Publications by authors named "John W Scott"

194 Publications

Calcium/calmodulin-dependent protein kinase kinase 2 regulates hepatic fuel metabolism.

Mol Metab 2022 May 11:101513. Epub 2022 May 11.

Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address:

Previously published research exposed that genetic loss of Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) confers protection against high fat diet (HFD)-induced insulin resistance. However, the precise mechanisms by which loss of CaMKK2 improves peripheral insulin sensitivity have yet to be fully identified. Herein, we report that liver-specific CaMKK2 knockout (CaMKK2) mice fed HFD show significant improvements in peripheral glucose tolerance and whole-body insulin sensitivity. Moreover, adenoviral rescue of hepatic CaMKK2 expression in whole body CaMKK2 knockout mice (CaMKK2) fed HFD is sufficient to induce whole-body insulin resistance. RNA-Seq analysis of livers from CaMKK2 mice maintained on HFD revealed that hepatic loss of CaMKK2 leads to activation of lipid metabolism and peroxisomal programs at the expense of glycolytic pathways. Stable isotope tracing led to the identification of GAPDH as a novel effector of CaMKK2 action in the liver. Traditional β-oxidation assays and a newly developed Seahorse assay using purified peroxisomes revealed that hepatocytes devoid of CaMKK2 display increased levels of β-oxidation due in part to improved peroxisomal activity. We performed a degenerate peptide library screen to identify phospho-targets of CaMKK2, which identified Pex3, a key peroxisomal biogenic factor required for functional interaction of the peroxisome with lipid droplets. Taken together, these findings highlight CaMKK2 as a hepatic fuel source regulator that coordinates mitochondrial and peroxisomal processing of metabolic substrates. Moreover, the collective improvements in hepatic and peripheral insulin sensitivity observed in the absence of CaMKK2 suggest that pharmacological inhibition of this kinase may provide a new therapeutic angle for treatment of dietary-induced metabolic diseases.
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http://dx.doi.org/10.1016/j.molmet.2022.101513DOI Listing
May 2022

Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator.

Biochem J 2022 05 13. Epub 2022 May 13.

St Vincent's Institute of Medical Research, Melbourne, Australia.

The AMP-activated protein kinase (AMPK) αβγ heterotrimer is a primary cellular energy sensor and central regulator of energy homeostasis. Activating skeletal muscle AMPK with small molecule drugs improves glucose uptake and provides opportunity for new strategies to treat type 2 diabetes and insulin resistance, with recent genetic and pharmacological studies indicating the α2β2γ1 isoform combination as the heterotrimer complex primarily responsible. With the goal of developing α2β2-specific activators, here we perform structure/function analysis of the 2-hydroxybiphenyl group of SC4, an activator with tendency for α2-selectivity that is also capable of potently activating β2 complexes. Substitution of the LHS 2-hydroxyphenyl group with polar-substituted cyclohexene-based probes resulted in two AMPK agonists, MSG010 and MSG011, which did not display α2-selectivity when screened against a panel of AMPK complexes. By radiolabel kinase assay, MSG010 and MSG011 activated α2β2γ1 AMPK with one order of magnitude greater potency than the pan AMPK activator MK-8722. A crystal structure of MSG011 complexed to AMPK α2β1γ1 revealed a similar binding mode to SC4 and the potential importance of an interaction between the SC4 2-hydroxyl group and a2-Lys31 for directing α2-selectivity. MSG011 induced robust AMPK signalling in mouse primary hepatocytes and commonly used cell lines, and in most cases this occurred in the absence of changes in phosphorylation of the kinase activation loop residue α-Thr172, a classical marker of AMP-induced AMPK activity. These findings will guide future design of α2β2-selective AMPK activators, that we hypothesise may avoid off-target complications associated with indiscriminate activation of AMPK throughout the body.
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http://dx.doi.org/10.1042/BCJ20220067DOI Listing
May 2022

Social Vulnerability And Outcomes For Access-Sensitive Surgical Conditions Among Medicare Beneficiaries.

Health Aff (Millwood) 2022 05;41(5):671-679

Andrew M. Ibrahim, University of Michigan, and HOK, Chicago, Illinois.

Concerns have been raised over wide variation in rates of unplanned (emergency or urgent) surgery for access-sensitive surgical conditions-diagnoses requiring surgery that preferably is planned (elective) but, when access is limited, may be delayed until worsening symptoms require riskier and costlier unplanned surgery. Yet little is known about geographic and community-level factors that may increase the likelihood of unplanned surgery with adverse outcomes. We examined the relationship between community-level social vulnerability and rates of unplanned surgery for three access-sensitive conditions in 2014-18 among fee-for-service Medicare beneficiaries ages 65-99. Compared with patients from communities with the lowest social vulnerability, those from communities with the highest vulnerability were more likely, overall, to undergo unplanned surgery (36.2 percent versus 33.5 percent). They were also more likely to experience worse outcomes largely attributable to differential rates of unplanned surgery, including higher rates of mortality (5.4 percent versus 5.0 percent) and additional surgery within thirty days (19.6 percent versus 18.1 percent). Our findings suggest that policy addressing community-level social vulnerability may mitigate the observed differences in surgical procedures and outcomes for access-sensitive conditions.
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http://dx.doi.org/10.1377/hlthaff.2021.01615DOI Listing
May 2022

Evaluating the complex association between Social Vulnerability Index and trauma mortality.

J Trauma Acute Care Surg 2022 05 26;92(5):821-830. Epub 2022 Jan 26.

From the Department of Surgery (P.U.N., A.S.), Brigham and Women's Hospital, Boston, Massachusetts; Center for Healthcare Outcomes and Policy (P.U.N., N.F.S., A.I., Z.F., M.R.H., J.W.S.), National Clinical Scholars Program (P.U.N.), University of Michigan Medical School (M.M.F.), and Department of Surgery (A.I., M.R.H., J.W.S.), University of Michigan, Ann Arbor, Michigan.

Introduction: Social determinants of health are known to impact patient-level outcomes, but they are often difficult to measure. The Social Vulnerability Index was created by the Centers for Disease Control to identify vulnerable communities using population-based measures. However, the relationship between SVI and trauma outcomes is poorly understood.

Methods: In this retrospective study, we merged SVI data with a statewide trauma registry and used three analytic models to evaluate the association between SVI quartile and inpatient trauma mortality: (1) an unadjusted model, (2) a claims-based model using only covariates available to claims datasets, and (3) a registry-based model incorporating robust clinical variables collected in accordance with the National Trauma Data Standard.

Results: We identified 83,607 adult trauma admissions from January 1, 2017, to September 30, 2020. Higher SVI was associated with worse mortality in the unadjusted model (odds ratio, 1.72 [95% confidence interval, 1.30-2.29] for highest vs. lowest SVI quintile). A weaker association between SVI and mortality was identified after adjusting for covariates common to claims data. Finally, there was no significant association between SVI and inpatient mortality after adjusting for covariates common to robust trauma registries (adjusted odds ratio, 1.10 [95% confidence interval, 0.80-1.53] for highest vs. lowest SVI quintile). Higher SVI was also associated with a higher likelihood of presenting with penetrating injuries, a shock index of >0.9, any Abbreviated Injury Scale score of >5, or in need of a blood transfusion (p < 0.05 for all).

Conclusion: Patients living in communities with greater social vulnerability are more likely to die after trauma admission. However, after risk adjustment with robust clinical covariates, this association was no longer significant. Our findings suggest that the inequitable burden of trauma mortality is not driven by variation in quality of treatment, but rather in the lethality of injuries. As such, improving trauma survival among high-risk communities will require interventions and policies that target social and structural inequities upstream of trauma center admission.

Level Of Evidence: Prognostic / Epidemiologic, Level IV.
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http://dx.doi.org/10.1097/TA.0000000000003514DOI Listing
May 2022

Failure to Rescue in Trauma: Early and Late Mortality in Low and High Performing Trauma Centers.

J Trauma Acute Care Surg 2022 Apr 21. Epub 2022 Apr 21.

Center for Healthcare Outcomes and Policy, University of Michigan, Ann Arbor, MI.

Background: Failure to Rescue (FTR) is defined as mortality following a complication. FTR has come under scrutiny as a quality metric to compare trauma centers. In contrast to elective surgery, trauma has an early period of high expected mortality due to injury sequelae rather than a complication. Here, we report FTR in early and late mortality using an externally validated trauma patient database, hypothesizing that centers with higher risk-adjusted mortality rates have higher risk-adjusted FTR rates.

Methods: The study included 114,220 patients at 34 Level I and II trauma centers in a statewide quality collaborative (2016-2020) with ISS ≥5. Emergency room deaths were excluded. Multivariate regression models were used to produce center-level adjusted rates for mortality and major complications. Centers were ranked on adjusted mortality rate and divided into quintiles. Early deaths (within 48 hours of presentation) and late deaths (after 48 hours) were analyzed.

Results: Overall, 6.7% of patients had a major complication and 3.1% died. There was no difference in the mean risk-adjusted complication rate amongst the centers. FTR was significantly different across the quintiles (13.8% at the very low mortality centers vs. 23.4% at the very high mortality centers, p < 0.001). For early deaths, there was no difference in FTR rates amongst the highest and lowest mortality quintiles. For late deaths, there was a twofold increase in the FTR rate between the lowest and highest mortality centers (9.7% vs. 19.3%, p < 0.001), despite no difference in the rates of major complications (5.9% vs. 6.0%, p = 0.42).

Conclusions: Low-performing trauma centers have higher mortality rates and lower rates of rescue following major complications. These differences are most evident in patients who survive the first 48 hours after injury. A better understanding of the complications and their role in mortality after 48 hours is an area of interest for quality improvement efforts.

Level Of Evidence: III.
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http://dx.doi.org/10.1097/TA.0000000000003662DOI Listing
April 2022

Value in Acute Care Surgery, Part 2: Defining and Measuring Quality Outcomes.

J Trauma Acute Care Surg 2022 Apr 8. Epub 2022 Apr 8.

Abstract: The prior article in this series delved into measuring cost in Acute Care Surgery, and this subsequent work explains in detail how quality is measured. Specifically, objective quality is based on outcome measures, both from administrative and clinical registry databases from a multitude of sources. Risk stratification is key in comparing similar populations across diseases and procedures. Importantly, a move toward focusing on subjective outcomes like patient reported outcomes measures and financial well-being are vital to evolving surgical quality measures for the 21st century.Level of Evidence: Review, N/a.
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http://dx.doi.org/10.1097/TA.0000000000003638DOI Listing
April 2022

Medicaid Expansion and Trauma Care: Evidence vs Politics.

Authors:
John W Scott

J Am Coll Surg 2022 01;234(1):95-96

Ann Arbor, MI.

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http://dx.doi.org/10.1097/XCS.0000000000000001DOI Listing
January 2022

An AMPKα2-specific phospho-switch controls lysosomal targeting for activation.

Cell Rep 2022 02;38(7):110365

Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, VIC 3065, Australia. Electronic address:

AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) are metabolic kinases that co-ordinate nutrient supply with cell growth. AMPK negatively regulates mTORC1, and mTORC1 reciprocally phosphorylates S345/7 in both AMPK α-isoforms. We report that genetic or torin1-induced loss of α2-S345 phosphorylation relieves suppression of AMPK signaling; however, the regulatory effect does not translate to α1-S347 in HEK293T or MEF cells. Dephosphorylation of α2-S345, but not α1-S347, transiently targets AMPK to lysosomes, a cellular site for activation by LKB1. By mass spectrometry, we find that α2-S345 is basally phosphorylated at 2.5-fold higher stoichiometry than α1-S347 in HEK293T cells and, unlike α1, phosphorylation is partially retained after prolonged mTORC1 inhibition. Loss of α2-S345 phosphorylation in endogenous AMPK fails to sustain growth of MEFs under amino acid starvation conditions. These findings uncover an α2-specific mechanism by which AMPK can be activated at lysosomes in the absence of changes in cellular energy.
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http://dx.doi.org/10.1016/j.celrep.2022.110365DOI Listing
February 2022

Financial Toxicity Among Surgical Patients Varies by Income and Insurance: A Cross-Sectional Analysis of the National Health Interview Survey.

Ann Surg 2022 Jan 21. Epub 2022 Jan 21.

National Clinician Scholars Program at the Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI Center for Healthcare Outcomes and Policy, University of Michigan, Ann Arbor, MI Department of Surgery, Stanford University, Stanford, CA Department of Surgery, Brigham and Women's Hospital, Boston, MA Department of Surgery, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1097/SLA.0000000000005382DOI Listing
January 2022

Insured but not Protected: Time to Eliminate Cost-sharing for Trauma Care.

Authors:
John W Scott

Ann Surg 2022 03;275(3):433-434

Center for Healthcare Outcomes and Policy, Department of Surgery, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1097/SLA.0000000000005289DOI Listing
March 2022

Surgical outcomes and travel burden among medicare beneficiaries living in Health Professional Shortage Areas.

Am J Surg 2022 Jan 22. Epub 2022 Jan 22.

Center for Healthcare Outcomes & Policy, University of Michigan, 2800 Plymouth Road, North Campus Research Complex, Bldg. 16, Ann Arbor, MI, 48109, USA; Department of Surgery, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA. Electronic address:

Background: Americans living in Health Professional Shortage Areas (HPSA) only have 44% of the required physician workforce to service their residents. We sought to determine whether residents living in HPSA have worse surgical outcomes than those living in non-HPSA.

Methods: We performed a retrospective review of 1,507,834 Medicare beneficiaries undergoing appendectomy, cholecystectomy, colectomy or hernia repair between 2014 and 2018. Multivariable logistical regression was used to determine the association of living in HPSA with rates of 30-day mortality.

Results: Compared with patients living in non-HPSA, patients living in HPSA traveled farther (median distance 35.3 miles vs. 11.7 miles, p < 0.001) and longer (median 45 min vs. 20 min, p < 0.001) for surgical care. Differences in rates of mortality between patients living in HPSA and non-HPSA (6.0% vs. 6.1%, OR = 0.97, 95% CI 0.97-0.97, p < 0.001) were small.

Conclusion: Medicare beneficiaries living in HPSA experience more than double the travel time and triple the travel distance to undergo common surgical procedures compared to those living in non-HPSA. For those able to overcome the travel burden, the differences in surgical outcomes were small.
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http://dx.doi.org/10.1016/j.amjsurg.2022.01.013DOI Listing
January 2022

Heterogeneous weathering of polypropylene in the marine environment.

Sci Total Environ 2022 Mar 22;812:152308. Epub 2021 Dec 22.

The Illinois Sustainable Technology Center, Prairie Research Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

Polypropylene (PP) inkjet cartridges spilled during January 2014 in the northwest Atlantic Ocean from a container ship and subsequently retrieved from beaches around Europe and the Azores along with a matching reference cartridge that had not been exposed to the environment were physically and chemically characterized. Compared with the reference, the cartridges retrieved from the marine environment exhibited considerable cracking-fracturing, discoloration, surface roughness, loss of gloss and staining. Infrared analysis revealed that weathering was highly heterogeneous, with the carbonyl index ranging from <0.1 to >0.9 over areas of sub-mm-dimensions. The high degree of weathering was partly attributed to the presence, quality, and distribution of the titanium dioxide pigment, TiO. Thus, in the absence of sufficient protection by encapsulation or addition of antioxidants, the ultraviolet light-absorbing pigment promoted the formation of free radicals and photocatalytic oxidation. The results of this study show that consumer plastics containing TiO for coloration or tinting purposes, when not designed for exterior use (in the absence of encapsulation or antioxidants), may experience accelerated weathering in the marine environment, and that estimates of plastic persistence should factor in the role of additives that promote photoactivity.
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http://dx.doi.org/10.1016/j.scitotenv.2021.152308DOI Listing
March 2022

The Impact of Medicare Coverage on Downstream Financial Outcomes for Adults Who Undergo Surgery.

Ann Surg 2022 01;275(1):99-105

Center for Healthcare Outcomes and Policy, University of Michigan, Ann Arbor, MI.

Objective: To evaluate the effects of gaining access to Medicare on key financial outcomes for surgical patients.

Summary Background Data: Surgical care poses a significant financial burden, especially among patients with insufficient financial risk protection. Medicare may mitigate the risk of these adverse circumstances, but the impact of Medicare eligibility on surgical patients remains poorly understood.

Methods: Regression discontinuity analysis of national, cross-sectional survey and cost data from the 2008 to 2018 National Health Interview Survey and Medical Expenditure Panel Survey. Patients were between the ages of 57 to 72 with surgery in the past 12 months. The primary outcomes were the presence of medical debt, delay/deferment of care due to cost, total annual out-of-pocket costs, and experiencing catastrophic health expenditures.

Results: Among 45,982,243 National Health Interview Survey patients, Medicare eligibility was associated with a 6.6 percentage-point decrease (95% confidence interval [CI]: -9.0% to -4.3) in being uninsured (>99% relative reduction), 7.6 percentage-point decrease (24% relative reduction) in having medical debt (95%CI: -14.1% to -1.1%), and 4.9 percentage-point decrease (95%CI: -9.4% to -0.4%) in deferrals/delays in medical care due to cost (28% relative reduction). Among 33,084,967 Medical Expenditure Panel Survey patients, annual out-of-pocket spending decreased by $1199 per patient (95%CI: -$1633 to -$765), a 33% relative reduction, and catastrophic health expenditures decreased by 7.3 percentage points (95%CI: -13.6% to -0.1%), a 55% relative reduction.

Conclusions: Medicare may reduce the economic burden of healthcare spending and delays in care for older adult surgical patients. These findings have important implications for policy discussions regarding changing insurance eligibility thresholds for the older adult population.
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http://dx.doi.org/10.1097/SLA.0000000000005272DOI Listing
January 2022

Neuropeptide Y1 receptor antagonism protects β-cells and improves glycemic control in type 2 diabetes.

Mol Metab 2022 01 7;55:101413. Epub 2021 Dec 7.

St. Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia; Department of Medicine, University of Melbourne, Fitzroy, VIC, 3065, Australia. Electronic address:

Objectives: Loss of functional β-cell mass is a key factor contributing to poor glycemic control in advanced type 2 diabetes (T2D). We have previously reported that the inhibition of the neuropeptide Y1 receptor improves the islet transplantation outcome in type 1 diabetes (T1D). The aim of this study was to identify the pathophysiological role of the neuropeptide Y (NPY) system in human T2D and further evaluate the therapeutic potential of using the Y1 receptor antagonist BIBO3304 to improve β-cell function and survival in T2D.

Methods: The gene expression of the NPY system in human islets from nondiabetic subjects and subjects with T2D was determined and correlated with the stimulation index. The glucose-lowering and β-cell-protective effects of BIBO3304, a selective orally bioavailable Y1 receptor antagonist, in high-fat diet (HFD)/multiple low-dose streptozotocin (STZ)-induced and genetically obese (db/db) T2D mouse models were assessed.

Results: In this study, we identified a more than 2-fold increase in NPY1R and its ligand, NPY mRNA expression in human islets from subjects with T2D, which was significantly associated with reduced insulin secretion. Consistently, the pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected β cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, we demonstrated that the inhibition of Y1 receptors by BIBO3304 led to reduced adiposity and enhanced insulin action in the skeletal muscle. Importantly, the Y1 receptor antagonist BIBO3304 treatment also improved β-cell function and preserved functional β-cell mass, thereby resulting in better glycemic control in both HFD/multiple low-dose STZ-induced and db/db T2D mice.

Conclusions: Our results revealed a novel causal link between increased islet NPY-Y1 receptor gene expression and β-cell dysfunction and failure in human T2D, contributing to the understanding of the pathophysiology of T2D. Furthermore, our results demonstrate that the inhibition of the Y1 receptor by BIBO3304 represents a potential β-cell-protective therapy for improving functional β-cell mass and glycemic control in T2D.
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http://dx.doi.org/10.1016/j.molmet.2021.101413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8733231PMC
January 2022

Decreasing time to antibiotic administration in open fractures of the femur and tibia through performance improvement in a statewide trauma: Collaborative quality initiative.

Surgery 2022 03 4;171(3):777-784. Epub 2021 Dec 4.

Department of Surgery, University of Michigan, Ann Arbor, MI.

Background: Open long-bone fractures represent a complex injury within the trauma system. Guidelines recommend antibiotics be given within 60 minutes of patient arrival to the emergency department. We sought to measure and improve the timeliness of antibiotic administration at the patient, hospital, and population level within a collaborative quality initiative.

Methods: Trauma collaborative quality initiative data (January 2017 to December 2020) were analyzed from 34 American College of Surgeons Committee on Trauma verified level 1 and level 2 trauma centers. Inclusion criteria were adult patients (≥16 years), injury severity score ≥5, and open tibia or femur fracture. After the baseline year, hospitals were scored annually on a pay-for-performance metric based on patients receiving antibiotics within 120 minutes of emergency department arrival. Univariate tests examined the differences between baseline and subsequent year(s) performance. A multivariable logistic regression assessed the factors associated with meeting this target time.

Results: There were 2,624 patients with an open long-bone fracture. In the baseline year (2017), 76.9% of patients received antibiotics in ≤120 minutes, with a mean time of 57.9 ± 63.3 minutes. After implementing collaborative quality initiative-wide targets, performance significantly improved in subsequent years (2018, 2019, 2020). The collaborative quality initiative achieved their goal of ≥85% of patients receiving antibiotics in ≤120 minutes in 2019 (87.9%) and 2020 (88.5%), with a mean time of 43.3 ± 54.8 minutes (P < .05 vs 2017).

Conclusion: A pay-for-performance process measure within a statewide trauma collaborative quality initiative improved the timely administration of antibiotics to patients with open fractures. Work remains to align compliance with the guideline target of <60 minutes and to identify factors involved in the delay of administration.
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http://dx.doi.org/10.1016/j.surg.2021.09.040DOI Listing
March 2022

Geriatric All-Terrain Vehicle Trauma: An Unhelmeted and Severely Injured Population.

J Surg Res 2022 02 23;270:555-563. Epub 2021 Nov 23.

Department of Surgery, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH, 03756; Geisel School of Medicine, 1 Rope Ferry Rd, Hanover, NH, 03755. Electronic address:

Background: All-terrain vehicle (ATV) use is widespread, however, little is known about injury patterns and outcomes in geriatric patients. We hypothesized that geriatric patients would have distinct and more severe injuries than non-geriatric adults after ATV trauma.

Methods: A retrospective cohort study was performed using the National Trauma Databank comparing non-geriatric (18-64) and geriatric adults (≥65) presenting after ATV trauma at Level 1 and 2 trauma centers from 2011 to 2015. Demographic, admission, and outcomes data were collected, including injury severity score (ISS), abbreviated injury scale (AIS) score, discharge disposition, and mortality. We performed univariate statistical tests between cohorts and multiple logistic regression models to assess for risk factors associated with severe injury (ISS>15) and mortality.

Results: 23,568 ATV trauma patients were identified, of whom 1,954 (8.3%) were geriatric. Geriatric patients had higher rates of severe injury(29.2 v 22.5%,p<0.0001), and thoracic (55.2 v 37.8%,p<0.0001) and spine (31.5 v 26.0%,p<0.0001) injuries, but lower rates of abdominal injuries (14.6 v 17.9%,p<0.001) as compared to non-geriatric adults. Geriatric patients had overall lower head injury rates (39.2 v 42.1%,p=0.01), but more severe head injuries (AIS>3) (36.2 vs 30.2%,p<0.001). Helmet use was significantly lower in geriatric patients (12.0 v 22.8%,p<0.0001). On multivariate analysis age increased the odds for both severe injury (OR 1.50, 95% CI 1.31-1.72, p<0.0001) and mortality (OR 5.07, 95% CI 3.42-7.50, p<0.0001).

Conclusions: While severe injury and mortality after ATV trauma occurred in all adults, geriatric adults suffered distinct injury patterns and were at greater risk for severe injury and mortality.
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http://dx.doi.org/10.1016/j.jss.2021.09.009DOI Listing
February 2022

Liposome-mediated detection of SARS-CoV-2 RNA-positive extracellular vesicles in plasma.

Nat Nanotechnol 2021 09 22;16(9):1039-1044. Epub 2021 Jul 22.

Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, LA, USA.

Plasma SARS-CoV-2 RNA may represent a viable diagnostic alternative to respiratory RNA levels, which rapidly decline after infection. Quantitative PCR with reverse transcription (RT-qPCR) reference assays exhibit poor performance with plasma, probably reflecting the dilution and degradation of viral RNA released into the circulation, but these issues could be addressed by analysing viral RNA packaged into extracellular vesicles. Here we describe an assay approach in which extracellular vesicles directly captured from plasma are fused with reagent-loaded liposomes to sensitively amplify and detect a SARS-CoV-2 gene target. This approach accurately identified patients with COVID-19, including challenging cases missed by RT-qPCR. SARS-CoV-2-positive extracellular vesicles were detected at day 1 post-infection, and plateaued from day 6 to the day 28 endpoint in a non-human primate model, while signal durations for 20-60 days were observed in young children. This nanotechnology approach uses a non-infectious sample and extends virus detection windows, offering a tool to support COVID-19 diagnosis in patients without SARS-CoV-2 RNA detectable in the respiratory tract.
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http://dx.doi.org/10.1038/s41565-021-00939-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440422PMC
September 2021

Out of Pocket Spending on Common Operations Among the Commercially Insured.

Ann Surg 2021 Jul 16. Epub 2021 Jul 16.

Department of Surgery, Brigham and Women's Hospital, Boston MA Center for Healthcare Outcomes and Policy, Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI Department of Surgery, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1097/SLA.0000000000005081DOI Listing
July 2021

Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes.

J Med Chem 2021 08 15;64(15):10849-10877. Epub 2021 Jul 15.

Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

CAMKK2 is a serine/threonine kinase and an activator of AMPK whose dysregulation is linked with multiple diseases. Unfortunately, STO-609, the tool inhibitor commonly used to probe CAMKK2 signaling, has limitations. To identify promising scaffolds as starting points for the development of high-quality CAMKK2 chemical probes, we utilized a hinge-binding scaffold hopping strategy to design new CAMKK2 inhibitors. Starting from the potent but promiscuous disubstituted 7-azaindole GSK650934, a total of 32 compounds, composed of single-ring, 5,6-, and 6,6-fused heteroaromatic cores, were synthesized. The compound set was specifically designed to probe interactions with the kinase hinge-binding residues. Compared to GSK650394 and STO-609, 13 compounds displayed similar or better CAMKK2 inhibitory potency , while compounds and had improved selectivity for CAMKK2 across the kinome. Our systematic survey of hinge-binding chemotypes identified several potent and selective inhibitors of CAMKK2 to serve as starting points for medicinal chemistry programs.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365604PMC
August 2021

Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965.

Biochem J 2021 08;478(15):2977-2997

Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

SBI-0206965, originally identified as an inhibitor of the autophagy initiator kinase ULK1, has recently been reported as a more potent and selective AMP-activated protein kinase (AMPK) inhibitor relative to the widely used, but promiscuous inhibitor Compound C/Dorsomorphin. Here, we studied the effects of SBI-0206965 on AMPK signalling and metabolic readouts in multiple cell types, including hepatocytes, skeletal muscle cells and adipocytes. We observed SBI-0206965 dose dependently attenuated AMPK activator (991)-stimulated ACC phosphorylation and inhibition of lipogenesis in hepatocytes. SBI-0206965 (≥25 μM) modestly inhibited AMPK signalling in C2C12 myotubes, but also inhibited insulin signalling, insulin-mediated/AMPK-independent glucose uptake, and AICA-riboside uptake. We performed an extended screen of SBI-0206965 against a panel of 140 human protein kinases in vitro, which showed SBI-0206965 inhibits several kinases, including members of AMPK-related kinases (NUAK1, MARK3/4), equally or more potently than AMPK or ULK1. This screen, together with molecular modelling, revealed that most SBI-0206965-sensitive kinases contain a large gatekeeper residue with a preference for methionine at this position. We observed that mutation of the gatekeeper methionine to a smaller side chain amino acid (threonine) rendered AMPK and ULK1 resistant to SBI-0206965 inhibition. These results demonstrate that although SBI-0206965 has utility for delineating AMPK or ULK1 signalling and cellular functions, the compound potently inhibits several other kinases and critical cellular functions such as glucose and nucleoside uptake. Our study demonstrates a role for the gatekeeper residue as a determinant of the inhibitor sensitivity and inhibitor-resistant mutant forms could be exploited as potential controls to probe specific cellular effects of SBI-0206965.
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http://dx.doi.org/10.1042/BCJ20210284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370752PMC
August 2021

Targeting zero preventable trauma readmissions.

J Trauma Acute Care Surg 2021 10;91(4):728-735

From the Department of Surgery (C.S.B., J.R.M., N.F.S., M.R.H., J.W.S.), University of Michigan, Ann Arbor, Michigan; Department of Surgery (P.U.N.), Brigham and Women's Hospital, Boston, Massachusetts; and Center for Healthcare Outcomes and Policy (P.U.N., C.S.B., J.R.M., N.F.S., M.R.H., J.W.S.), and National Clinical Scholars Program (P.U.N.), University of Michigan, Ann Arbor, Michigan.

Background: Nearly 1-in-10 trauma patients in the United States are readmitted within 30 days of discharge, with a median hospital cost of more than $8,000 per readmission. There are national efforts to reduce readmissions in trauma care, but we do not yet understand which are potentially preventable. Our study aims to quantify the potentially preventable readmissions (PPRs) in trauma care to serve as the anchor point for ongoing efforts to curb hospital readmissions and ultimately, bring preventable readmissions to zero.

Methods: We identified inpatient hospitalizations after trauma and readmissions within 90 days in the 2017 National Readmissions Database (NRD). Potentially preventable readmissions were defined as the Agency for Healthcare Research and Quality-defined Ambulatory Care Sensitive Conditions, in addition to superficial surgical site infection, acute kidney injury/acute renal failure, and aspiration pneumonitis. Mean costs for these admissions were calculated using the NRD. A multivariable logistic regression model was used to characterize the relationship between patient characteristics and PPR.

Results: A total of 1,320,083 patients were admitted for trauma care in the 2017 NRD, and 137,854 (10.4%) were readmitted within 90 days of discharge. Of these readmissions, 22.7% were potentially preventable. The mean cost was $10,001/PPR, resulting in $313,802,278 in cost to the US health care system. Of readmitted trauma patients younger than 65 years, Medicaid or Medicare patients had 2.7-fold increased odds of PPRs compared with privately insured patients. Patients of any age with congestive heart failure had 2.9 times increased odds of PPR, those with chronic obstructive pulmonary disease or complicated diabetes mellitus had 1.8 times increased odds, and those with chronic kidney disease had 1.7 times increased odds. Furthermore, as the days from discharge increased, the proportion of readmissions due to PPRs increased.

Conclusion: One-in-five trauma readmissions are potentially preventable, which account for more than $300 million annually in health care costs. Improved access to postdischarge ambulatory care may be key to minimizing PPRs, especially for those with certain comorbidities.

Level Of Evidence: Economic and value-based evaluations, level II.
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http://dx.doi.org/10.1097/TA.0000000000003351DOI Listing
October 2021

Insult to injury: National analysis of return to work and financial outcomes of trauma patients.

J Trauma Acute Care Surg 2021 07;91(1):121-129

From the National Clinician Scholars Program (P.U.N., K.K.T.), Institute for Healthcare Policy and Innovation and Center for Healthcare Outcomes and Policy (P.U.N., K.K.T., B.S., N.F.S., M.R.H., J.W.S.), University of Michigan, Ann Arbor, Michigan; Department of Surgery (P.U.N., G.A.A.), Brigham and Women's Hospital, Boston, Massachusetts; Department of Surgery (K.K.T.), Stanford University, Stanford, California; Center for Surgery and Public Health (G.A.A.), Brigham and Women's Hospital, Boston, Massachusetts; and Department of Surgery (N.F.S., M.R.H., J.W.S.), University of Michigan, Ann Arbor, Michigan.

Background: While much of trauma care is rightly focused on improving inpatient survival, the ultimate goal of recovery is to help patients return to their daily lives after injury. Although the overwhelming majority of trauma patients in the United States survive to hospital discharge, little is known nationally regarding the postdischarge economic burden of injuries among trauma survivors.

Methods: We used the National Health Interview Survey from 2008 to 2017 to identify working-age trauma patients, aged 18 to 64 years, who sustained injuries requiring hospitalization. We used propensity score matching to identify noninjured respondents. Our primary outcome measure was postinjury return to work among trauma patients. Our secondary outcomes included measures of food insecurity, medical debt, accessibility and affordability of health care, and disability.

Results: A nationally weighted sample of 319,580 working-age trauma patients were identified. Of these patients, 51.7% were employed at the time of injury, and 58.9% of them had returned to work at the time of interview, at a median of 47 days postdischarge. Higher rates of returning to work were associated with shorter length of hospital stay, higher education level, and private health insurance. Injury was associated with food insecurity at an adjusted odds ratio (aOR) of 1.8 (95% confidence interval, 1.40-2.37), with difficulty affording health care at aOR of 1.6 (1.00-2.47), with medical debt at aOR of 2.6 (2.11-3.20), and with foregoing care due to cost at aOR of 2.0 (1.52-2.63). Working-age trauma patients had disability at an aOR of 17.6 (12.93-24.05).

Conclusion: The postdischarge burden of injury among working-age US trauma survivors is profound-patients report significant limitations in employment, financial security, disability, and functional independence. A better understanding of the long-term impact of injury is necessary to design the interventions needed to optimize postinjury recovery so that trauma survivors can lead productive and fulfilling lives after injury.

Level Of Evidence: Economic & Value-Based Evaluations, level II; Prognostic, level II.
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http://dx.doi.org/10.1097/TA.0000000000003135DOI Listing
July 2021

Prehospital care for traumatic spinal cord injury by first responders in 8 sub-Saharan African countries and 6 other low- and middle-income countries: A scoping review.

Afr J Emerg Med 2021 Sep 6;11(3):339-346. Epub 2021 Jun 6.

Michigan Center for Global Surgery, United States of America.

Introduction: Traumatic spinal cord injury (TSCI) constitutes a considerable portion of the global injury burden, disproportionately affecting low- and middle-income countries (LMICs). Prehospital care can address TSCI morbidity and mortality, but emergency medical services are lacking in LMICs. The current standard of prehospital care for TSCI in sub-Saharan Africa and other LMICs is unknown.

Methods: This review sought to describe the state of training and resources for prehospital TSCI management in sub-Saharan Africa and other LMICs. Articles published between 1 January 1995 and 1 March 2020 were identified using PMC, MEDLINE, and Scopus databases following PRISMA-ScR guidelines. Inclusion criteria spanned first responder training programs delivering prehospital care for TSCI. Two reviewers assessed full texts meeting inclusion criteria for quality using the Newcastle-Ottawa Scale and extracted relevant characteristics to assess trends in the state of prehospital TSCI care in sub-Saharan Africa and other LMICs.

Results: Of an initial 482 articles identified, 23 met inclusion criteria, of which ten were set in Africa, representing eight countries. C-spine immobilization precautions for suspected TSCI patients is the most prevalent prehospital TSCI intervention for and is in every LMIC first responder program reviewed, except one. Numerous first responder programs providing TSCI care operate without C-collar access (n = 13) and few teach full spinal immobilization (n = 5). Rapid transport is most frequently reported as the key mortality-reducing factor (n = 11). Despite more studies conducted in the Southeast Asia/Middle East (n = 13), prehospital TSCI studies in Africa are more geographically diverse, but responder courses are shorter, produce fewer professional responders, and have limited C-collar availability.

Discussion: Deficits in training and resources to manage TSCI highlights the need for large prospective trials evaluating alternative C-spine immobilization methods for TCSI that are more readily available across diverse LMIC environments and the importance of understanding resource variability to sustainably improve prehospital TSCI care.
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http://dx.doi.org/10.1016/j.afjem.2021.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187159PMC
September 2021

Hospital effects drive variation in access to inpatient rehabilitation after trauma.

J Trauma Acute Care Surg 2021 08;91(2):413-421

From the Department of Surgery (A.L., J.R.M., N.F.S., M.R.H., J.B.D., J.W.S.), Center for Health Outcomes and Policy (A.L., J.R.M., Z.F., M.R.H., J.B.D., J.W.S.), and Department of Orthopaedic Surgery (B.W.O.), University of Michigan, Ann Arbor, Michigan.

Background: Postacute care rehabilitation is critically important to recover after trauma, but many patients do not have access. A better understanding of the drivers behind inpatient rehabilitation facility (IRF) use has the potential for major cost-savings as well as higher-quality and more equitable patient care. We sought to quantify the variation in hospital rates of trauma patient discharge to inpatient rehabilitation and understand which factors (patient vs. injury vs. hospital level) contribute the most.

Methods: We performed a retrospective cohort study of 668,305 adult trauma patients admitted to 900 levels I to IV trauma centers between 2011 and 2015 using the National Trauma Data Bank. Participants were included if they met the following criteria: age >18 years, Injury Severity Score of ≥9, identifiable injury type, and who had one of the Centers for Medicare & Medicaid Services preferred diagnoses for inpatient rehabilitation under the "60% rule."

Results: The overall risk- and reliability-adjusted hospital rates of discharge to IRF averaged 18.8% in the nonelderly adult cohort (18-64 years old) and 23.4% in the older adult cohort (65 years or older). Despite controlling for all patient-, injury-, and hospital-level factors, hospital discharge of patients to IRF varied substantially between hospital quintiles and ranged from 9% to 30% in the nonelderly adult cohort and from 7% to 46% in the older adult cohort. Proportions of total variance ranged from 2.4% (patient insurance) to 12.1% (injury-level factors) in the nonelderly adult cohort and from 0.3% (patient-level factors) to 26.0% (unmeasured hospital-level factors) in the older adult cohort.

Conclusion: Among a cohort of injured patients with diagnoses that are associated with significant rehabilitation needs, the hospital at which a patient receives their care may drive a patient's likelihood of recovering at an IRF just as much, if not more, than their clinical attributes.

Level Of Evidence: Care management, level IV.
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http://dx.doi.org/10.1097/TA.0000000000003215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375412PMC
August 2021

Perfluoroalkylated Substances (PFAS) Associated with Microplastics in a Lake Environment.

Toxics 2021 May 11;9(5). Epub 2021 May 11.

Annis Water Resources Institute, Grand Valley State University, Muskegon, MI 49441, USA.

The presence of both microplastics and per- and polyfluoroalkyl substances (PFAS) is ubiquitous in the environment. The ecological impacts associated with their presence are still poorly understood, however, these contaminants are extremely persistent. Although plastic in the environment can concentrate pollutants, factors such as the type of plastic and duration of environmental exposure as it relates to the degree of adsorption have received far less attention. To address these knowledge gaps, experiments were carried out that examined the interactions of PFAS and microplastics in the field and in a controlled environment. For field experiments, we measured the abundance of PFAS on different polymer types of microplastics that were deployed in a lake for 1 month and 3 months. Based on these results, a controlled experiment was conducted to assess the adsorption properties of microplastics in the absence of associated inorganic and organic matter. The adsorption of PFAS was much greater on the field-incubated plastic than what was observed in the laboratory with plastic and water alone, 24 to 259 times versus one-seventh to one-fourth times background levels. These results suggest that adsorption of PFAS by microplastics is greatly enhanced by the presence of inorganic and/or organic matter associated with these materials in the environment, and could present an environmental hazard for aquatic biota.
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http://dx.doi.org/10.3390/toxics9050106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151042PMC
May 2021

Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders.

Int J Mol Sci 2021 Apr 14;22(8). Epub 2021 Apr 14.

St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.

As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle-brain, liver-brain and gut-brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise-brain communication and their benefits for physiology and brain function.
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http://dx.doi.org/10.3390/ijms22084052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070923PMC
April 2021

Evaluating a Novel Prehospital Emergency Trauma Care Assessment Tool (PETCAT) for Low- and Middle-Income Countries in Sierra Leone.

World J Surg 2021 08 28;45(8):2370-2377. Epub 2021 Apr 28.

University of Michigan Health System, Ann Arbor, MI, USA.

Background: WHO recommends training lay first responders (LFRs) as the first step toward formal emergency medical services development, yet no tool exists to evaluate LFR programs.

Methods: We developed Prehospital Emergency Trauma Care Assessment Tool (PETCAT), a seven-question survey administered to first-line hospital-based healthcare providers, to independently assess LFR prehospital intervention frequency and quality. PETCAT surveys were administered one month pre-LFR program launch (June 2019) in Makeni, Sierra Leone and again 14 months post-launch (August 2020). Using a difference-in-differences approach, PETCAT was also administered in a control city (Kenema) with no LFR training intervention during the study period at the same intervals to control for secular trends. PETCAT measured change in both the experimental and control locations. Cronbach's alpha, point bi-serial correlation, and inter-rater reliability using Cohen's Kappa assessed PETCAT reliability.

Results: PETCAT administration to 90 first-line, hospital-based healthcare providers found baseline prehospital intervention were rare in Makeni and Kenema prior to LFR program launch (1.2/10 vs. 1.8/10). Fourteen months post-LFR program implementation, PETCAT demonstrated prehospital interventions increased in Makeni with LFRs (5.2/10, p < 0.0001) and not in Kenema (1.2/10) by an adjusted difference of + 4.6 points/10 (p < 0.0001) ("never/rarely" to "half the time"), indicating negligible change due to secular trends. PETCAT demonstrated high reliability (Cronbach's α = 0.93, Cohen's K = 0.62).

Conclusions: PETCAT measures changes in rates of prehospital care delivery by LFRs in a resource-limited African setting and may serve as a robust tool for independent EMS quality assessment.
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http://dx.doi.org/10.1007/s00268-021-06140-1DOI Listing
August 2021

Assessment of Potentially Preventable Hospital Readmissions After Major Surgery and Association With Public vs Private Health Insurance and Comorbidities.

JAMA Netw Open 2021 04 1;4(4):e215503. Epub 2021 Apr 1.

Department of Surgery, University of Michigan, Ann Arbor.

Importance: Rehospitalization after major surgery is common and represents a significant cost to the health care system. Little is known regarding the causes of these readmissions and the degree to which they may be preventable.

Objective: To evaluate the degree to which readmissions after major surgery are potentially preventable.

Design, Setting, And Participants: This retrospective cohort study used a weighted sample of 1 937 354 patients from the 2017 National Readmissions Database to evaluate all adult inpatient hospitalizations for 1 of 7 common major surgical procedures. Statistical analysis was performed from January 14 to November 30, 2020.

Main Outcomes And Measures: The study calculated 90-day readmission rates as well as rates of readmissions that were considered potentially preventable. Potentially preventable readmissions (PPRs) were defined as those with a primary diagnosis code for superficial surgical site infection, acute kidney injury, aspiration pneumonitis, or any of the Agency for Healthcare Research and Quality-defined ambulatory care sensitive conditions. Multivariable logistic regression was used to identify factors associated with PPRs.

Results: A total weighted sample of 1 937 354 patients (1 048 046 women [54.1%]; mean age, 66.1 years [95% CI, 66.0-66.3 years]) underwent surgical procedures; 164 755 (8.5%) experienced a readmission within 90 days. Potentially preventable readmissions accounted for 29 321 (17.8%) of all 90-day readmissions, for an estimated total cost to the US health care system of approximately $296 million. The most common reasons for PPRs were congestive heart failure exacerbation (34.6%), pneumonia (12.0%), and acute kidney injury (22.5%). In a multivariable model of adults aged 18 to 64 years, patients with public health insurance (Medicare or Medicaid) had more than twice the odds of PPR compared with those with private insurance (adjusted odds ratio, 2.09; 95% CI, 1.94-2.25). Among patients aged 65 years or older, patients with private insured had 18% lower odds of PPR compared with patients with Medicare as the primary payer (adjusted odds ratio, 0.82; 95% CI, 0.74-0.90).

Conclusions And Relevance: This study suggests that nearly 1 in 5 readmissions after surgery are potentially preventable and account for nearly $300 million in costs. In addition to better inpatient care, improved access to ambulatory care may represent an opportunity to reduce costly readmissions among surgical patients.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.5503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044735PMC
April 2021

Regulation of Pancreatic β-Cell Function by the NPY System.

Endocrinology 2021 08;162(8)

St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.

The neuropeptide Y (NPY) system has been recognized as one of the most critical molecules in the regulation of energy homeostasis and glucose metabolism. Abnormal levels of NPY have been shown to contribute to the development of metabolic disorders including obesity, cardiovascular diseases, and diabetes. NPY centrally promotes feeding and reduces energy expenditure, while the other family members, peptide YY (PYY) and pancreatic polypeptide (PP), mediate satiety. New evidence has uncovered additional functions for these peptides that go beyond energy expenditure and appetite regulation, indicating a more extensive function in controlling other physiological functions. In this review, we will discuss the role of the NPY system in the regulation of pancreatic β-cell function and its therapeutic implications for diabetes.
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http://dx.doi.org/10.1210/endocr/bqab070DOI Listing
August 2021
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