Publications by authors named "John W Scott"

166 Publications

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

JAMA Netw Open 2021 Apr 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
April 2021

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

Endocrinology 2021 Apr 7. Epub 2021 Apr 7.

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

The neuropeptide Y (NPY) system has been recognised 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
April 2021

Compound- and fiber type-selective requirement of AMPKγ3 for insulin-independent glucose uptake in skeletal muscle.

Mol Metab 2021 Mar 30:101228. Epub 2021 Mar 30.

Nestlé Research, Société des Produits Nestlé S.A., EPFL Innovation Park, Lausanne, 1015, Switzerland; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, 2200, Denmark. Electronic address:

Objective: The metabolic master-switch AMP-activated protein kinase (AMPK) mediates insulin-independent glucose uptake in muscle and regulates the metabolic activity of brown and beige adipose tissue (BAT). The regulatory AMPKγ3 isoform is uniquely expressed in skeletal muscle and also potentially in BAT. Here, we investigated the role that AMPKγ3 plays in mediating skeletal muscle glucose uptake and whole-body glucose clearance in response to small-molecule activators that act on AMPK via distinct mechanisms. We also assessed if γ3 plays a role in adipose thermogenesis and browning.

Methods: Global AMPKγ3 knockout (KO) mice were generated. A systematic whole-body, tissue and molecular phenotyping linked to glucose homeostasis was performed in γ3 KO and wild type (WT) mice. Glucose uptake in glycolytic and oxidative skeletal muscle ex vivo, as well as blood glucose clearance in response to small molecule AMPK activators that target nucleotide-binding domain of γ subunit (AICAR) and allosteric drug and metabolite (ADaM) site located at the interface of the α and β subunit (991, MK-8722) were assessed. Oxygen consumption, thermography, and molecular phenotyping with a β3-adrenergic receptor agonist (CL-316,243) treatment were performed to assess BAT thermogenesis, characteristics and function.

Results: Genetic ablation of γ3 did not affect body weight, body composition, physical activity, and parameters associated with glucose homeostasis under chow or high fat diet. γ3 deficiency had no effect on fiber-type composition, mitochondrial content and components, or insulin-stimulated glucose uptake in skeletal muscle. Glycolytic muscles in γ3 KO mice showed a partial loss of AMPKα2 activity, which was associated with reduced levels of AMPKα2 and β2 subunit isoforms. Notably, γ3 deficiency resulted in a selective loss of AICAR-, but not MK-8722-induced blood glucose-lowering in vivo and glucose uptake specifically in glycolytic muscle ex vivo. We detected γ3 in BAT and found that it preferentially interacts with α2 and β2. We observed no differences in oxygen consumption, thermogenesis, morphology of BAT and inguinal white adipose tissue (iWAT), or markers of BAT activity between WT and γ3 KO mice.

Conclusions: These results demonstrate that γ3 plays a key role in mediating AICAR- but not ADaM site binding drug-stimulated blood glucose clearance and glucose uptake specifically in glycolytic skeletal muscle. We also showed that γ3 is dispensable for β3-adrenergic receptor agonist-induced thermogenesis and browning of iWAT.
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http://dx.doi.org/10.1016/j.molmet.2021.101228DOI Listing
March 2021

Injured and broke: The impacts of the Ghana National Health Insurance Scheme (NHIS) on service delivery and catastrophic health expenditure among seriously injured children.

Afr J Emerg Med 2021 Mar 16;11(1):144-151. Epub 2020 Nov 16.

Department of Surgery, University of Washington, Seattle, WA, USA, Global Injury Control Section, Harborview Injury Prevention and Research Center.

Introduction: Ghana implemented a National Health Insurance Scheme (NHIS) in 2003 as a step toward universal health coverage. We aimed to determine the effect of the NHIS on timeliness of care, mortality, and catastrophic health expenditure (CHE) among children with serious injuries at a trauma center in Ghana.

Methods: We performed a retrospective cohort study of injured children aged <18 years who required surgery (i.e., proxy for serious injury) at Komfo Anokye Teaching Hospital from 2015 to 2016. Household income data was obtained from the Ghana Statistical Service. CHE was defined as out-of-pocket payments to annual household income ≥10%. Differences in insured and uninsured children were described. Multivariable regression was used to assess the effect of NHIS on time to surgery, length of stay, in-hospital mortality, out-of-pocket expenditure and CHE.

Results: Of the 263 children who met inclusion criteria, 70% were insured. Mechanism of injury, triage scores and Kampala Trauma Score II were similar in both groups (all  > 0.10). Uninsured children were more likely to have a delay in care for financial reasons (17.3 vs 6.4%,  < 0.001) than insured children, and the families of uninsured children paid a median of 1.7 times more out-of-pocket costs than families with insured children (p < 0.001). Eighty-six percent of families of uninsured children experienced CHE compared to 54% of families of insured children (p < 0.001); however, 64% of all families experienced CHE. Insurance was protective against CHE (aOR 0.21, 95%CI 0.08-0.55).

Conclusions: NHIS did not improve timeliness of care, length of stay or mortality. Although NHIS did provide some financial risk protection for families, it did not eliminate out-of-pocket payments. The families of most seriously injured children experienced CHE, regardless of insurance status. NHIS and similar financial risk pooling schemes could be strengthened to better provide financial risk protection and promote quality of care for injured children.
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http://dx.doi.org/10.1016/j.afjem.2020.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910164PMC
March 2021

Threats to the Affordable Care Act and surgical care: What has been gained, and what could be lost.

Surgery 2021 Feb 27. Epub 2021 Feb 27.

Institute for Healthcare Policy and Innovation, University of Michigan Medical School, Ann Arbor, MI; Division of General Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI. Electronic address: https://twitter.com/jzayanian.

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http://dx.doi.org/10.1016/j.surg.2021.01.031DOI Listing
February 2021

The ACA at 10 Years: Evaluating the Evidence and Navigating an Uncertain Future.

J Surg Res 2021 Feb 25;263:102-109. Epub 2021 Feb 25.

Center for Healthcare Outcomes and Policy, University of Michigan, Ann Arbor, Michigan; Department of Surgery, University of Michigan, Ann Arbor, Michigan. Electronic address:

The year 2020 marks the 10th anniversary of the signing of the Affordable Care Act (ACA). Perhaps the greatest overhaul of the US health care system in the past 50 y, the ACA sought to expand access to care, improve quality, and reduce health care costs. Over the past decade, there have been a number of challenges and changes to the law, which remains in evolution. While the ACA's policies were not intended to specifically target surgical care, surgical patients, surgeons, and the health systems within which they function have all been greatly affected. This article aims to provide a brief overview of the impact of the ACA on surgical patients in reference to its tripartite aim of improving access, improving quality, and reducing costs.
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http://dx.doi.org/10.1016/j.jss.2020.12.056DOI Listing
February 2021

Rare earth elements in plastics.

Sci Total Environ 2021 Jun 6;774:145405. Epub 2021 Feb 6.

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

Because of their unique properties, rare earth elements (REEs), comprising the lanthanide elements plus Sc and Y, have a variety of integral applications in modern electronic equipment. Consequently, it has been suggested that REEs may act as contaminants of and tracers for recycled electrical and electronic plastics in consumer goods. In this study, REEs have been determined in a range of consumer plastics of different polymeric makeup (n = 31), and purchased new and in societal circulation, by inductively coupled plasma-mass spectrometry following acid digestion. Samples were also screened by X-ray fluorescence spectrometry for Br and Sb as markers of brominated flame retardants and the retardant synergist, SbO, respectively. One or more REE was detected in 24 samples, with four samples returning detectable concentrations of all REEs analysed and with total REE concentrations up to 8 mg kg. REEs were most commonly observed in samples containing Br and Sb at levels insufficient to effect flame retardancy and, therefore, likely derived from recycled electronic plastic, but were not detectable in new electrical plastics. Various REEs were also present in plastics with no detectable Br and Sb, however, and where unregulated recycling is prohibited (e.g. food packaging). This observation, and correlations between pairs of REEs for all samples considered, suggests a more generic source of these elements in consumer plastics in addition to the recycling of electrical and electronic waste. REEs reported in the literature for beached marine plastics were characterised by similar concentrations and inter-element correlations, suggesting that REEs are ubiquitous and pervasive contaminants of both contemporary and historical consumer and environmental plastics.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145405DOI Listing
June 2021

Sensitive tracking of circulating viral RNA through all stages of SARS-CoV-2 infection.

J Clin Invest 2021 04;131(7)

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

BACKGROUNDCirculating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA may represent a more reliable indicator of infection than nasal RNA, but quantitative reverse transcription PCR (RT-qPCR) lacks diagnostic sensitivity for blood samples.METHODSA CRISPR-augmented RT-PCR assay that sensitively detects SARS-CoV-2 RNA was employed to analyze viral RNA kinetics in longitudinal plasma samples from nonhuman primates (NHPs) after virus exposure; to evaluate the utility of blood SARS-CoV-2 RNA detection for coronavirus disease 2019 (COVID-19) diagnosis in adults cases confirmed by nasal/nasopharyngeal swab RT-PCR results; and to identify suspected COVID-19 cases in pediatric and at-risk adult populations with negative nasal swab RT-qPCR results. All blood samples were analyzed by RT-qPCR to allow direct comparisons.RESULTSCRISPR-augmented RT-PCR consistently detected SARS-CoV-2 RNA in the plasma of experimentally infected NHPs from 1 to 28 days after infection, and these increases preceded and correlated with rectal swab viral RNA increases. In a patient cohort (n = 159), this blood-based assay demonstrated 91.2% diagnostic sensitivity and 99.2% diagnostic specificity versus a comparator RT-qPCR nasal/nasopharyngeal test, whereas RT-qPCR exhibited 44.1% diagnostic sensitivity and 100% specificity for the same blood samples. This CRISPR-augmented RT-PCR assay also accurately identified patients with COVID-19 using one or more negative nasal swab RT-qPCR results.CONCLUSIONResults of this study indicate that sensitive detection of SARS-CoV-2 RNA in blood by CRISPR-augmented RT-PCR permits accurate COVID-19 diagnosis, and can detect COVID-19 cases with transient or negative nasal swab RT-qPCR results, suggesting that this approach could improve COVID-19 diagnosis and the evaluation of SARS-CoV-2 infection clearance, and predict the severity of infection.TRIAL REGISTRATIONClinicalTrials.gov. NCT04358211.FUNDINGDepartment of Defense, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and the National Center for Research Resources.
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http://dx.doi.org/10.1172/JCI146031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011898PMC
April 2021

Geriatric Snowmobile Trauma: Longer Courses After Similar Injuries.

J Surg Res 2021 Jun 4;262:85-92. Epub 2021 Feb 4.

Department of Surgery, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, New Hampshire; Geisel School of Medicine, Hanover, New Hampshire. Electronic address:

Background: Snowmobiling is a popular activity that leads to geriatric trauma admissions; however, this unique trauma population is not well characterized. We aimed to compare the injury burden and outcomes for geriatric versus nongeriatric adults injured riding snowmobiles.

Materials And Methods: A retrospective cohort study was performed using the National Trauma Databank comparing nongeriatric (18-64) and geriatric adults (≥65) presenting after snowmobile-related trauma at level 1 and 2 trauma centers from 2011 to 2015. Demographic, admission, injury, and outcome data were collected and compared. A multivariate logistic regression model assessed for risk factors associated with severe injury (Injury Severity Score >15). Analysis was also performed using chi square, analysis of variance, and Kruskal-Wallis testing.

Results: A total of 2471 adult patients with snowmobile trauma were identified; 122 (4.9%) were geriatric. Rates of severe injury (Injury Severity Score >15) were similar between groups, 27.5% in geriatric patients and 22.5% in nongeriatric adults (P = 0.2). Geriatric patients experienced higher rates of lower extremity injury (50.4 versus 40.3%, P = 0.03), neck injury (4.1 versus 1.4%, P = 0.02), and severe spine injury (20.6 versus 7.0%, P = 0.004). Geriatric patients had longer hospitalizations (5 versus 3 d, P < 0.0001), rates of discharge to a facility (36.8% versus 12%, P < 0.0001), and higher mortality (4.1 versus 0.6%, P < 0.0001). Geriatric age did not independently increase the risk for severe injury.

Conclusions: Geriatric age was not a significant predictor of severe injury after snowmobile trauma; however, geriatric patients suffered unique injuries, had longer hospitalizations, had higher rates of discharge to a facility, and had higher mortality. Tailored geriatric care may improve outcomes in this unique sport-related trauma population.
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http://dx.doi.org/10.1016/j.jss.2020.12.060DOI Listing
June 2021

Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase.

Int J Mol Sci 2021 Jan 27;22(3). Epub 2021 Jan 27.

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

Physical exercise elicits physiological metabolic perturbations such as energetic and oxidative stress; however, a diverse range of cellular processes are stimulated in response to combat these challenges and maintain cellular energy homeostasis. AMP-activated protein kinase (AMPK) is a highly conserved enzyme that acts as a metabolic fuel sensor and is central to this adaptive response to exercise. The complexity of AMPK's role in modulating a range of cellular signalling cascades is well documented, yet aside from its well-characterised regulation by activation loop phosphorylation, AMPK is further subject to a multitude of additional regulatory stimuli. Therefore, in this review we comprehensively outline current knowledge around the post-translational modifications of AMPK, including novel phosphorylation sites, as well as underappreciated roles for ubiquitination, sumoylation, acetylation, methylation and oxidation. We provide insight into the physiological ramifications of these AMPK modifications, which not only affect its activity, but also subcellular localisation, nutrient interactions and protein stability. Lastly, we highlight the current knowledge gaps in this area of AMPK research and provide perspectives on how the field can apply greater rigour to the characterisation of novel AMPK regulatory modifications.
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http://dx.doi.org/10.3390/ijms22031229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866021PMC
January 2021

Quantifying lives lost due to variability in emergency general surgery outcomes: Why we need a national emergency general surgery quality improvement program.

J Trauma Acute Care Surg 2021 Apr;90(4):685-693

From the Department of Surgery (Z.G.H., M.P.J., J.M.H., E.G., Z.C., A.S., A.H.H.), Brigham and Women's Hospital, Center for Surgery and Public Health, Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Surgery (J.W.S.), University of Michigan, Ann Arbor, Michigan; Department of Emergency Medicine (E.G.), Brigham and Women's Hospital, Boston, Massachusetts; and The Dean's Office, Medical College (A.H.H.), Aga Khan University, Karachi, Pakistan.

Background: Nearly 4 million Americans present to hospitals with conditions requiring emergency general surgery (EGS) annually, facing significant morbidity and mortality. Unlike elective surgery and trauma, there is no dedicated national quality improvement program to improve EGS outcomes. Our objective was to estimate the number of excess deaths that could potentially be averted through EGS quality improvement in the United States.

Methods: Adults with the American Association for the Surgery of Trauma-defined EGS diagnoses were identified in the Nationwide Emergency Department Sample 2006 to 2014. Hierarchical logistic regression was performed to benchmark treating hospitals into reliability adjusted mortality quintiles. Weighted generalized linear modeling was used to calculate the relative risk of mortality at each hospital quintile, relative to best-performing quintile. We then calculated the number of excess deaths at each hospital quintile versus the best-performing quintile using techniques previously used to quantify potentially preventable trauma deaths.

Results: Twenty-six million EGS patients were admitted, and 6.5 million (25%) underwent an operation. In-hospital mortality varied from 0.3% to 4.1% across the treating hospitals. Relative to the best-performing hospital quintile, an estimated 158,177 (153,509-162,736) excess EGS deaths occurred at lower-performing hospital quintiles. Overall, 47% of excess deaths occurred at the worst-performing hospitals, while 27% of all excess deaths occurred among the operative cohort.

Conclusion: Nearly 200,000 excess EGS deaths occur across the United States each decade. A national initiative to enable structures and processes of care associated with optimal EGS outcomes is urgently needed to achieve "Zero Preventable Deaths after Emergency General Surgery."

Level Of Evidence: Care management, level IV.
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http://dx.doi.org/10.1097/TA.0000000000003074DOI Listing
April 2021

Wastewater treatment alters microbial colonization of microplastics.

PLoS One 2021 6;16(1):e0244443. Epub 2021 Jan 6.

Department of Biology, Loyola University Chicago, Chicago, Illinois, United States of America.

Microplastics are ubiquitous contaminants in aquatic habitats globally, and wastewater treatment plants (WWTPs) are point sources of microplastics. Within aquatic habitats microplastics are colonized by microbial biofilms, which can include pathogenic taxa and taxa associated with plastic breakdown. Microplastics enter WWTPs in sewage and exit in sludge or effluent, but the role that WWTPs play in establishing or modifying microplastic bacterial assemblages is unknown. We analyzed microplastics and associated biofilms in raw sewage, effluent water, and sludge from two WWTPs. Both plants retained >99% of influent microplastics in sludge, and sludge microplastics showed higher bacterial species richness and higher abundance of taxa associated with bioflocculation (e.g. Xanthomonas) than influent microplastics, suggesting that colonization of microplastics within the WWTP may play a role in retention. Microplastics in WWTP effluent included significantly lower abundances of some potentially pathogenic bacterial taxa (e.g. Campylobacteraceae) compared to influent microplastics; however, other potentially pathogenic taxa (e.g. Acinetobacter) remained abundant on effluent microplastics, and several taxa linked to plastic breakdown (e.g. Klebsiella, Pseudomonas, and Sphingomonas) were significantly more abundant on effluent compared to influent microplastics. These results indicate that diverse bacterial assemblages colonize microplastics within sewage and that WWTPs can play a significant role in modifying the microplastic-associated assemblages, which may affect the fate of microplastics within the WWTPs and the environment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244443PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787475PMC
January 2021

Factors associated with optimal patient outcomes after operative repair of isolated hip fractures in the elderly.

Trauma Surg Acute Care Open 2020 22;5(1):e000630. Epub 2020 Dec 22.

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

Background: Increased time to operative intervention is associated with a greater risk of mortality and complications in adults with a hip fracture. This study sought to determine factors associated with timeliness of operation in elderly patients presenting with an isolated hip fracture and the influence of surgical delay on outcomes.

Methods: Trauma quality collaborative data (July 2016 to June 2019) were analyzed. Inclusion criteria were patients ≥65 years with an injury mechanism of fall, Abbreviated Injury Scale (AIS) 2005 diagnosis of hip fracture, and AIS extremity ≤3. Exclusion criteria included AIS in other body regions >1 and non-operative management. We examined the association of demographic, hospital, injury presentation, and comorbidity factors on a surgical delay >48 hours and patient outcomes using multivariable regression analysis.

Results: 10 182 patients fit our study criteria out of 212 620 patients. Mean age was 82.7±8.6 years and 68.7% were female. Delay in operation >48 hours occurred in 965 (9.5%) of patients. Factors that significantly increased mortality or discharge to hospice were increased age, male gender, emergency department hypotension, functionally dependent health status (FDHS), advanced directive, liver disease, angina, and congestive heart failure (CHF). Delay >48 hours was associated with increased mortality or discharge to hospice (OR 1.52; 95% CI 1.13 to 2.06; p<0.01). Trauma center verification level, admission service, and hip fracture volume were not associated with mortality or discharge to hospice. Factors associated with operative delay >48 hours were male gender, FDHS, CHF, chronic renal failure, and advanced directive. Admission to the orthopedic surgery service was associated with less incidence of delay >48 hours (OR 0.43; 95% CI 0.29 to 0.64; p<0.001).

Discussion: Hospital verification level, admission service, and patient volume did not impact the outcome of mortality/discharge to hospice. Delay to operation >48 hours was associated with increased mortality. The only measured modifiable characteristic that reduced delay to operative intervention was admission to the orthopedic surgery service.

Level Of Evidence: III.
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http://dx.doi.org/10.1136/tsaco-2020-000630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757513PMC
December 2020

Is Initial Board Certification Associated with Better Early-Career Surgical Outcomes?

Ann Surg 2020 Dec 18;Publish Ahead of Print. Epub 2020 Dec 18.

Center for Surgical Training and Research, Department of Surgery, University of Michigan, Ann Arbor, MI Department of Surgery, University of Michigan, Ann Arbor, MI American Board of Surgery, Philadelphia, Pennsylvania Consulting for Statistics, Computing and Analytics Research, University of Michigan, Ann Arbor, MI Center for Healthcare Outcomes and Policy, Department of Surgery, University of Michigan, Ann Arbor, MI.

Objective: To determine if initial American Board of Surgery certification in general surgery is associated with better risk-adjusted patient outcomes for Medicare patients undergoing partial colectomy by an early career surgeon.

Background: Board certification is a voluntary commitment to professionalism, continued learning and delivery of high-quality patient care. Not all surgeons are certified, and some have questioned the value of certification due to limited evidence that board-certified surgeons have better patient outcomes. In response, we examined the outcomes of certified vs. non-certified early career general surgeons.

Methods: We identified Medicare patients who underwent a partial colectomy between 2008-2016 and were operated on by a non-subspecialty trained surgeon within their first 5 years of practice. Surgeon certification status was determined using American Board of Surgery data. Generalized linear mixed models were used to control for patient-, procedure- and hospital-level effects. Primary outcomes were the occurrence of severe complications and occurrence of death within 30 days.

Results: We identified 69,325 patients who underwent a partial colectomy by an early career general surgeon. The adjusted rate of severe complications after partial colectomy by certified (n = 4,239) vs. non-certified (n = 191) early-career general surgeons was 9.1% vs. 10.7% (OR 0.83, p = 0.03). Adjusted mortality rate for certified vs. non-certified early-career general surgeons was 4.9% vs. 6.1% (OR 0.79, p = 0.01).

Conclusion: Patients undergoing partial colectomy by an early career general surgeon have decreased odds of severe complications and death when their surgeon is board certified.
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http://dx.doi.org/10.1097/SLA.0000000000004709DOI Listing
December 2020

The impact of data feedback on continuous quality improvement projects in Rwanda: A mixed methods analysis.

Afr J Emerg Med 2020 3;10(Suppl 1):S78-S84. Epub 2020 Sep 3.

Virginia Commonwealth University, United States of America.

Background: Injuries are a leading cause of death and disability globally. Over 90% of injury-related mortality happens in low- and middle- income countries (LMICs). Rwanda's pre-hospital emergency system - Service d'Aide Medicale Urgente (SAMU) - and their partners created an electronic pre-hospital registry and Continuous Quality Improvement (CQI) project in 2014. The CQI showed progress in quality of care, sparking interest in factors enabling the project's success. Healthcare workers (HCW) are critical pieces of this success, yet we found a void of information linking pre-hospital HCW motivation to CQI programs like SAMU's.

Methods: Our mixed methods approach included a 40-question survey using questions regarding HCW motivation. We scored the surveys to compare SAMU staff motivation with other HCWs in LMICs, and used a Likert scale to elicit agreement or disagreement. A semi-structured interview based on employee motivation theory qualitatively explored SAMU staff motivation using constructivist grounded theory. To find interview themes, two researchers independently performed line-by-line analysis.

Results: SAMU staff received 5-21% higher motivation scores relative to other cohorts of HCWs in LMICs. Questions showing disagreement (five) asked about reprimand, damaged social standing, and ease of using the CQI technology. Three questions did not show consensus. Questions showing agreement (23) and strong agreement (nine) asked about organizational commitment, impact, and research improving patient care. Major themes were: improvements in quality of care, changes in job expectations, views on research, and positive experiences with data feedback.

Conclusions: The CQI project provides constant feedback vital to building and sustaining successful health systems. It encourages communication, collaboration, and personal investment, which increase organizational commitment. Continuous feedback provides opportunities for personal and professional development by uncovering gaps in knowledge, patient care, and technological understanding. Complete, personalized data input encouraged by the CQI improves resource allocation, building robust health systems that improve HCW agency and motivation.
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http://dx.doi.org/10.1016/j.afjem.2020.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723911PMC
September 2020

Geriatric Skiers: Active But Still at Risk, a National Trauma Data Bank Study.

J Surg Res 2021 Mar 3;259:121-129. Epub 2020 Dec 3.

Department of Surgery, Dartmouth Hitchcock Medical Center, Hanover, New Hampshire; Geisel School of Medicine, Hanover, New Hampshire. Electronic address:

Background: Downhill skiing accounts for a large portion of geriatric sport-related trauma. We assessed the national burden of geriatric versus nongeriatric ski trauma.

Materials And Methods: Adults presenting to level 1/2 trauma centers after ski-associated injuries from 2011 to 2015 were identified from the National Trauma Data Bank by ICD-9 code. We compared demographics, injury patterns, and outcomes between geriatric (age ≥65 y) and nongeriatric adult skiers (age 18-64 y). A multiple regression analysis assessed for risk factors associated with severe injury (Injury Severity Score >15).

Results: We identified 3255 adult ski trauma patients, and 16.7% (543) were geriatric. Mean ages for nongeriatric versus geriatric skiers were 40.8 and 72.1 y, respectively. Geriatric skiers more often suffered head (36.7 versus 24.3%, P < 0.0001), severe head (abbreviated injury scale score >3, 49.0 versus 31.5%, P < 0.0001) and thorax injuries (22.2 versus 18.1%, P = 0.03) as compared with nongeriatric skiers. Geriatric skiers were also more often admitted to the ICU (26.5 versus 14.9%, P < 0.0001), discharged to a facility (26.7 versus 11.6%, P < 0.0001), and suffered higher mortality rates (1.3 versus 0.4%, P = 0.004). Independent risk factors for severe injury included being male (OR: 1.68, CI: 1.22-2.31), helmeted (OR: 1.41, CI: 1.07-1.85), and having comorbidities (OR: 1.37, CI: 1.05-1.80). Geriatric age was not independently associated with severe injury.

Conclusions: At level 1/2 trauma centers, geriatric age in ski trauma victims was associated with unique injury patterns, higher acuity, increased rates of facility care at discharge, and higher mortality as compared with nongeriatric skiers. Our findings indicate the need for specialized care after high impact geriatric ski trauma.
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http://dx.doi.org/10.1016/j.jss.2020.11.013DOI Listing
March 2021

Evaluating the association between American Association for the Surgery of Trauma emergency general surgery anatomic severity grades and clinical outcomes using national claims data.

J Trauma Acute Care Surg 2021 02;90(2):296-304

From the Department of Surgery (J.W.S., N.S., M.H.), and Center for Health Outcomes and Policy (J.W.S., N.S., Z.F., M.H.), University of Michigan, Ann Arbor, Michigan; Department of Surgery (K.S.), Stanford University, Stanford; and Outcomes Research Group (G.U.), University of California Davis, Sacramento, California.

Background: Emergency general surgery (EGS) encompasses a heterogeneous population of acutely ill patients, and standardized methods for determining disease severity are essential for comparative effectiveness research and quality improvement initiatives. The American Association for the Surgery of Trauma (AAST) has developed a grading system for the anatomic severity of 16 EGS conditions; however, little is known regarding how well these AAST EGS grades can be approximated by diagnosis codes in administrative databases.

Methods: We identified adults admitted for 16 common EGS conditions in the 2012 to 2017q3 National Inpatient Sample. Disease severity strata were assigned using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes based on AAST EGS anatomic severity grades. We evaluated whether assigned EGS severity (multiple strata or dichotomized into less versus more complex) were associated with in-hospital mortality, complications, length of stay, discharge disposition, and costs. Analyses were adjusted for age, sex, comorbidities, hospital traits, geography, and year.

Results: We identified 10,886,822 EGS admissions. The number of anatomic severity strata derived from ICD-9/10-CM codes varied by EGS condition and by year. Four conditions mapped to four strata across all years. Two conditions mapped to four strata with ICD-9-CM codes but only two or three strata with ICD-10-CM codes. Others mapped to three or fewer strata. When dichotomized into less versus more complex disease, patients with more complex disease had worse outcomes across all 16 conditions. The addition of multiple strata beyond a binary measure of complex disease, however, showed inconsistent results.

Conclusion: Classification of common EGS conditions according to anatomic severity is feasible with International Classification of Diseases codes. No condition mapped to five distinct severity grades, and the relationship between increasing grade and outcomes was not consistent across conditions. However, a standardized measure of severity, even if just dichotomized into less versus more complex, can inform ongoing efforts aimed at optimizing outcomes for EGS patients across the nation.

Level Of Evidence: Prognostic, level III.
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http://dx.doi.org/10.1097/TA.0000000000003030DOI Listing
February 2021

Exploring the factors motivating continued Lay First Responder participation in Uganda: a mixed-methods, 3-year follow-up.

Emerg Med J 2021 Jan 30;38(1):40-46. Epub 2020 Oct 30.

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.

Background: The WHO recommends training lay first responders (LFRs) as the first step towards establishing emergency medical services (EMS) in low-income and middle-income countries. Understanding social and financial benefits associated with responder involvement is essential for LFR programme continuity and may inform sustainable development.

Methods: A mixed-methods follow-up study was conducted in July 2019 with 239 motorcycle taxi drivers, including 115 (75%) of 154 initial participants in a Ugandan LFR course from July 2016, to evaluate LFR training on participants. Semi-structured interviews and surveys were administered to samples of initial participants to assess social and economic implications of training, and non-trained motorcycle taxi drivers to gauge interest in LFR training. Themes were determined on a per-question basis and coded by extracting keywords from each response until thematic saturation was achieved.

Results: Three years post-course, initial participants reported new knowledge and skills, the ability to help others, and confidence gain as the main benefits motivating continued programme involvement. Participant outlook was unanimously positive and 96.5% (111/115) of initial participants surveyed used skills since training. Many reported sensing an identity change, now identifying as first responders in addition to motorcycle taxi drivers. Drivers reported they believe this led to greater respect from the Ugandan public and a prevailing belief that they are responsible transportation providers, increasing subsequent customer acquisition. Motorcycle taxi drivers who participated in the course reported a median weekly income value that is 24.39% higher than non-trained motorcycle taxi counterparts (p<0.0001).

Conclusions: A simultaneous delivery of sustained social and perceived financial benefits to LFRs are likely to motivate continued voluntary participation. These benefits appear to be a potential mechanism that may be leveraged to contribute to the sustainability of future LFR programmes to deliver basic prehospital emergency care in resource-limited settings.
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http://dx.doi.org/10.1136/emermed-2020-210076DOI Listing
January 2021

Catastrophic Health Expenditures Across Insurance Types and Incomes Before and After the Patient Protection and Affordable Care Act.

JAMA Netw Open 2020 09 1;3(9):e2017696. Epub 2020 Sep 1.

Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor.

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http://dx.doi.org/10.1001/jamanetworkopen.2020.17696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516626PMC
September 2020

Medicaid Expansion and Surgical Care-Evaluating the Evidence.

JAMA Surg 2020 Sep 23. Epub 2020 Sep 23.

Department of Surgery, University of Michigan, Ann Arbor.

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http://dx.doi.org/10.1001/jamasurg.2020.1995DOI Listing
September 2020

"Secret Shoppers" Expose Disparities in Access to Surgical Care.

Ann Surg 2020 10;272(4):554-555

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

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http://dx.doi.org/10.1097/SLA.0000000000004372DOI Listing
October 2020

Evaluation of a Lay First Responder Program in Sierra Leone as a Scalable Model for Prehospital Trauma Care.

Injury 2020 Nov 3;51(11):2565-2573. Epub 2020 Sep 3.

Michigan Center for Global Surgery, Ann Arbor, Michigan, 1500 E Medical Center Dr, Ann Arbor, MI, United States; University of Michigan Health System, Department of Surgery, 1500 E Medical Center Dr, Ann Arbor, MI, United States.

Introduction: Few countries in Sub-Saharan Africa have robust emergency medical services (EMS). The World Health Organization (WHO) recommends scaling-up lay first responder programs as the first step toward formal EMS development.

Materials And Methods: We trained and equipped 4,529 lay first responders (LFRs) between June-December 2019 in Bombali District, Sierra Leone, with a 5-hour hands-on, contextually-adapted prehospital trauma course to cover 535,000 people. Instructors trained 1,029 LFRs and 50 local trainers in a training-of-trainers (TOT) model, who then trained an additional 3,500 LFRs. A validated, 23-question pre-/post-test measured knowledge improvement, while six- and nine-month follow-up tests measured knowledge retention. Incident reports tracked patient encounters to assess longitudinal impact.

Results: Median pre-/post-test scores improved by 43.5 percentage points (34.8% vs. 78.3%, p<0.0001). Knowledge retention was assessed at six months, with median score dropping to 60.9%, while at nine months, median score dropped to 43.5%. Lay first responders participating in courses led by TOT trainers had a pre-/post-test median score improvement of 30.4 percentage points (21.7% vs. 52.2%, p<0.0001). LFRs treated 1,850 patients over six months, most frequently utilizing hemorrhage control skills in 61.2% of encounters (1,133/1,850). The plurality of patients were young adult males (36.8%) and 48.7% of encounters were motorcycle injury-related.

Conclusion: A 5-hour first responder course targeting laypeople demonstrates significant emergency care knowledge improvement and retention. By training networks of transportation providers, lay first responder programs represent a robust and scalable prehospital emergency care alternative for low-resource settings.
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http://dx.doi.org/10.1016/j.injury.2020.09.001DOI Listing
November 2020

CaMKK2 is inactivated by cAMP-PKA signaling and 14-3-3 adaptor proteins.

J Biol Chem 2020 11 9;295(48):16239-16250. Epub 2020 Sep 9.

St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, Parkville, Australia. Electronic address:

The calcium-calmodulin-dependent protein kinase kinase-2 (CaMKK2) is a key regulator of cellular and whole-body energy metabolism. It is known to be activated by increases in intracellular Ca, but the mechanisms by which it is inactivated are less clear. CaMKK2 inhibition protects against prostate cancer, hepatocellular carcinoma, and metabolic derangements induced by a high-fat diet; therefore, elucidating the intracellular mechanisms that inactivate CaMKK2 has important therapeutic implications. Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues. PKA-dependent phosphorylation of Ser directly impairs calcium-calmodulin activation, whereas phosphorylation of Ser and Ser mediate recruitment of 14-3-3 adaptor proteins that hold CaMKK2 in the inactivated state by preventing dephosphorylation of phospho-Ser We also report the crystal structure of 14-3-3ζ bound to a synthetic diphosphorylated peptide that reveals how the canonical (Ser) and noncanonical (Ser) 14-3-3 consensus sites on CaMKK2 cooperate to bind 14-3-3 proteins. Our findings provide detailed molecular insights into how cAMP-PKA signaling inactivates CaMKK2 and reveals a pathway to inhibit CaMKK2 with potential for treating human diseases.
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http://dx.doi.org/10.1074/jbc.RA120.013756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705300PMC
November 2020

Association of timing of initiation of pharmacologic venous thromboembolism prophylaxis with outcomes in trauma patients.

J Trauma Acute Care Surg 2021 01;90(1):54-63

From the Inpatient Pharmacy (J.P.H.), Saint Joseph Mercy Hospital; Department of Pharmacy (E.J.H.), Center for Health Outcomes and Policy (A.H.C.-N., J.W.S., M.R.H.), and Department of Surgery (J.W.S., M.R.H.), University of Michigan, Ann Arbor, Michigan; and Department of Surgery (W.L.W.), The Ohio State University Wexner Medical Center, Columbus, Ohio.

Background: Patients are at a high risk for developing venous thromboembolism (VTE) following traumatic injury. We examined the relationship between timing of initiation of pharmacologic prophylaxis with VTE complications.

Methods: Trauma quality collaborative data from 34 American College of Surgeons Committee on Trauma-verified levels I and II trauma centers were analyzed. Patients were excluded if they were on anticoagulant therapy at the time of injury, had hospitalization <48 hours, or received no or nonstandard pharmacologic VTE prophylaxis (heparin drip). Patient comparison groups were based on timing of initiation of VTE prophylaxis relative to hospital presentation (0 to <24 hours, 24 to <48 hours, ≥48 hours). Risk-adjusted rates of VTE events were calculated accounting for patient factors including type of pharmacologic agent in addition to standard trauma patient confounders. A sensitivity analysis was performed excluding patients who received blood in the first 4 hours and/or patients with a significant traumatic brain injury.

Results: Within the 79,386 patients analyzed, there were 1,495 (1.9%) who experienced a VTE complication and 1,437 (1.8%) who died. After adjusting for type of prophylaxis and patient factors, the risk of a VTE event was significantly increased in the 24- to <48-hour (odds ratio, 1.26; 95% confidence interval, 1.09-1.47; p = 0.002) and ≥48-hour (odds ratio, 2.35; 95% confidence interval, 2.04-2.70; p < 0.001) cohorts relative to patients initiated at 0 to <24 hours. These VTE event findings remained significant after exclusion of perceived higher-risk patients in a sensitivity analysis.

Conclusion: Early initiation of pharmacologic VTE prophylaxis in stable trauma patients is associated with lower rates of VTE.

Level Of Evidence: Diagnostic, level III.
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http://dx.doi.org/10.1097/TA.0000000000002912DOI Listing
January 2021

Protein kinase A negatively regulates VEGF-induced AMPK activation by phosphorylating CaMKK2 at serine 495.

Biochem J 2020 09;477(17):3453-3469

Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07743 Jena, Germany.

Activation of AMP-activated protein kinase (AMPK) in endothelial cells by vascular endothelial growth factor (VEGF) via the Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) represents a pro-angiogenic pathway, whose regulation and function is incompletely understood. This study investigates whether the VEGF/AMPK pathway is regulated by cAMP-mediated signalling. We show that cAMP elevation in endothelial cells by forskolin, an activator of the adenylate cyclase, and/or 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterases, triggers protein kinase A (PKA)-mediated phosphorylation of CaMKK2 (serine residues S495, S511) and AMPK (S487). Phosphorylation of CaMKK2 by PKA led to an inhibition of its activity as measured in CaMKK2 immunoprecipitates of forskolin/IBMX-treated cells. This inhibition was linked to phosphorylation of S495, since it was not seen in cells expressing a non-phosphorylatable CaMKK2 S495C mutant. Phosphorylation of S511 alone in these cells was not able to inhibit CaMKK2 activity. Moreover, phosphorylation of AMPK at S487 was not sufficient to inhibit VEGF-induced AMPK activation in cells, in which PKA-mediated CaMKK2 inhibition was prevented by expression of the CaMKK2 S495C mutant. cAMP elevation in endothelial cells reduced basal and VEGF-induced acetyl-CoA carboxylase (ACC) phosphorylation at S79 even if AMPK was not inhibited. Together, this study reveals a novel regulatory mechanism of VEGF-induced AMPK activation by cAMP/PKA, which may explain, in part, inhibitory effects of PKA on angiogenic sprouting and play a role in balancing pro- and anti-angiogenic mechanisms in order to ensure functional angiogenesis.
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http://dx.doi.org/10.1042/BCJ20200555DOI Listing
September 2020

The Utility of Perforated Appendix Rate as a Proxy for Timely Access to Care.

JAMA Surg 2020 11;155(11):1081-1082

Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

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http://dx.doi.org/10.1001/jamasurg.2020.2504DOI Listing
November 2020

Developing a Lay First Responder Program in Chad: A 12-Month Follow-Up Evaluation of a Rural Prehospital Emergency Care Program.

Prehosp Disaster Med 2020 Oct 29;35(5):546-553. Epub 2020 Jul 29.

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

Introduction: The World Health Organization (WHO; Geneva, Switzerland) recommends lay first responder (LFR) programs as a first step toward establishing formal Emergency Medical Services (EMS) in low- and middle-income countries (LMICs) to address injury. There is a scarcity of research investigating LFR program development in predominantly rural settings of LMICs.

Study Objective: A pilot LFR program was launched and assessed over 12 months to investigate the feasibility of leveraging pre-existing transportation providers to scale up prehospital emergency care in rural, low-resource settings of LMICs.

Methods: An LFR program was established in rural Chad to evaluate curriculum efficacy, using a validated 15-question pre-/post-test to measure participant knowledge improvement. Pre-/post-test score distributions were compared using a Wilcoxon Signed-Rank test. For test evaluation, each pre-test question was mapped to its corresponding post-test analog and compared using McNemar's Chi-Squared Test to examine knowledge acquisition on a by-question basis. Longitudinal prehospital care was evaluated with incident reports, while program cost was tracked using a one-way sensitivity analysis. Qualitative follow-up surveys and semi-interviews were conducted at 12 months, with initial participants and randomly sampled motorcycle taxi drivers, and used a constructivist grounded theory approach to understand the factors motivating continued voluntary participation to inform future program continuity. The consolidated criteria for reporting qualitative research (COREQ) checklist was used to guide design, analysis, and reporting the qualitative results.

Results: A total of 108 motorcycle taxi participants demonstrated significant knowledge improvement (P <.001) across three of four curricular categories: scene safety, airway and breathing, and bleeding control. Lay first responders treated 71 patients over six months, encountering five deaths, and provided patient transport in 82% of encounters. Lay first responders reported an average confidence score of 8.53/10 (n = 38). In qualitative follow-up surveys and semi-structured interviews, the ability to care for the injured, new knowledge/skills, and the resultant gain in social status and customer acquisition motivated continued involvement as LFRs. Ninety-six percent of untrained, randomly sampled motorcycle taxi drivers reported they would be willing to pay to participate in future training courses.

Conclusion: Lay first responder programs appear feasible and cost-effective in rural LMIC settings. Participants demonstrate significant knowledge acquisition, and after 12 months of providing emergency care, report sustained voluntary participation due to social and financial benefits, suggesting sustainability and scalability of LFR programs in low-resource settings.
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http://dx.doi.org/10.1017/S1049023X20000977DOI Listing
October 2020

Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms.

Nat Metab 2020 09 27;2(9):873-881. Epub 2020 Jul 27.

Centre for Metabolism, Obesity and Diabetes Research and the Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Long-chain fatty acids (LCFAs) play important roles in cellular energy metabolism, acting as both an important energy source and signalling molecules. LCFA-CoA esters promote their own oxidation by acting as allosteric inhibitors of acetyl-CoA carboxylase, which reduces the production of malonyl-CoA and relieves inhibition of carnitine palmitoyl-transferase 1, thereby promoting LCFA-CoA transport into the mitochondria for β-oxidation. Here we report a new level of regulation wherein LCFA-CoA esters per se allosterically activate AMP-activated protein kinase (AMPK) β1-containing isoforms to increase fatty acid oxidation through phosphorylation of acetyl-CoA carboxylase. Activation of AMPK by LCFA-CoA esters requires the allosteric drug and metabolite site formed between the α-subunit kinase domain and the β-subunit. β1 subunit mutations that inhibit AMPK activation by the small-molecule activator A769662, which binds to the allosteric drug and metabolite site, also inhibit activation by LCFA-CoAs. Thus, LCFA-CoA metabolites act as direct endogenous AMPK β1-selective activators and promote LCFA oxidation.
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http://dx.doi.org/10.1038/s42255-020-0245-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502547PMC
September 2020

Genetic loss of AMPK-glycogen binding destabilises AMPK and disrupts metabolism.

Mol Metab 2020 11 29;41:101048. Epub 2020 Jun 29.

Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Level 5, 215 Spring Street, Melbourne, Victoria 3000, Australia. Electronic address:

Objective: Glycogen is a major energy reserve in liver and skeletal muscle. The master metabolic regulator AMP-activated protein kinase (AMPK) associates with glycogen via its regulatory β subunit carbohydrate-binding module (CBM). However, the physiological role of AMPK-glycogen binding in energy homeostasis has not been investigated in vivo. This study aimed to determine the physiological consequences of disrupting AMPK-glycogen interactions.

Methods: Glycogen binding was disrupted in mice via whole-body knock-in (KI) mutation of either the AMPK β1 (W100A) or β2 (W98A) isoform CBM. Systematic whole-body, tissue and molecular phenotyping was performed in KI and respective wild-type (WT) mice.

Results: While β1 W100A KI did not affect whole-body metabolism or exercise capacity, β2 W98A KI mice displayed increased adiposity and impairments in whole-body glucose handling and maximal exercise capacity relative to WT. These KI mutations resulted in reduced total AMPK protein and kinase activity in liver and skeletal muscle of β1 W100A and β2 W98A, respectively, versus WT mice. β1 W100A mice also displayed loss of fasting-induced liver AMPK total and α-specific kinase activation relative to WT. Destabilisation of AMPK was associated with increased fat deposition in β1 W100A liver and β2 W98A skeletal muscle versus WT.

Conclusions: These results demonstrate that glycogen binding plays critical roles in stabilising AMPK and maintaining cellular, tissue and whole-body energy homeostasis.
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http://dx.doi.org/10.1016/j.molmet.2020.101048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393401PMC
November 2020

The Surgical Health Services Research Agenda for the COVID-19 Pandemic.

Ann Surg 2020 09;272(3):e226-e229

Center for Surgery and Public Health, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1097/SLA.0000000000004126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467032PMC
September 2020