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There is a paucity of literature evaluating new-onset diabetes mellitus (NODM) after resection of pancreatic cystic lesions (PCLs). We sought to characterize the incidence and risk factors associated with NODM after partial pancreatectomy for PCLs.We utilized the IBM MarketScan Database (2012-2018) to identify all nondiabetic adults who underwent partial pancreatectomy for PCLs. Patients with any other pancreatic disease were excluded. We performed Kaplan-Meier analysis and multivariable Cox proportional hazards regression to define the incidence and risk factors of postoperative NODM.Among 311 patients, the overall risk (95% confidence interval) of NODM was 9.1% (6.3-12.9%), 15.1% (11.3-20.2%), and 20.2% (15.3-26.4%) at 6, 12 and 24 months, respectively. Multivariable analysis (adjusted hazard ratio; 95% confidence interval) revealed that older age (1.97; 1.04-3.72; 55-64 vs 18-54 years), obesity (2.63; 1.35-5.12), hypertension (1.79; 1.01-3.17), and cardiovascular disease (2.54; 1.02-6.28) were independent predictors of NODM. Rates of NODM were similar after distal pancreatectomy versus pancreaticoduodenectomy.Within 2 years, 1 in 5 patients without any other pancreatic disease will develop NODM after partial pancreatectomy for PCLs. Those with advanced age, metabolic syndrome features, and/or cardiovascular disease may benefit from preoperative counseling and intensive postoperative monitoring, education, and treatment for diabetes mellitus.

Background and Aims : EUS-guided needle-based confocal laser endomicroscopy (nCLE) improves the diagnostic accuracy of pancreatic cystic lesions (PCLs) but concerns regarding its expense have limited widespread adoption of this technology. We conducted a cost-benefit analysis to assess the healthcare resource implications of adding EUS-nCLE to the standard of care (SOC) management of PCLs. Methods : A post-hoc analysis of a prospective study (2015-2018) evaluating EUS-nCLE for the diagnosis of PCLs was performed. The SOC diagnosis was based on clinical history, PCL morphology, and cyst fluid analysis. A minimum of 5-years of surveillance was included, the cost of EUS and MRI/MRCP was derived from institutional billing data (US$), and the total hospital costs (adjusted for inflation) for pancreatic operations were derived from the National (US) Readmission Database. Results : A reference diagnosis was available in 93 subjects (mean cyst size=36.4±15.7 mm; surgical histopathology, n=67 and diagnostic molecular markers in cyst fluid, n=26). SOC and nCLE were discordant in 13 (14%) subjects. The addition of nCLE led to 11 subjects being clinically downstaged from mucinous to non-mucinous not warranting surgery (total cost savings= $1,080,418), 1 subject upstaged from non-mucinous to mucinous, warranting surgical resection (cost savings of 5-years surveillance: $46,200), and 1 subject incorrectly classified as non-mucinous (cost excess of 5-years surveillance: $46,200). Overall, the addition of nCLE led to a net savings of $ 442,438 (mean: $ 4,757.40 /patient) for this cohort. Conclusions : EUS-nCLE is potentially cost-beneficial in the management of PCLs (≥ 3 cm) by preventing at least one unnecessary pancreatic surgery for every ten subjects undergoing evaluation by current practices. ClinicalTrials.gov number: NCT02516488.

Background The impact of sleep disordered breathing (SDB) on heart failure (HF) is increasingly recognized. However, limited data exist in support of quantification of the clinical and financial impact of SDB on HF hospitalizations. Methods A sleep-heart registry included all patients who underwent inpatient sleep testing during hospitalization for HF at a single cardiac center. Readmission data and actual costs of readmissions were obtained from the institutional honest broker. Patients were classified based on the inpatient sleep study as having no SDB, obstructive sleep apnea (OSA), or central sleep apnea (CSA). Cumulative cardiac readmission rates and costs through 3 and 6 months post-discharge were calculated. Unadjusted and adjusted (age, sex, body mass index, and left ventricular ejection fraction) modeling of cost was performed. Results The cohort consisted of 1547 patients, 393 (25%) had no SDB, 438 (28%) had CSA, and 716 (46%) had OSA. Within 6 months of discharge, 195 CSA patients (45%), 264 OSA patients (37%), and 109 no SDB patients (28%) required cardiovascular readmissions. Similarly, 3- and 6-month mortality rates were higher in both SDB groups than those with no SDB. Both unadjusted and adjusted readmission costs were higher in the OSA and CSA groups compared to no SDB group at 3 and 6 months post-discharge with the CSA and OSA group costs nearly double (~ $16,000) the no SDB group (~ $9000) through 6 months. Interpretation Previously undiagnosed OSA and CSA are common in patients hospitalized with HF and are associated with increased readmissions rate and mortality.

Background Central sleep apnea (CSA) is associated with increased mortality and morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Treatment of CSA with a certain type of adaptive servo-ventilation (ASV) device that targets minute ventilation (ASVmv) was found to be harmful in these patients. A newer generation of ASV devices that target peak flow (ASVpf) is presumed to have different effects on ventilation and airway patency. We analyzed our registry of patients with HFrEF-CSA to examine the effect of exposure to ASV and role of each type of ASV device on mortality. Methods This is a retrospective cohort study in patients with HFrEF and CSA who were treated with ASV devices between 2008 and 2015 at a single institution. Mortality data were collected through the institutional data honest broker. Usage data were obtained from vendors’ and manufacturers’ servers. Median follow-up was 64 months. Results The registry included 90 patients with HFrEF-CSA who were prescribed ASV devices. Applying a 3-h-per-night usage cutoff, we found a survival advantage at 64 months for those who used the ASV device above the cutoff (n = 59; survival 76%) compared to those who did not (n = 31; survival 49%; hazard ratio 0.44; CI 95%, 0.20 to 0.97; P = 0.04). The majority (n = 77) of patients received ASVpf devices with automatically adjusting end-expiratory pressure (EPAP) and the remainder (n = 13) received ASVmv devices mostly with fixed EPAP (n = 12). There was a trend towards a negative correlation between ASVmv with fixed EPAP and survival. Conclusion In this population of patients with HFrEF and CSA, there was no evidence that usage of ASV devices was associated with increased mortality. However, there was evidence of differential effects of type of ASV technology on mortality.

Purpose Clinically severe obesity (SO) is a known risk factor for worsened outcomes and recurrence of acute diverticulitis. Paucity of data exist on outcomes of diverticulitis after bariatric surgery. Methods The Nationwide Readmissions Database was queried for diverticulitis hospitalizations between the years 2010 and 2014. We restricted analysis to patients with SO and those who had bariatric surgery (BRS). Outcomes of mortality, surgical events, and recurrent diverticulitis admissions were compared using multivariable analysis and one-to-one propensity score matching. Results Among 52,274 diverticulitis admissions, 91.2% (47,694) patients had SO and 8.8% (4580) had prior BRS. Patients with SO had higher odds of suffering mortality on index diverticulitis admission when compared to those with prior BRS [adjusted odds ratio (aOR): 10.55; 95%CI 1.45,76.75]. Patients with SO were also more likely to undergo emergency surgery (aOR: 1.71; 95%CI 1.25,2.34) and colectomy (aOR: 1.45; 95%CI 1.26,1.68). Rates of recurrent diverticulitis readmissions within 30 days and 6 months were also higher in patients with SO compared to BRS patients (aOR: 7.94; 95%CI 1.09,57.83 and aOR: 1.98; 95%CI 1.14,3.43, respectively). Propensity score matching confirmed our findings of increased rates of mortality (OR: 17.28; 95%CI 2.02,147.6), recurrent diverticulitis, and worsened surgical outcomes within 30 days in patients with SO compared to BRS. Conclusion This study is first to show improved outcomes and less recurrent hospitalizations for diverticulitis after bariatric surgery compared to patients with clinically severe obesity. Further studies are needed to understand mechanisms leading to this improvement and the role of weight loss in prevention of severe diverticulitis.

Introduction Acute pancreatitis (AP) occurs among patients with pancreas-sufficient cystic fibrosis (PS-CF) but is reportedly less common among patients with pancreas-insufficient cystic fibrosis (PI-CF). The incidence of AP may be influenced by cystic fibrosis transmembrane conductance regulator (CFTR) modulator use. We hypothesized that CFTR modulators would reduce AP hospitalizations, with the greatest benefit in PS-CF. Methods MarketScan (2012-2018) was queried for AP hospitalizations and CFTR modulator use among patients with CF. Multivariable Poisson models that enabled crossover between CFTR modulator treatment groups were used to analyze the rate of AP hospitalizations on and off therapy. Pancreas insufficiency was defined by the use of pancreas enzyme replacement therapy. Results A total of 10,417 patients with CF were identified, including 1,795 who received a CFTR modulator. AP was more common in PS-CF than PI-CF (2.9% vs 0.9%, P = 0.007). Overall, the observed rate ratio of AP during CFTR modulator use was 0.33 (95% confidence interval [CI] 0.10, 1.11, P = 0.07) for PS-CF and 0.38 (95% CI 0.16, 0.89, P = 0.03) for PI-CF, indicating a 67% and 62% relative reduction in AP hospitalizations, respectively. In a subset analysis of 1,795 patients who all had some CFTR modulator use, the rate ratio of AP during CFTR modulator use was 0.36 (95% CI 0.13, 1.01, P = 0.05) for PS-CF and 0.53 (95% CI 0.18, 1.58, P = 0.26) for PI-CF. Discussion CFTR modulator use is associated with a reduction in AP hospitalizations among patients with CF. These observational data support the prospective study of CFTR modulators to reduce AP hospitalizations among patients with CF.

Introduction Despite the increasing availability of advanced endoscopic resections and its favorable safety profile, surgery for nonmalignant colorectal polyps has continually increased. We sought to evaluate readmission rates and outcomes of elective surgery for nonmalignant colorectal polyps on a national level in the United States. Methods The Nationwide Readmissions Database (2010-2014 [International Classification of Diseases, Ninth Revision] and 2016-2018 [International Classification of Diseases, 10th Revision]) was used to identify all adult subjects (age ≥18 years) who underwent elective surgical resection of nonmalignant colorectal polyps. Multivariable analyses were performed for predictors of postoperative morbidity and 30-day readmission. Results Elective surgery for nonmalignant colorectal polyps was performed in 108,468 subjects from 2010 to 2014 and in 54,956 subjects from 2016 to 2018, most of whom were laparoscopic. Postoperative morbidity and 30-day readmission rates were 20.5% and 8.5% from 2010 to 2014, and 13.0% and 7.6% from 2016 to 2018, respectively. Index admission mortality rates were 0.3-0.4%; mortality rates were higher in those with postoperative morbidity. Multivariable analyses revealed that male sex, ≥3 comorbidities, insurance status, and open surgery predicted an increased risk of both postoperative morbidity and 30-day readmission. In addition, postoperative morbidity (2010-2014 [odds ratio 1.58; 95% confidence interval 1.44-1.74] and 2016-2018 [odds ratio 1.55; 95% confidence interval 1.37-1.75]) predicted early readmission. Discussion In this investigation of national practices, elective surgery for nonmalignant colorectal polyps remains common. There is considerable risk of adverse postoperative outcomes, which highlights the importance of increasing awareness of the range of endoscopic resections and referring subjects to expert endoscopy centers.

In recent years, internal, two-phase, flow-induced vibration (FIV) has received elevated attention in various fields while assessing piping system fatigue life. Regarding the oil and gas industry, in particular, assessing FIV impact is essential for ensuring the integrity of flow lines, both onshore and offshore.This study conducted a series of experimental tests at various superficial gas and liquid velocities to investigate the effects of flow parameters on the structural dynamics of a horizontal 6-inch ID polycarbonate test section. The relationship between flow characteristics and the structural response was examined in detail. A novel methodology was developed and implemented to achieve non-intrusive, simultaneous measurement of pipe motion and liquid distribution.The presented results reveal that downward deflection generally decreased with increasing superficial gas velocity and increased with increasing superficial liquid velocity. It was also found that as superficial gas velocity increased, the range of frequencies experienced by the test section increased, with increased participation from higher frequencies in the range. Film and slug body liquid holdups are strongly related to the observed deflection amplitudes.

Purpose : The aim of the study is to determine whether initiating vasopressin earlier in septic shock reduces organ dysfunction and in-hospital all-cause mortality. Methods : This multicenter, retrospective, cohort study evaluated patients admitted to the medical intensive care unit between October 2011 and August 2018 with septic shock who received vasopressin within 48 hours of shock onset. The primary composite outcome was the proportion of patients with a change in the Sequential Organ Failure Assessment score greater than 3 from baseline to 72 hours after initiation of vasopressin and/or in-hospital all-cause mortality. Secondary outcomes included time to hemodynamic stability, acute kidney injury, and intensive care unit length of stay. Results : A total of 385 patients included in the final evaluation with a mean Acute Physiology and Chronic Health Evaluation II score of 31 and a mean baseline Sequential Organ Failure Assessment score of 13. Median time to initiation of vasopressin after norepinephrine was 7.3 hours. The primary composite outcome was significantly reduced in patients who had vasopressin initiated earlier in septic shock (odds ratio = 1.08, 95% confidence interval = 1.03-1.13, Plt; 0.001). After controlling for baseline data in a multivariable regression model the primary outcome remained statistically significant (odds ratio = 1.04, 95% confidence interval = 1.02-1.07, P = 0.001). Conclusions : Early initiation of vasopressin in septic shock may reduce the risk of in-hospital all-cause mortality and/or organ dysfunction.

Background Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. Recent advances in immunotherapy have resulted in the development of chimeric antigen receptor–modified T-cell (CAR-T) therapy, such as axicabtagene ciloleucel (axi-cel). However, axi-cel administration is not without risks of toxicity. Patients and Methods This retrospective study of 37 patients with relapsed or refractory diffuse large B-cell lymphoma evaluated the incidence and severity of common and severe safety events after axi-cel treatment in a real-world setting. Ninety percent of patients had received 3 or more prior lines of therapy (median prior therapies 3, range 2-7) before receiving CAR-T therapy, and 32.4% had relapsed after prior stem-cell transplantation. Results All but one patient experienced cytokine release syndrome (CRS) of any grade (97.3%). Of those 36 patients, 83.3% experienced maximum CRS grade of 1 or 2, occurring after a median of 27 hours and persisting for a median of 6 days. Twenty-seven patients (73.0%) experienced neurotoxicity of any grade. Of those 27 patients, 96.3% experienced maximum neurotoxicity grade of 2 or higher, occurring after a median of 145 hours (6 days) and persisting for a median of 7 days. All 10 patients aged 65 or older had neurotoxicity of grade 2 or higher, compared to 59.3% (11/27) under age 65 (P = .02). Patients with baseline Eastern Cooperative Oncology Group performance status score of 2 were significantly more likely to have shorter time to neurotoxicity compared to patients with performance status of 0 (P = .01). Conclusion With more real-life experience and data, we will be able to define and refine management of toxicities unique to CAR-T therapy.

Background 18 F‐Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) positive (PET+) cytologically indeterminate thyroid nodules (ITNs) have variable cancer risk in the literature. The benign call rate (BCR) of Afirma Gene Classifier (Gene Expression Classifier, GEC, or Genome Sequence Classifier, GSC) in (PET +) ITNs is unknown. Methods This is a retrospective study at our institution of all patients with (PET+) ITNs (Bethesda III/IV) from 1 January 2010 to 21 May 2019 who underwent Afirma testing and/or surgery or repeat FNA with benign cytology. Results Forty‐five (PET+) ITNs were identified: 31 Afirma‐tested (GEC = 20, GSC = 11) and 14 either underwent surgery (n = 13) or repeat FNA (Benign cytology) (n = 1) without Afirma. The prevalence of cancer and noninvasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP) including only resected nodules and ITN with repeat benign FNA (n = 33) was 36.4% (12/33). Excluding all Afirma “suspicious” non‐resected ITNs and assuming all Afirma “benign” ITNs were truly benign, that prevalence was 28.6% (12/42). The BCR with GSC was 64% compared to 25% with GEC (p = 0.056). Combining GSC/GEC‐tested ITNs, the BCR was higher in ITNs demonstrating low/very low‐risk sonographic pattern by the American Thyroid Association (ATA) classification and ITNs scoring, In this study, the prevalence of cancer and noninvasive follicular thyroid neoplasm with papillary‐like nuclear features in PET positive cytologically indeterminate thyroid nodules was 28.6–36.4% depending on the method of calculation. The benign call rate of Afirma GSC in these nodules was 64%. When combining Afirma GEC/GSC tested PET positive cytologically indeterminate thyroid nodules, the benign call rate was higher in nodules with a lower risk sonographic pattern.

Background EUS-guided needle-based confocal laser endomicroscopy (nCLE) has not been widely adopted for the differentiation of pancreatic cystic lesions (PCLs), perhaps due to a perceived difficulty in learning novel CLE image patterns. Hence, we sought to investigate the optimal teaching modality for interpretation of nCLE imaging from PCLs. Methods Sixteen nCLE-naive observers blinded to clinical data were randomized into didactic (classroom-based) versus self-directed (computer-based) teaching groups to review nCLE videos and differentiate mucinous and non-mucinous PCLs. The study was conducted concurrently for both groups in 3 phases. Phase-1-Teaching: both groups received an overview of EUS-nCLE of PCLs. Phase-2-Training: assessment of 20 EUS-nCLE subject-videos; the didactic group had a feedback session with an nCLE expert while the self-directed group received this information via pre-recorded presentation. Phase-3-Testing: assessment of 50 EUS-nCLE subject-videos. Results For all observers (n = 16), the diagnostic accuracy for nCLE-based differentiation of mucinous from non-mucinous PCLs was higher (p=0.005) in the Phase-3-Testing (94.6%, 95%CI: 92-96%) than in Phase-2-Training (89.9%, 95%CI: 85-93%). During Phase-3-Testing, both the didactic and self-directed teaching groups achieved a comparable (p=0.48) diagnostic accuracy of 93.9% and 95.4%, respectively. The interobserver agreement (kappa, standard error) for the differentiation of mucinous from non-mucinous PCLs improved from Phase-2-Training to Phase-3-Testing stage, and was “substantial” for both the didactic (k=0.81, 0.03) and self-directed (k=0.79, 0.03) training groups. Conclusion Notwithstanding didactic and self-directed teaching, a ‘training’ and ‘test’ strategy accomplished high diagnostic accuracies and considerable interobserver agreement among naive observers for EUS-nCLE image differentiation of PCLs; Clinical trial NCT02516488 ( https://clinicaltrials.gov/ct2/show/NCT02516488 )

Chronic pancreatitis (CP) is a progressive disease that leads to eventual loss of endocrine and exocrine function. Total pancreatectomy and islet autotransplantation (TPIAT) is a treatment option for patients with CP; however, predicting postoperative metabolic outcomes remains elusive. In this single-center retrospective study, we report pre-TPIAT characteristics, beta cell function indices, islet yield, and post-TPIAT glucose management data to further understand their relationship. Islet yield, glucose level, and insulin requirement for 72 hours postoperatively were collected for a total of 13 TPIAT recipients between 9-2013 and 9-2018. In addition, their glucose control and basal insulin requirements at 3, 6, and 12 months post-TPIAT were analyzed. All 13 subjects had normal baseline fasting glucose levels. Median islet yield was 4882 IEq/kg (interquartile range 3412 to 8987). Median postoperative total insulin requirement on day 3 was 0.43 units/kg. Pre-TPIAT baseline glucose, insulin, or c-peptide level did not have a significant correlation with the islet yield. Similarly, there was no correlation between islet yield and insulin requirement at 72-hour postoperatively. However, there was an inverse correlation between the absolute islet yield (IEq) and insulin requirement at 6 months and 12 months following post-TPIAT. Further analysis of the relationship between 72-hour post-op insulin requirement and insulin requirement at discharge, 3, 6, and 12 months showed a positive correlation. Despite the finding of inverse correlation of islet yield with long-term basal insulin requirement, this study was not able to detect a correlation between the preoperative parameters to postoperative short-term or long-term outcome as noted in other studies. The 72-hour postoperative insulin requirement is a helpful postoperative predictor of patients needing long-term insulin management following TPIAT. This observation may identify a high-risk group of patients in need of more intensive diabetes education and insulin treatment prior to hospital discharge.

Aims and Objectives: Takotsubo cardiomyopathy (TCMP) is an acquired cardiomyopathy associated with physical, emotional, and surgical stress. Current literature on TCMP in liver transplant recipients (LTRs) is limited to case reports and case series. Methods: The Nationwide Readmission Database was utilized to identify all adults with an index admission for LT between 2010 and 2014 who developed TCMP. The prevalence of TCMP at the LT admission or readmission within the calendar year was examined. Predictors of development and health-care utilization of patients with and without TCMP in LTR were compared. Multivariable regression analysis was performed. Results: The prevalence of TCMP in LTRs was found to be 0.5% (141/28,067). Most of these patients developed early TCMP on the index admission for LT (n = 115; 82%). Older (57.5 ± 1.3 vs. 55.1 ± 0.3 years, P < 0.001) females (adjusted odds ratio [aOR]: 2.27; confidence interval [CI]: 1.20–4.27; P = 0.01) with ≥4 Elixhauser comorbidity (aOR: 2.36; CI: 1.15–4.83; P = 0.02) were predisposed to develop TCMP in LTRs. LT at a medium-sized center (aOR: 0.17; CI: 0.03–0.88) has a protective effect on the development of TCMP. Increased health-care utilization in the form of mechanical ventilation, hemodialysis, vasopressors, and intra-aortic balloon pumps is observed in patients with TCMP. This resulted in increased length of stay and cost in patients with TCMP. Moreover, increased mortality was seen in patients who developed TCMP within the same calendar year. Conclusion: This is the first report showing the prevalence of TCMP in LTRs to be 0.5%. Older females with increased comorbidity are predisposed to TCMP. Patients who developed TCMP necessitate a higher acuity of medical care and cause an increased health-care burden and ultimately experience an increase in mortality.

Colorectal cancer incidence is rising in adults

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased mortality and readmissions in patients with heart failure (HF). The effect of in-hospital diagnosis and treatment of OSA during decompensated HF episodes remains unknown. METHODS: A single site randomized controlled trial in hospitalized patients with decompensated HF (n=150) who were diagnosed with OSA during the hospitalization. All participants received guideline directed therapy for HF decompensation. Participants were randomized to an intervention arm which received positive airway pressure (PAP) therapy during the hospitalization (n=75) and a control arm (n=75). The primary outcome was discharge left ventricular ejection fraction (LVEF). RESULTS: LVEF changed in the PAP arm from 25.5 (10.4) at baseline, to 27.3 (11.9) at discharge. In the control group, LVEF was 27.3 (11.7) at baseline and 28.8 (10.5) at conclusion. There was no significant effect on LVEF of in-hospital PAP compared to control (p = 0.84) in the intention to treat analysis. On treatment analysis in the intervention arm showed a significant increase in LVEF in participants who used PAP ≥ 3 hours per night (n=36, 48%) compared to those who used it less (p=0.01). There was a dose effect with higher hours of usage associated with more improvement in LVEF. Follow-up of readmissions after 6-months post discharge revealed a >60% decrease in readmissions for patients who used PAP ≥3 hours/night compared to those who used it less than 3 hours/night (p

Introduction Patients with thermal burns become zinc deficient due to exudative losses, increased urinary excretion, and reduction of carrier proteins which results in impaired immunity, wound healing and glucose control. Previous trials have demonstrated improved wound healing utilizing fixed zinc supplementation, but none have assessed the potential benefits associated with normalizing serum zinc concentrations. The objective of this study was to compare the impact of zinc normalization on clinical outcomes in patients with severe thermal burns. Methods This retrospective, single-center study of patients with at least 10% total body surface area (TBSA) burn and three serum zinc concentrations compared the ratio of hospital length of stay (LOS) over TBSA burned (LOS/TBSA index) between those with normal (≥60 mcg/mL) and non-normal ( Results A total of 56 patients were included for evaluation (11 normal and 45 non-normal). Burn size was 20.5% TBSA [11–29] for those with normal zinc and 27.3% [22–36] for non-normal; number of grafts for each group was 1 [0–1] vs 2 [1–3] respectively. LOS/TBSA index did not differ significantly between groups (1.10 normal vs. 1.21 non-normal, unadjusted p = 0.69; p = 0.75 adjusting for number of grafts). Time to 90% epithelialization was reduced in the normal group (27.5 vs. 57 days, p = 0.02), but this did not remain statistically significant after adjustment for %TBSA and number of grafts (p = 0.18). The groups did not differ significantly in incidence of infection or hyperglycemia in either unadjusted or adjusted analyses. Conclusions This was the first study, to our knowledge, to assess the clinical impact of normalizing serum zinc levels in patients with severe burns. Our results suggest the normalization of serum zinc levels through individualized zinc supplementation is not associated with improvement in clinical outcomes during hospitalization and therefore fixed-dose zinc supplementation without acquisition of serum zinc measurements should be considered.

Background Comorbidities of tobacco and alcohol abuse and obesity are major risk factors for colon carcinogenesis. These risk factors are considered the most prevalent modifiable risk factors linked to malignancies including colorectal cancer (CRC) in both high- and low-income countries. The aim of this study was to investigate the relationship between number of comorbidities and age of CRC diagnosis in US male veteran population. Methods A retrospective single-center study using chart review and the International Classification of Diseases, Ninth Revision (ICD-9) codes to identify patients with a diagnosis of CRC and comorbidities of tobacco abuse, alcohol abuse, hypertension (HTN), diabetes mellitus (DM) and chronic kidney disease (CKD). The primary aim was to study effect of these comorbidities on age of CRC diagnosis. Univariable and then multivariable logistic regression models were fit to age at diagnosis for each patient variable. Results A total of 362 patients were included in the study. The mean age of CRC diagnosis was 66.8. Eighty percent were Caucasians, and 20% were African Americans. African Americans were diagnosed with CRC 3.8 years younger compared to Caucasians (P = 0.01). Controlling for other variables in the multivariable model, age at CRC diagnosis was significantly lower for African Americans and for patients with higher total counts for tobacco and alcohol abuse and obesity. HTN, DM and CKD were not associated with a lower age of CRC diagnosis. Conclusions Tobacco and alcohol abuse and obesity have negative cumulative effect on age of CRC diagnosis in US male veteran population. Patients with increasing number of these comorbidities are associated with significantly lower age of CRC diagnosis. It is important to identify veterans with these comorbidities and encourage CRC screening.

Obesity is a known risk factor for diverticulitis. Our objective was to examine the less investigated impact of morbid obesity (MO) on admissions and clinical course of diverticulitis in a US representative database. We retrospectively queried the 2010–2014 Nationwide Readmission Database to compare diverticulitis hospitalizations in 48,651 MO and 841,381 non-obese patients. Outcomes of mortality, clinical course, surgical events, and readmissions were compared using multivariable and propensity-score-matched analyses. The number of MO patients admitted with diverticulitis increased annually from 7570 in 2010 to 11,935 in 2014, while the total number of patients admitted with diverticulitis decreased (p = 0.003). Multivariable analysis demonstrates that MO was associated with increased mortality (adjusted odds ratio [aOR] 1.54; 95% confidence internal [CI]: 1.16, 2.05), intensive care admissions (aOR = 1.92; 95% CI: 1.61, 2.31), emergent surgery (aOR = 1.20; 95% CI: 1.11, 1.30), colectomy (aOR = 1.13; 95% CI: 1.08, 1.18), open laparotomy (aOR = 1.28; 95% CI: 1.21, 1.34), and colostomy (aOR = 1.34; 95% CI: 1.25, 1.43). Additionally, MO was associated with higher risk for multiple readmissions for diverticulitis within 30 days (aOR = 1.45; 95% CI: 1.08, 1.96) and 6 months (aOR = 1.21; 95% CI: 1.03, 1.42). A one-to-one matched propensity-score analysis confirmed our multivariable analysis findings. Analysis of national data demonstrates an increasing trend of MO patients’ admissions for diverticulitis, with a presentation at a younger age. Furthermore, MO is associated with an increased risk of adverse outcomes and readmissions of diverticulitis. Future strategies are needed to ameliorate these outcomes.

Background The mechanism and markers of cardiovascular disease (CVD) in obstructive sleep apnea (OSA) remain unknown. The microcirculation is the site of early changes in OSA patients who are free of CVD risk. Methods Patients with newly diagnosed moderate to severe OSA (n = 7) were studied before and 12 weeks after intensive treatment with continuous positive airway pressure (CPAP), along with weight and age matched controls (n = 7). Microcirculatory vessels were isolated from gluteal biopsies and changes in critical functional genes were measured. Results The following genes changed after 12 weeks of intensive CPAP therapy in the microcirculatory vessels: angiotensin receptor type 1 (AGTR-1) (11.6 (3.4) to 6 (0.8); P = 0.019); NADPH oxidase (NOX4) (0.85 (0.02) to 0.79 (0.11); P = 0.016); and dimethylarginine dimethylaminohydrolase (DDAH 1) (1 (0.31) to 0.55 (0.1); P = 0.028). Despite decreased nitric oxide (NO) availability as measured indirectly through brachial artery flow-mediated dilation, endothelial NO synthase (NOS3) did not change with CPAP. Other disease markers of OSA that changed with treatment in the microcirculation were endothelin, hypoxia inducible factor 1a, nuclear factor kappa B, interleukin-8, and interleukin-6. Conclusions In this ex vivo evaluation of the microcirculation of patients with OSA and no CVD risk, several pathways of CVD were activated supporting that OSA independently induces microcirculatory endothelial dysfunction and serving as disease-specific markers for future pharmacological targeting of OSA-related CVD risk. The findings support the role of renin–angiotensin activation and endothelial oxidative stress in the decreased microcirculatory NO availability in OSA.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators significantly improve pulmonary function in patients with cystic fibrosis (CF) but the effect on hepatobiliary outcomes remains unknown. We hypothesized that CF patients on CFTR modulators would have a decreased incidence of cirrhosis compared to patients not on CFTR modulators or on ursodiol.To investigate the effect of CFTR modulators on the development of cirrhosis in patients with CF.A retrospective analysis was performed using Truven MarketScan from January 2012 through December 2017 including all patients with a diagnosis of CF. Patients were excluded if they underwent a liver transplantation or if they had other etiologies of liver disease including viral hepatitis or alcohol use. Subjects were grouped by use of CFTR modulators, ursodiol, dual therapy, or no therapy. The primary outcome was development of cirrhosis. Kaplan-Meier curves estimated the incidence of cirrhosis and log-rank tests compared incidence curves between treatment groups.A total of 7201 patients were included, of which 955 (12.6%) used a CFTR modulator, 529 (7.0%) used ursodiol, 105 (1.4%) used combination therapy, and 5612 (74.3%) used neither therapy. The incidence of cirrhosis was 0.1% at 1 year and 0.7% at 4 years in untreated patients, 5.9% and 10.1% in the Ursodiol group, and 1.0% and 1.0% in patients who received both therapies. No patient treated with CFTR modulators alone developed cirrhosis. Patients on CFTR modulators alone had lower cirrhosis incidence than untreated patients (CFTR modulators are associated with a reduction in the incidence of cirrhosis compared to other therapies in patients with CF.

"Superhenhanced" transcription of specific oncogenes by aberrant looping of upstream enhancer elements to marked transcriptional regulatory regions is a mechanism of oncogene overexpression. Therefore, compounds that target key positive regulators of RNA polymerase II (RNAPII) activity, such as CDK7 and CDK9, can relatively selectively reduce expression of such superenhanced oncogenes and are in clinical trials. We have previously reported activity of the CDK7 inhibitor THZ1 in medullary thyroid cancer (MTC) along with identification of a superenhancer in RET. CDK7 inhibitors also are reported to be active in anaplastic thyroid cancer cell lines. In the present study, we extend this work to both CDK7 and CDK9 inhibitors, and to a more extensive set of thyroid cancer cell lines. We selected 8 thyroid cancer cell lines (TPC1, FTC133, BCPAP, SW1376; K1, THJ-16T, C643, and 8505C) from a variety of histological subtypes with different driver mutations for treatment with a CDK7 (THZ1) or CDK9 (AZD4573) inhibitors. Cell viability assays were performed to determine IC50 and Western blots were performed for target validation. IC50 values ranged from 5-100 nM for both compounds for all cell lines demonstrating broad activity and robust activity. Unexpectedly, both compounds inhibited both CDK7 RNAPII phosphorylation (Ser5) and CDK9 RNAPII phosphorylation (Ser2) due to a loss of total RNAPII protein levels in all cell lines. Further time course studies two cell lines, 8505C (BRAFV600E) and TPC1 (RET/PTC) showed the loss off RNAPII occurred rapidly (1-3 hours) with stable RNAPII mRNA levels by qRTPCR. We therefore hypothesized that RNAPII stalling induced by inhibition of CDK7 may cause loss of RNAPII protein stability through ubiquitination and proteasome-mediated degradation. Immunoprecipitation-Western blots demonstrated variable baseline levels of RNAPII ubiquitination in 8505C (low) and TPC1 (high) cells. THZ1 treatment induced ubiquitination of RNAPII in 8505C cells signficantly, while a modest increase beyond the higher baseline occurred in TPC1. Bortezomib (proteasome inhibitor) treatment rescued THZ1-reduced RNAPII protein levels in both cell lines. In summary, human thyroid cancer cell lines are broadly sensitive to CDK7 and CDK9 inhibitors. CDK 7 and 9 inhibitors reduce RNAPII levels and THZ1 induces RNAPII ubiquitination and proteasome degradation demonstrating a new mode of action for the reduced RNAPII activity induced by these inhibitors. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:42 p.m. - 1:47 p.m.

BackgroundChimeric antigen receptor T-cell (CAR-T) infusion is associated with early toxicity. Yet, whether early toxicity development holds ramifications for long-term outcomes is unknown.MethodsFrom a large cohort of consecutive adult patients treated with CAR-T therapies for relapsed or refractory lymphomas from 2016 to 2019, we assessed progression-free survival (PFS), by toxicity development (cytokine release syndrome (CRS), neurotoxicity, or cardiotoxicity]. We also assessed the relationship of toxicity development to objective disease response, and overall survival (OS). Multivariable regression was utilized to evaluate relationships between standard clinical and laboratory measures and disease outcomes. Differences in outcomes, by toxicity status, were also assessed via 30-day landmark analysis. Furthermore, we assessed the effects of early anti-CRS toxicity therapy use (at ≤grade 2 toxicity) on maximum toxicity grade observed, and long-term disease outcomes (PFS and OS).ResultsOverall, from 102 CAR-T-treated patients, 90 were identified as treated with single-agent therapy, of which 88.9% developed toxicity (80 CRS, 41 neurotoxicity, and 17 cardiotoxicity), including 28.9% with high-grade (≥3) events. The most common manifestations were hypotension at 96.6% and fever at 94.8%. Among patients with cardiac events, there was a non-significant trend toward a higher prevalence of concurrent or preceding high-grade (≥3) CRS. 50.0% required tocilizumab or corticosteroids. The median time to toxicity was 3 days; high grade CRS development was associated with cardiac and neurotoxicity. In multivariable regression, accounting for disease severity and traditional predictors of disease response, moderate (maximum grade 2) CRS development was associated with higher complete response at 1 year (HR: 2.34; p=0.07), and longer PFS (HR: 0.41; p=0.02, in landmark analysis), and OS (HR: 0.43; p=0.03). Among those with CRS, relative blood pressure (HR: 2.25; p=0.004), respectively, also associated with improved PFS. There was no difference in disease outcomes, or maximum toxicity grade (CRS, neurotoxicity, or cardiotoxicity) observed, based on the presence or absence of the use of early CRS-directed therapies.ConclusionsAmong adult lymphoma patients, moderate toxicity manifest as grade 2 CRS after CAR-T infusion may associate with favorable clinical outcomes. Further studies are needed to confirm these findings.

Ibrutinib is associated with dramatic efficacy against B-cell malignancies. Yet, ibrutinib is linked with potentially-limiting cardiotoxicity, including emerging reports of profound hypertension. However, the long-term incidence, severity, and impacts of hypertension development during ibrutinib-use are unknown. Therefore, from 562 consecutive patients treated with ibrutinib for B-cell malignancies between 2009-2016 we assessed the incidence of new/incident or worsened hypertension [systolic blood pressure (BP) cutoff of 130mmHg]. Observed incident-hypertension rates were compared to Framingham-heart predicted incident-hypertension rates. We also evaluated the relationship of hypertension on ibrutinib to the development of other major-adverse-cardiovascular-events (MACE), including arrhythmias, myocardial infarction, stroke, heart failure, and cardiovascular death. Further, we assessed the preventative and modulatory effects of antihypertensives, by medication-class, on ibrutinib-related hypertension. Overall, 78.3% of ibrutinib-users developed new or worsened hypertension [mean systolic BP increase 5.2mmHg ({plus minus}20.7)] over a median of 30months. New hypertension developed in 71.6% of ibrutinib-users (467 observed vs. 39 Framingham-predicted cases per 1,000 person-years), with a time-to-50% cumulative incidence of 4.2months. Among those without preceding hypertension, 17.7% developed high-grade (BP g160/100mmHg) hypertension. In multivariable regression containing known predictors of MACE, new or worsened hypertension was associated with increased MACE [hazard ratio (HR) 2.17, 95%CI 1.08-4.38]. No single-antihypertensive class was associated with prevention or control of ibrutinib-related hypertension. However, antihypertensive initiation was associated with a lower risk of MACE (HR 0.40, CI 0.24-0.66). Collectively, these data suggest ibrutinib is associated with substantial increase in the incidence and severity of hypertension, and that hypertension development may suggest a higher risk of subsequent cardiotoxic events.

Evolving epidemiological data, backed by mechanistic evidence, supports a paradoxical increase in the risk of colorectal cancer after Roux-en-Y gastric bypass surgery (RYGB). We examined the risk of colonic polyps after RYGB. A single-center retrospective study included colonoscopies performed between the years 1994 and 2018. To focus on the long-term impact of RYGB on precancerous colonic polyps, we compared patients at average risk for CRC who underwent colonoscopy ≥ 5 years after RYGB (n = 86) versus pre-RYGB (n = 106). We analyzed our data using inverse probability of treatment weighting (IPTW) using propensity scores in order to account for multiple potential confounders. After IPTW, we found no statistical differences between pre- and post-RYGB patients for risk of any polyp (33.2% pre- vs. 32.7% post-RYGB). However, the percentage of serrated polyps was higher ≥ 5 years post-RYGB compared with pre-RYGB (8.7% vs. 2.1%, p = 0.04, relative risk = 4.22; 95% CI 0.97, 18.4). Body mass index ≥ 30 kg/m2 at time of colonoscopy was associated with a greater risk for any polyp after RYGB (OR 6.23; 95% CI 1.16, 33.41). There was also a trend towards increased risk of polyps in post-RYGB patients who were current smokers (OR = 4.97; 95% CI 0.82, 30) or with age > 55 years (OR = 2.49; 95% CI 0.88, 7.00). Our data suggest that RYGB is associated with an increased risk of serrated polyps after 5 years from surgery. Prospective studies defining this risk and examining mechanisms will be instrumental for application of CRC preventative strategies in this population.

Background: The Afirma Gene Expression Classifier (GEC) has been used to further characterize cytologically indeterminate (cyto-I) thyroid nodules into either benign or suspicious categories. However, its relatively low positive predictive value (PPV) limited its use as a classifier for patients with suspicious results. The Afirma Gene Sequencing Classifier (GSC) was developed to improve PPV while maintaining a high negative predictive value (NPV), yet real-world assessment of its performance is lacking. Methods: We analyzed all patients who had cyto-I nodules and molecular testing with either GEC or GSC between 2011 and 2018 at a single academic medical center. Clinical information was obtained for 343 GEC-tested nodules and 164 GSC-tested nodules. Results: The GSC had a statistically significant higher benign call rate (76.2% vs. 48.1%, p

The number of individuals who succumb to thyroid cancer has been increasing and those who are refractory to standard care have limited therapeutic options, highlighting the importance of developing new treatments for patients with aggressive forms of the disease. Mutational activation of MAPK signaling, through BRAF and RAS mutations and/or gene rearrangements, and activation of PI3K signaling, through mutational activation of PIK3CA or loss of PTEN, are well described in aggressive thyroid cancer. We previously reported overactivation and overexpression of p21-activated kinases (PAKs) in aggressive human thyroid cancer invasive fronts and determined that PAK1 functionally regulated thyroid cancer cell migration. We reported mechanistic crosstalk between the MAPK and PAK pathways that are BRAF-dependent but MEK independent, suggesting that PAK and MEK inhibition might be synergistic. In the present study, we tested this hypothesis. Pharmacologic inhibition of group I PAKs using two PAK kinase inhibitors, G-5555 or FRAX1036, reduced thyroid cancer cell viability, cell cycle progression and migration and invasion, with greater potency for G-5555. Combination of G-5555 with vemurafenib was synergistic in BRAFV600E-mutated thyroid cancer cell lines. Finally, G-5555 restrained thyroid size of BRAFV600E-driven murine papillary thyroid cancer by >50% (P P = 0.0167), despite maintenance of MAPK activity. Taken together, these findings suggest both that group I PAKs may be a new therapeutic target for thyroid cancer and that PAK activation is functionally important for BRAFV600E-mediated thyroid cancer development.

Background Despite high prevalence and clinical implications of disturbed sleep during pregnancy, information on changes in sleep across pregnancy and postpartum is incomplete. Moreover, predictors of differential patterns of sleep quality across the perinatal period are poorly defined. Methods This study examined subjective sleep quality using the Pittsburgh Sleep Quality Index during each trimester of pregnancy and at 4-11 weeks postpartum among 133 women inclusive of nulliparous and multiparous African Americans and Whites. Results At any given assessment, 53%-71% of women reported poor overall sleep quality (Pittsburgh Sleep Quality Index total score > 5). Moreover, 92% reported poor overall sleep quality during at least 1 assessment, including 88% at some time during gestation. Compared to nulliparous women, multiparous women reported poorer overall sleep quality, shorter sleep duration, and poorer sleep efficiency during the first trimester; poorer overall sleep quality and longer sleep latency in the second trimester; and more frequent sleep disturbances (eg, night time and early morning awakenings) during the third trimester. Among nulliparous as well as multiparous women, specific aspects of sleep (eg, subjective sleep quality, sleep disturbances, sleep efficiency) were poorer in African American compared to White women at different time points during pregnancy. No effects of race or parity were observed on sleep parameters at postpartum. Conclusions Poor sleep quality during pregnancy as well as early postpartum is highly prevalent among both African American and White women. Both multiparous status and African American race are associated with more disturbed sleep at some time points during pregnancy. These individual differences should be considered in future research and clinical efforts to promote perinatal sleep health.

Pazopanib (PAZ), a tyrosine kinase inhibitor used in the treatment of soft tissue sarcoma (STS), should not be administered with acid‐suppressive medications (ASMs) due to decreased drug solubility. Common practice for patients requiring ASM with PAZ is to separate administration by 12 hours; however, there is little real‐world evidence describing clinical outcomes using this strategy. The aim of this study was to determine whether concomitant ASM impacted efficacy and adverse event rates in patients with STS receiving PAZ. Medical records were retrospectively reviewed for patients with STS who received PAZ from June 2011 to July 2017. Patients were stratified into two groups, PAZ with or without ASM (PAZ + ASM or PAZ only). The primary objective was to determine whether progression‐free survival (PFS) differed between groups. Secondary objectives were to determine overall survival (OS) and occurrence of grade 3/4 toxicities. Ninety‐one patients were included in the study, 42 patients in the PAZ + ASM group and 49 in the PAZ only group. Median PFS was significantly shorter in the PAZ + ASM group than the PAZ only group (5.3 vs. 6.7 months). The PAZ + ASM group also had a 74% higher relative risk of progression or death than the PAZ only group, but there was no difference in OS. Regarding adverse events, the PAZ + ASM group trended toward lower levels of grade 3/4 hypertension (19% vs. 37%). These results suggest that ASM should be avoided in patients with STS receiving PAZ. Larger studies are needed to further elucidate the impact of ASM use with PAZ in clinical practice.

Oxandrolone has proven benefits in thermal burn injury and has become a standard of care. Transaminitis is the most frequent side effect of oxandrolone use, although no risk factors have been identified that increase the risk of transaminitis. The objective was to evaluate the frequency of transaminitis while on oxandrolone and to identify risk factors leading to an increased risk of transaminitis in adult burn patients. This multicenter retrospective risk factor analysis compared two patient groups with and without occurrence of transaminitis, which was detected by an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >100 mg/dL. Secondary outcomes included percentage increase from baseline for AST/ALT, length of stay, and mortality. After univariable analysis, a multivariable logistic regression analysis was performed to detect possible risk factors leading to transaminitis. A total of 309 patients were included, with transaminitis occurring in 128 patients (41.4%) after 13 (interquartile range [IQR] 8–23) days on oxandrolone. After multivariable analysis, age (odds ratio [OR] 0.91; 95% confidence interval [CI] 0.84–0.99 for a 5-year increase in age), intravenous vasopressor use (OR 1.85; 95% CI 1.05–3.27), and amiodarone use (OR 2.51; 95% CI 1.09–5.77) were independent predictors of transaminitis, controlling for TBSA%. Transaminitis was not significantly associated with length of stay or mortality after adjusting for age and TBSA%. We conclude that patients who are younger and have concurrent amiodarone or vasopressor use have the highest risk of developing oxandrolone induced transaminitis and should be monitored closely.

Early readmission in patients with decompensated liver cirrhosis leads to an enormous burden on health care use. A retrospective cohort study using the 2013 and 2014 Nationwide Readmission Database (NRD) was conducted. Patients with a diagnoses of cirrhosis and at least one feature of decompensation were included. The primary outcome was to develop a validated risk model for early readmission. Secondary outcomes were to study the 30-day all-cause readmission rate and the most common reasons for readmission. A multivariable logistic regression model was fit to identify predictors of readmissions. Finally, a risk model, the Mumtaz readmission risk score, was developed for prediction of 30-day readmission based on the 2013 NRD and validated on the 2014 NRD. A total of 123,011 patients were included. The 30-day readmission rate was 27%, with 79.6% of patients readmitted with liver-related diagnoses. Age65 years; Medicare or Medicaid insurance; nonalcoholic etiology of cirrhosis; ≥3 Elixhauser score; presence of hepatic encephalopathy, ascites, variceal bleeding, hepatocellular carcinoma, paracentesis, or hemodialysis; and discharge against medical advice were independent predictors of 30-day readmission. This validated model enabled patients with decompensated cirrhosis to be stratified into groups with low (20%), medium, (20%-30%), and high (30%) risk of 30-day readmissions. Conclusion: One third of patients with decompensated cirrhosis are readmitted within 30 days of discharge. The use of a simple risk scoring model with high generalizability, based on demographics, clinical features, and interventions, can bring refinement to the prediction of 30-day readmission in high-risk patients; the Mumtaz readmission risk score highlights the need for targeted interventions in order to decrease rates of readmission within this population.

While cholecystectomy (CCY) is the standard of care for gallstone-related acute cholecystitis, percutaneous cholecystostomy-tube (CCYT-tube) is an alternative option in patients with significant comorbid conditions. We sought to identify immediate and longitudinal hospital outcomes of patients who underwent CCYT-tube placement and determine predictors of CCYT-tube placement and eventual CCY on a national level in the US. We identified all adults (age ≥ 18 years) with a primary diagnosis of acute calculous cholecystitis from January to November 2013 in the Nationwide Readmissions Database (NRD). The NRD allows longitudinal follow-up of a patient for one calendar year. Outcomes of patients undergoing CCY and CCYT-tube were compared. Separate univariable and multivariable regression analyses were performed to identify predictors of CCYT-tube placement and failure to undergo subsequent CCY. A total of 181,262 patients had an index hospitalization with acute cholecystitis where 178,095 (98.3%) patients underwent only CCY and 3167 (1.7%) patients were managed with CCYT-tubes. Among patients with CCYT-tube, 1196 (37.8%) underwent eventual CCY in 2013, while 1971 (62.2%) did not. One in five patients with CCYT-tube were readmitted within 30 days of hospital discharge. Multivariable analysis demonstrated that increasing age, male gender, coronary artery disease, cirrhosis, atrial fibrillation, diastolic congestive heart failure, and sepsis were associated with CCYT-tube placement. Longitudinal follow-up revealed that older age (OR 1.16, 95% CI 1.09–1.23), Elixhauser comorbidity score 3–4 (OR 1.94, 95% CI 1.03–3.63), cirrhosis (OR 3.28, 95% CI 1.59–6.79), and diastolic congestive heart failure (OR 2.47, 95% CI 1.33–4.60) were associated with failure to undergo subsequent CCY. In this national survey, nearly two in three patients who receive CCYT-tube for acute cholecystitis do not get CCY during longitudinal data capture within the same calendar year. Future research needs to target novel options for drainage of the gallbladder in high-risk patient populations.