shows a loss of microstructural integrity of the NBM-WM tract, which suggests that a loss of cholinergic projections in this PD subtype already presents in de novo PD patients.

Co-use of non-medical opioids (NMO) and methamphetamine is increasing. So too is the use of the psychoactive botanical "kratom," including among people with NMO and methamphetamine use histories. We assessed characteristics associated with respondent groups who reported lifetime methamphetamine and/or kratom use within a nationally representative US sample using 2019 National Survey on Drug Use and Health data from respondents reporting lifetime NMO use (diverted prescription opioids, heroin). Weighted prevalence estimates for demographic, mental health, and substance use outcomes were determined. Logistic regression examined associations between group membership and outcomes. Among this sample of respondents with lifetime NMO use, 67.6% (95% CI = 65.6-69.4%) reported only NMO use; 4.6% (3.9-5.4%) reported NMO+Kratom; 24.7% (22.7-26.7%) reported NMO+Methamphetamine; and 3.2% (2.5-3.9%) reported NMO+Methamphetamine+Kratom. Compared to those in the NMO-only group, the NMO+Kratom group was more likely to report past-year serious mental illness (SMI; OR = 2.27), suicidality (OR = 1.89), and past-month psychological distress (OR = 1.88). The NMO+Methamphetamine+Kratom group was more likely to report past-year SMI (OR = 2.65), past-month psychological distress (OR = 2.06), and unmet mental health needs (OR = 2.03); increased odds for drug injection, opioid withdrawal, and perceived treatment need also emerged. Risk factors were observed for all groups but were greatest among those reporting use of all three substances.

Background The ability of antituberculosis drugs to cross the blood–brain barrier and reach the central nervous system is critical to their effectiveness in treating tuberculosis meningitis (TBM). We sought to fill a critical knowledge gap by providing data on the ability of new and repurposed antituberculosis drugs to penetrate into the cerebrospinal fluid (CSF). Methods We conducted a clinical pharmacology study among patients treated for TBM in Tbilisi, Georgia, from January 2019 until January 2020. Serial serum and CSF samples were collected while patients were hospitalized. CSF was collected from routine lumbar punctures with the timing of the lumbar puncture alternating between 2 and 6 hours to capture early and late CSF penetration. Results A total of 17 patients treated for TBM (8 with confirmed disease) were included; all received linezolid, with a subset receiving cycloserine (5), clofazimine (5), delamanid (4), and bedaquiline (2). All CSF measurements of bedaquiline (12), clofazimine (24), and delamanid (19) were below the limit of detection. The median CSF concentrations of cycloserine at 2 and 6 hours were 15.90 and 15.10 µg/mL with adjusted CSF/serum ratios of 0.52 and 0.66. CSF concentrations of linezolid were 0.90 and 3.14 µg/mL at 2 and 6 hours, with adjusted CSF/serum ratios of 0.25 and 0.59, respectively. CSF serum linezolid concentrations were not affected by rifampin coadministration. Conclusions Based on moderate to high CSF penetration, linezolid and cycloserine may be effective drugs for TBM treatment, whereas the utility of bedaquiline, delamanid, and clofazimine is uncertain given their low CSF penetration.

In the second part of the Society of Cardiovascular Anesthesiologists Extracorporeal Membrane Oxygenation (ECMO) working group expert consensus statement, venoarterial (VA) and venovenous (VV) ECMO management and troubleshooting in the operating room are discussed. Expert consensus statements are provided about intraoperative monitoring, anesthetic drug dosing, and management of intraoperative problems in VA and VV ECMO patients.

Objective: Inhalant abuse has been a source of increasing concern because of its easy accessibility and affordability. Anecdotal reports have previously described ethyl chloride as a potential cause of altered mental state and neurologic symptoms. Its use has been thought to be found most often in adolescents and among men who have sex with men. Common acute symptoms include confusion, dizziness, headache, nausea, and fatigue. We describe two cases of adult patients who presented to one general hospital emergency department with ethyl chloride toxicity. The first presented with acute delirium; the second with a picture of chronic neurological symptomatology. It is important that clinicians become familiar with ethyl chloride intoxication because of its prevalence and potential to present with varying acute and chronic symptomatology.

PurposeTo investigate the characteristics and rate of central visual field loss after optic disc hemorrhage (DH).DesignProspective cohort study.MethodsThree hundred forty-three eyes of 220 subjects who had ≥3 years of follow-up with a minimum of 5 visits with 10-2 and 24-2 visual field (VF) were recruited. Rates of 10-2 mean deviation (MD) loss in each hemifield and predefined zones were compared using linear mixed-effects models in DH and non-DH eyes. Clustered pointwise regression analysis was also used to define central VF progressors and compared with 24-2 VF loss using guided progression analysis.ResultsThirty-nine eyes with DH and 304 eyes without DH had a mean follow-up of 5.2 years. Eyes with DH had rates of 10-2 MD loss that were 3 times faster than non-DH eyes (mean difference -0.36 dB/year [95% confidence interval 0.54-0.18]; P < .001) and were 3.7 times more likely to progress (P=.002). A larger proportion of glaucomatous eyes showed central VF progression rather than peripheral VF progression in the DH group (30.8% vs. 20.5%) compared with the non-DH group (10.9% vs. 9.2%). In early glaucoma, the rate of 10-2 MD loss was 5.5 times faster in DH eyes than in non-DH eyes (P < .001). Superonasal and superotemporal central VF regions progressed more rapidly than other regions, especially in DH eyes.ConclusionCentral VF loss is accelerated in glaucoma eyes with DH and it corresponds topographically to the DH location. In patients with glaucoma with DH, one should consider supplementing 10-2 VFs with 24-2 VFS to monitor the disease.

Background and study aims The aim of this study was to assess long-term clinical outcomes beyond 6 years in patients who underwent per-oral endoscopic myotomy (POEM) for the treatment of achalasia. Patients and methods Patients with achalasia who underwent POEM between 2010 and 2012 and had follow-up of at least 6 years were retrospectively identified at eight tertiary care centers. The primary outcome evaluated was clinical success defined by an Eckardt symptom score (ESS) ≤ 3 for the duration of the follow-up period. The clinical success cohort was compared to failure (ESS > 3 at any time during follow-up) in order to identify characteristics associated with symptom relapse. The incidence of patient-reported gastroesophageal reflux (GER) was also evaluated. Results Seventy-three patients with 6-year follow-up data were identified. Sustained clinical remission was noted in 89 % (65/73) at 6-years. Mean ESS decreased from 7.1 ± 2.3 pre-procedure to 1.1 ± 1.1 at 6 years (P Conclusions In patients with achalasia, POEM provides high initial clinical success with excellent long-term outcomes. There are high rates of patient-reported gastroesophageal reflux post-procedure which persist at long-term follow-up.

Localized cartilage lesions in early osteoarthritis and acute joint injuries are usually treated surgically to restore function and relieve pain. However, a persistent clinical challenge remains in how to repair the cartilage lesions. We expressed doublecortin (DCX) in human adipose-derived stromal/stem cells (hASCs) and engineered hASCs into cartilage tissues using an in vitro 96-well pellet culture system. The cartilage tissue constructs with and without DCX expression were implanted in the knee cartilage defects of rabbits (n = 42) and monkeys (n = 12). Cohorts of animals were euthanized at 6, 12, and 24 months after surgery to evaluate the cartilage repair outcomes. We found that DCX expression in hASCs increased expression of growth differentiation factor 5 (GDF5) and matrilin 2 in the engineered cartilage tissues. The cartilage tissues with DCX expression significantly enhanced cartilage repair as assessed macroscopically and histologically at 6, 12, and 24 months after implantation in the rabbits and 24 months after implantation in the monkeys, compared to the cartilage tissues without DCX expression. These findings suggest that hASCs expressing DCX may be engineered into cartilage tissues that can be used to treat localized cartilage lesions.

Objectives Both combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have demonstrated encouraging efficacy for treatment of non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study (NCT02944396) evaluated the quadruple combination of veliparib with nivolumab and doublet CT in patients with unresectable advanced/metastatic NSCLC. Materials and Methods Patients were enrolled into five dosing cohorts: patients received veliparib 120 mg twice daily (BID) combined with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and paclitaxel 200 mg/m2 (C/PAC) or veliparib 80/120/200/240 mg BID in combination with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and pemetrexed 500 mg/m2 (C/PEM). Primary objective was to identify the recommended phase 2 dose (RP2D) of veliparib + nivolumab + CT. Safety, tolerability, and efficacy of this combination were also assessed. Results Twenty-five patients were enrolled: 6 patients received veliparib 120 mg BID + nivolumab + C/PAC and 19 received veliparib (80–240 mg BID) + nivolumab + C/PEM. No dose-limiting toxicities were reported, and the RP2Ds were veliparib 120 mg BID + nivolumab + C/PAC, and veliparib 240 mg BID + nivolumab + C/PEM. The most common any-grade adverse events (AEs) were fatigue (56%), nausea (52%), and anemia (48%). Grade 3/4 AEs included anemia (32%) and neutropenia (24%), and the most frequent serious AE was malignant neoplasm progression (12%). Veliparib exhibited approximately dose proportional kinetics in the dose range 80–240 mg BID combined with nivolumab and C/PEM, with no effects on pemetrexed pharmacokinetics. Overall, the confirmed objective response rate was 40%, and best overall response was 64%. Conclusion Veliparib combined with nivolumab and platinum doublet CT was tolerated in patients with advanced/metastatic NSCLC, and no evidence of drug–drug interaction was observed. Although preliminary, this quadruple therapy may have promising antitumor activity.

Excessive, chronic alcohol consumption can lead to alcoholic liver disease. The etiology of alcoholic liver disease is multifactorial and is influenced by alterations in gene expression and changes in fatty acid metabolism, oxidative stress, and insulin resistance. These events can lead to steatosis, fibrosis, and eventually to cirrhosis and liver cancer. Many of these functions are regulated by peroxisome proliferator-activated receptors (PPARs). Thus, it is not surprising that PPARs can modulate the mechanisms that cause alcoholic liver disease. While the roles of PPARα and PPARγ are clearer, the role of PPARβ/δ in alcoholic liver disease requires further clarification. This review summarizes the current understanding based on recent studies that indicate that PPARβ/δ can likely be targeted for the treatment and/or the prevention of alcoholic liver disease.

Background The amounts of circulating cell-free DNA (cfDNA) and circulating-tumor DNA (ctDNA) present in peripheral blood liquid biopsies can vary due to preanalytic/analytic variables. In this study, we examined the impact of patient age, sex, stage, and tumor type on cfDNA yield, ctDNA fraction, and estimated ctDNA quantity from a large cohort of clinical liquid biopsy samples. Methods We performed a retrospective analysis of 12 139 consecutive samples received for liquid biopsy (FoundationOne® Liquid) clinical testing. Results Significant differences in both cfDNA yield and estimated ctDNA quantity were observed based on the underlying tumor type that initiated the liquid biopsy analysis and the stage of the patient (P Conclusions In this study, we show that ctDNA quantity varied significantly based on patient age, sex, stage, and tumor type, which could offer an explanation as to why certain liquid biopsy specimens are more likely to fail sequencing or provide clinically meaningful results. In addition, this could affect future clinical decisions on the blood sample volumes required to allow successful liquid biopsy testing.

Background Although lesion transmurality is required for durable pulmonary vein isolation, excess ablation is associated with increased risk of complications. Objective We sought to understand the impact of interrupted radiofrequency (RF) delivery conditions on lesion characteristics in the atrial free wall. Methods Thirty-three (11 left atrial, 22 right atrial) RF ablation lesions were created in the atria of 6 swine using power control mode (25 W, target contact force 15 g) with 1 of 3 conditions: 15 seconds ablation (n = 8), 30 seconds ablation (n = 14), or 2 15-second ablations at the same site separated by a 2-minute interruption (15 seconds × 2) (n = 11). Results Thirty of 33 lesions were transmural. Rates of transmurality (P = .45) and endocardial lesion width (5.6 ± 1.2 mm, P = .70) were similar between conditions. Mean tissue thickness was 1.7 ± 0.8 mm for transmural lesions. Wide variability in bipolar electrogram attenuation was observed across and within conditions and there were no significant between-group differences. Although impedance reductions were numerically greater in the 30-second and 15-second × 2 conditions (-14.6 ± 6.6 ohms and -14.0 ± 4.4 ohms, respectively) compared to the 15-second condition (-10.3 ± 6.4 ohms), variability was large, and differences were not statistically significant (P = .243). Impedance changes after ablation were largely transient. Conclusion A single 15-second ablation at 25 W (target contact force of 15 g) with good stability produced similarly sized lesions compared to 30-second ablations and 2 15-second ablations at the same site in atrial free wall tissue. These data suggest over-ablation in the atria is common, larger-diameter lesions may require greater power, and many clinically available parameters of lesion size may be unreliable on the posterior wall.

Introduction A high tumor mutational burden (TMB) (≥10 mut/Mb) has been associated with improved clinical benefit in non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI) and is a tumor agnostic indication for pembrolizumab across tumor types. We explored whether combining TMB with programmed cell death ligand 1 (PD-L1) and pretreatment neutrophil-lymphocyte ratio (NLR) was associated with improved outcomes in ICI-treated NSCLC. Methods We retrospectively analyzed patients treated with ICI with Foundation One genomic testing, including TMB. Optimal cutoff for prediction of response by TMB was determined by receiver operating characteristic analysis, and area under the curve (AUC) was calculated for all 3 biomarkers and combinations. Cox model was used to assess prognostic factors of overall survival (OS) and time to progression (TTP). Survival cutoffs calculated with Kaplan-Meier survival curves were TMB ≥10 mut/Mb, PD-L1 ≥50%, NLR Results Data from 88 patients treated were analyzed. The optimal TMB cutoff was 9.24 mut/Mb (AUC, 0.62), improving to 0.74 combining all 3 biomarkers. Adjusted Cox model showed that TMB ≥10 mut/Mb was an independent factor of OS (hazard ratio [HR], 0.31; 95% confidence interval; 0.14-0.69; P = .004) and TTP (HR, 0.46; 95% CI, 0.27-0.77; P = .003). The combination of high TMB with positive PD-L1 and low NLR was significantly associated with OS (P = .038) but not TTP. Conclusions TMB has modest predictive and prognostic power for clinical outcomes after ICI treatment. The combination of TMB, PD-L1, and NLR status improves this power.

OBJECTIVE: Emergency departments (EDs) are well positioned to deliver suicide prevention services. This study examined hospital and community correlates of recommended practices. METHOD: This study examined results from a national survey of ED nursing directors (N=513) focusing on hospital- and community-level variation in the routine provision of four recommended practices: suicide risk screening, access to means assessment, safety planning, and follow-up referrals. RESULTS: Few significant differences existed between hospitals that routinely provided these practices and hospitals that did not. Routine scheduling of follow-up appointments was associated with presence of formal contractual relationships with outpatient mental health facilities (p=0.005). Routine provision of safety planning was associated with higher levels of psychiatrist or psychologist staffing (p=.03). DISCUSSION: There were few differences in the hospital and community characteristics between EDs that routinely provided recommended care and those that did not, suggesting few structural barriers to implementation of these recommended services for high-risk ED patients.

Introduction There are insufficient data on surface mold brachytherapy (SMB) in treating oral cancers. We reviewed our institutional experience to investigate the efficacy and toxicity of this treatment modality. Material and methods We retrospectively reviewed all the patients treated between 1989 and 2018 with high-dose-rate iridium-192 SMB for oral and oropharyngeal squamous cell carcinomas at our institution. Surface mold brachytherapy was delivered via an acrylic surface mold with 1–5 inserted catheters spaced 1 cm apart fabricated by our dental oncologist. The Kaplan-Meier product estimator was used to assess local control (LC), locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS). Cox proportional hazards regression analysis was used to assess the relationship of various variables and patient outcomes. Results Eighteen patients met the inclusion criteria and were evaluated. Indications for treatment were primary tumor (n = 13), local recurrence (2), locoregional recurrence (1), and oligometastatic disease (1). Ten patients received SMB alone and 8 received external beam radiotherapy with an SMB boost. The acute toxicity outcomes were as follows: no toxicity (n = 1), grade 1 (7), grade 2 (9), and grade 3 (1). Late effects were rare, only occurring in 3 patients. The one- and two-year LC were 81% and 68%, LRC 77% and 64%, DMFS 81% and 81%, and OS 77% and 46%. Conclusions Surface mold brachytherapy is a viable modality as either primary or boost treatment for superficial oral cancers. In our patients, this treatment method has a low toxicity profile and resulted in reasonable LC.