Evolutionary isolation of ryanodine receptor isoform 1 for muscle-based thermogenesis in mammals.

Resting skeletal muscle generates heat for endothermy in mammals but not amphibians, while both use the same Ca2+-handling proteins and membrane structures to conduct excitation-contraction coupling apart from having different ryanodine receptor (RyR) isoforms for Ca2+ release. The sarcoplasmic reticulum (SR) generates heat following Adenosine triphosphate (ATP) hydrolysis at the Ca2+ pump, which is amplified by increasing RyR1 Ca2+ leak in mammals, subsequently increasing cytoplasmic [Ca2+] ([Ca2+]cyto). For thermogenesis to be functional, rising [Ca2+]cyto must not interfere with cytoplasmic effectors of the sympathetic nervous system (SNS) that likely increase RyR1 Ca2+ leak; nor should it compromise the muscle remaining relaxed. To achieve this, Ca2+ activated, regenerative Ca2+ release that is robust in lower vertebrates needs to be suppressed in mammals. However, it has not been clear whether: i) the RyR1 can be opened by local increases in [Ca2+]cyto; and ii) downstream effectors of the SNS increase RyR Ca2+ leak and subsequently, heat generation. By positioning amphibian and malignant hyperthermia-susceptible human-skinned muscle fibers perpendicularly, we induced abrupt rises in [Ca2+]cyto under identical conditions optimized for activating regenerative Ca2+ release as Ca2+ waves passed through the junction of fibers. Only mammalian fibers showed resistance to rising [Ca2+]cyto, resulting in increased SR Ca2+ load and leak. Fiber heat output was increased by cyclic adenosine monophosphate (cAMP)-induced RyR1 phosphorylation at Ser2844 and Ca2+ leak, indicating likely SNS regulation of thermogenesis. Thermogenesis occurred despite the absence of SR Ca2+ pump regulator sarcolipin. Thus, evolutionary isolation of RyR1 provided increased dynamic range for thermogenesis with sensitivity to cAMP, supporting endothermy.

Large-scale genomic investigation of pediatric cholestasis reveals a novel hepatorenal ciliopathy caused by PSKH1 mutations.

PURPOSE: Pediatric cholestasis is the phenotypic expression of clinically and genetically heterogeneous disorders of bile acid synthesis and flow. Although a growing number of monogenic causes of pediatric cholestasis have been identified, the majority of cases remain undiagnosed molecularly. METHODS: In a cohort of 299 pediatric participants (279 families) with intrahepatic cholestasis, we performed exome sequencing as a first-tier diagnostic test. RESULTS: A likely causal variant was identified in 135 families (48.56%). These comprise 135 families that harbor variants spanning 37 genes with established or tentative links to cholestasis. In addition, we propose a novel candidate gene (PSKH1) (HGNC:9529) in 4 families. PSKH1 was particularly compelling because of strong linkage in 3 consanguineous families who shared a novel hepatorenal ciliopathy phenotype. Two of the 4 families shared a founder homozygous variant, whereas the third and fourth had different homozygous variants in PSKH1. PSKH1 encodes a putative protein serine kinase of unknown function. Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays. CONCLUSION: Our results support the use of genomics in the workup of pediatric cholestasis and reveal PSKH1-related hepatorenal ciliopathy as a novel candidate monogenic form.

CaMKK2 as an emerging treatment target for bipolar disorder.

Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder.

Linking Trauma Registry Patients With Insurance Claims: Creating a Longitudinal Patient Record.

INTRODUCTION: Trauma registries and their quality improvement programs only collect data from the acute hospital admission, and no additional information is captured once the patient is discharged. This lack of long-term data limits these programs' ability to affect change. The goal of this study was to create a longitudinal patient record by linking trauma registry data with third party payer claims data to allow the tracking of these patients after discharge. METHODS: Trauma quality collaborative data (2018-2019) was utilized. Inclusion criteria were patients age ≥18, ISS ≥5 and a length of stay ≥1 d. In-hospital deaths were excluded. A deterministic match was performed with insurance claims records based on the hospital name, date of birth, sex, and dates of service (±1 d). The effect of payer type, ZIP code, International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis specificity and exact dates of service on the match rate was analyzed. RESULTS: The overall match rate between these two patient record sources was 27.5%. There was a significantly higher match rate (42.8% versus 6.1%, P < 0.001) for patients with a payer that was contained in the insurance collaborative. In a subanalysis, exact dates of service did not substantially affect this match rate; however, specific International Classification of Diseases, Tenth Revision, Clinical Modification codes (i.e., all 7 characters) reduced this rate by almost half. CONCLUSIONS: We demonstrated the successful linkage of patient records in a trauma registry with their insurance claims. This will allow us to the collect longitudinal information so that we can follow these patients' long-term outcomes and subsequently improve their care.

Variation in Risk-Adjusted Ventilator-Associated Pneumonia Days Within a Quality Collaborative.

INTRODUCTION: Ventilator-associated pneumonia (VAP) is associated with increased mortality, prolonged mechanical ventilation, and longer intensive care unit stays. The rate of VAP (VAPs per 1000 ventilator days) within a hospital is an important quality metric. Despite adoption of preventative strategies, rates of VAP in injured patients remain high in trauma centers. Here, we report variation in risk-adjusted VAP rates within a statewide quality collaborative. METHODS: Using Michigan Trauma Quality Improvement Program data from 35 American College of Surgeons-verified Level I and Level II trauma centers between November 1, 2020 and January 31, 2023, a patient-level Poisson model was created to evaluate the risk-adjusted rate of VAP across institutions given the number of ventilator days, adjusting for injury severity, physiologic parameters, and comorbid conditions. Patient-level model results were summed to create center-level estimates. We performed observed-to-expected adjustments to calculate each center's risk-adjusted VAP days and flagged outliers as hospitals whose confidence intervals lay above or below the overall mean. RESULTS: We identified 538 VAP occurrences among a total of 33,038 ventilator days within the collaborative, with an overall mean of 16.3 VAPs per 1000 ventilator days. We found wide variation in risk-adjusted rates of VAP, ranging from 0 (0-8.9) to 33.0 (14.4-65.1) VAPs per 1000 d. Several hospitals were identified as high or low outliers. CONCLUSIONS: There exists significant variation in the rate of VAP among trauma centers. Investigation of practices and factors influencing the differences between low and high outlier institutions may yield information to reduce variation and improve outcomes.

Association of Health Professional Shortage Area Hospital Designation With Surgical Outcomes and Expenditures Among Medicare Beneficiaries.

OBJECTIVE: To compare surgical outcomes and expenditures at hospitals located in Health Professional Shortage Areas to nonshortage area designated hospitals among Medicare beneficiaries. BACKGROUND: More than a quarter of Americans live in federally designated Health Professional Shortage Areas. Although there is growing concern that medical outcomes may be worse, far less is known about hospitals providing surgical care in these areas. METHODS: Cross-sectional retrospective study from 2014 to 2018 of 842,787 Medicare beneficiary patient admissions to hospitals with and without Health Professional Shortage Area designations for common operations including appendectomy, cholecystectomy, colectomy, and hernia repair. We assessed risk-adjusted outcomes using multivariable logistic regression accounting for patient factors, admission type, and year were compared for each of the 4 operations. Hospital expenditures were price-standardized, risk-adjusted 30-day surgical episode payments. Primary outcome measures included 30-day mortality, hospital readmissions, and 30-day surgical episode payments. RESULTS: Patients (mean age=75.6 years, males=44.4%) undergoing common surgical procedures in shortage area hospitals were less likely to be White (84.6% vs 88.4%, P <0.001) and less likely to have≥2 Elixhauser comorbidities (75.5% vs 78.2%, P <0.001). Patients undergoing surgery at Health Professional Shortage Area hospitals had lower risk-adjusted rates of 30-day mortality (6.05% vs 6.69%, odds ratio=0.90, CI, 0.90-0.91, P <0.001) and readmission (14.99% vs 15.74%, odds ratio=0.94, CI, 0.94-0.95, P <0.001). Medicare expenditures at Health Professional Shortage Area hospitals were also lower than nonshortage designated hospitals ($28,517 vs $29,685, difference= -$1168, P <0.001). CONCLUSIONS: Patients presenting to Health Professional Shortage Area hospitals obtain safe care for common surgical procedures without evidence of higher expenditures among Medicare beneficiaries. These findings should be taken into account as current legislative proposals to increase funding for care in these underserved communities are considered.

Surgical Procedures at Critical Access Hospitals Within Hospital Networks.

OBJECTIVE: To compare surgical outcomes and expenditures at critical access hospitals that do versus do not participate in a hospital network among Medicare beneficiaries. BACKGROUND: Critical access hospitals provide essential care to more than 80 million Americans. These hospitals, often rural, are located more than 35 miles away from another hospital and are required to maintain patient transfer agreements with other facilities capable of providing higher levels of care. Some critical access hospitals have gone further to formally participate in a hospital network. METHODS: This was a cross-sectional retrospective study from 2014 to 2018 comparing 16,128 Medicare beneficiary admissions for appendectomy, cholecystectomy, colectomy, or hernia repair at critical access hospitals that do versus do not participate in a hospital network. Thirty-day mortality and readmissions were risk adjusted using multivariable logistic regression accounting for patient and hospital factors. Price-standardized, risk-adjusted Medicare expenditures were compared for the 30-day total episode payments consisting of index hospitalization, physician services, readmissions, and postacute care payments. RESULTS: Beneficiaries (average age = 75.7 years, SD = 7.4) who obtained care at critical access hospitals in a hospital network were more likely to carry ≥2 Elixhauser comorbidities (68.7% vs. 62.8%, P < 0.001). Rates of 30-day mortality were higher at critical access hospitals in a hospital network (4.30% vs. 3.81%, OR = 1.11, P < 0.001). Similarly, readmission rates were higher at critical access hospitals that were in a hospital network (15.13% vs. 14.34%, OR = 1.06, P < 0.001). Additionally, total episode payments were found to be $960 higher per patient at critical access hospitals that were in a hospital network ($23,878 vs. $22,918, P < 0.001). CONCLUSIONS: Critical access hospitals within hospital networks provided care to more medically complex patients and were associated with worse clinical outcomes and higher costs among Medicare beneficiaries undergoing common general surgery operations.

Unmet Social Health Needs as a Driver of Inequitable Outcomes After Surgery: A Cross-sectional Analysis of the National Health Interview Survey.

OBJECTIVE: This study aims to identify opportunities to improve surgical equity by evaluating unmet social health needs by race, ethnicity, and insurance type. BACKGROUND: Although inequities in surgical care and outcomes based on race, ethnicity, and insurance have been well documented for decades, underlying drivers remain poorly understood. METHODS: We used the 2008-2018 National Health Interview Survey to identify adults age 18 years and older who reported surgery in the past year. Outcomes included poor health status (self-reported), socioeconomic status (income, education, employment), and unmet social health needs (food, housing, transportation). We used logistic regression models to progressively adjust for the impact of patient demographics, socioeconomic status, and unmet social health needs on health status. RESULTS: Among a weighted sample of 14,471,501 surgical patients, 30% reported at least 1 unmet social health need. Compared with non-Hispanic White patients, non-Hispanic Black, and Hispanic patients reported higher rates of unmet social health needs. Compared with private insurance, those with Medicaid or no insurance reported higher rates of unmet social health needs. In fully adjusted models, poor health status was independently associated with unmet social health needs: food insecurity [adjusted odds ratio (aOR)=2.14; 95% confidence interval (CI): 1.89-2.41], housing instability (aOR=1.69; 95% CI: 1.51-1.89), delayed care due to lack of transportation (aOR=2.58; 95% CI: 2.02-3.31). CONCLUSIONS: Unmet social health needs vary significantly by race, ethnicity, and insurance, and are independently associated with poor health among surgical populations. As providers and policymakers prioritize improving surgical equity, unmet social health needs are potential modifiable targets.

Association of Intellectual Disability with Delayed Presentation and Worse Outcomes in Emergency General Surgery.

OBJECTIVE: To examine the association between intellectual disability and both severity of disease and clinical outcomes among patients presenting with common emergency general surgery (EGS) conditions. BACKGROUND: Accurate and timely diagnosis of EGS conditions is crucial for optimal management and patient outcomes. Individuals with intellectual disabilities may be at increased risk of delayed presentation and worse outcomes for EGS; however, little is known about surgical outcomes in this population. METHODS: Using the 2012-2017 Nationwide Inpatient Sample, we conducted a retrospective cohort analysis of adult patients admitted for 9 common EGS conditions. We performed multivariable logistic and linear regression to examine the association between intellectual disability and the following outcomes: EGS disease severity at presentation, any surgery, complications, mortality, length of stay, discharge disposition, and inpatient costs. Analyses were adjusted for patient demographics and facility traits. RESULTS: Of 1,317,572 adult EGS admissions, 5,062 (0.38%) patients had a concurrent ICD-9/-10 code consistent with intellectual disability. EGS patients with intellectual disabilities had 31% higher odds of more severe disease at presentation compared with neurotypical patients (aOR 1.31; 95% CI 1.17-1.48). Intellectual disability was also associated with a higher rate of complications and mortality, longer lengths of stay, lower rate of discharge to home, and higher inpatient costs. CONCLUSION: EGS patients with intellectual disabilities are at increased risk of more severe presentation and worse outcomes. The underlying causes of delayed presentation and worse outcomes must be better characterized to address the disparities in surgical care for this often under-recognized but highly vulnerable population.

High Deductibles are Associated With Severe Disease, Catastrophic Out-of-Pocket Payments for Emergency Surgical Conditions.

BACKGROUND: Out-of-pocket spending has risen for individuals with private health insurance, yet little is known about the unintended consequences that high levels of cost-sharing may have on delayed clinical presentation and financial outcomes for common emergency surgical conditions. METHODS: In this retrospective analysis of claims data from a large commercial insurer (2016-2019), we identified adult inpatient admissions following emergency department presentation for common emergency surgical conditions (eg, appendicitis, cholecystitis, diverticulitis, and intestinal obstruction). Primary exposure of interest was enrollment in a high-deductible health insurance plan (HDHP). Our primary outcome was disease severity at presentation-determined using ICD-10-CM diagnoses codes and based on validated measures of anatomic severity (eg, perforation, abscess, diffuse peritonitis). Our secondary outcome was catastrophic out-of-pocket spending, defined by the World Health Organization as out-of-pocket spending >10% of annual income. RESULTS: Among 43,516 patients [mean age 48.4 (SD: 11.9) years; 51% female], 41% were enrolled HDHPs. Despite being younger, healthier, wealthier, and more educated, HDHP enrollees were more likely to present with more severe disease (28.5% vs 21.3%, P <0.001; odds ratio (OR): 1.34, 95% CI: 1.28-1.42]); even after adjusting for relevant demographics (adjusted OR: 1.23, 95% CI: 1.18-1.31). HDHP enrollees were also more likely to incur 30-day out-of-pocket spending that exceeded 10% of annual income (20.8% vs 6.4%, adjusted OR: 3.93, 95% CI: 3.65-4.24). Lower-income patients, Black patients, and Hispanic patients were at highest risk of financial strain. CONCLUSIONS: For privately insured patients presenting with common surgical emergencies, high-deductible health plans are associated with increased disease severity at admission and a greater financial burden after discharge-especially for vulnerable populations. Strategies are needed to improve financial risk protection for common surgical emergencies.

The National Provider Identifier Taxonomy: Does it Align With a Surgeon's Actual Clinical Practice?

INTRODUCTION: The taxonomy code(s) associated with each National Provider Identifier (NPI) entry should characterize the provider's role (e.g., physician) and any specialization (e.g., orthopedic surgery). While the intent of the taxonomy system was to monitor medical appropriateness and the expertise of care provided, this system is now being used by researchers to identify providers and their practices. It is unknown how accurate the taxonomy codes are in describing a provider's true specialization. METHODS: Department websites of orthopedic surgery and general surgery from three large academic institutions were queried for practicing surgeons. The surgeon's specialty and subspeciality information listed was compared to the provider's taxonomy code(s) listed on the National Plan and Provider Enumeration System (NPPES). The match rate between these data sources was evaluated based on the specialty, subspecialty, and institution. RESULTS: There were 295 surgeons (205 general surgery and 90 orthopedic surgery) and 24 relevant taxonomies (8 orthopedic and 16 general or plastic) for analysis. Of these, 294 surgeons (99%) selected their general specialty taxonomy correctly, while only 189 (64%) correctly chose an appropriate subspecialty. General surgeons correctly chose a subspecialty more often than orthopedic surgeons (70 versus 51%, P = 0.002). The institution did not affect either match rate, however there were some differences noted in subspecialty match rates inside individual departments. CONCLUSIONS: In these institutions, the NPI taxonomy is not accurate for describing a surgeon's subspecialty or actual practice. Caution should be taken when utilizing this variable to describe a surgeon's subspecialization as our findings might apply in other groups.

Financial outcomes after pediatric critical illness among commercially insured families.

Critical illness results in subjective financial distress for families, but little is known about objective caregiver finances after a child's pediatric intensive care unit (PICU) hospitalization. Using statewide commercial insurance claims linked to cross-sectional commercial credit data, we identified caregivers of children with PICU hospitalizations in January-June 2020 and January-June 2021. Credit data included delinquent debt, debt in collections (medical and non-medical), low credit score (< 660), and a composite of any debt or poor credit and were measured in January 2021 for all caregivers. For the 2020 cohort ("post-PICU"), credit outcomes in January 2021 were measured at least 6 months following PICU hospitalization and reflect financial status after the hospitalization. For the 2021 cohort (comparison), financial outcomes were measured prior to their child's PICU hospitalization and therefore reflect pre-hospitalization financial status. We identified 2032 caregivers, 1017 post-PICU caregivers and 1015 comparison cohort caregivers, of which 1016 and 1014 were matched to credit data, respectively. Post-PICU caregivers had higher adjusted odds of having any delinquent debt [aOR 1.25; 95%CI 1.02-1.53; p = 0.03] and having a low credit score [aOR 1.29; 95%CI 1.06-1.58; p = 0.01]. However, there was no difference in the amount of delinquent debt or debt in collections among those with nonzero debt. Overall, 39.5% and 36.5% of post-PICU and comparator caregivers, respectively, had delinquent debt, debt in collections or poor credit. Many caregivers of critically ill children have financial debt or poor credit during hospitalization and post-discharge. However, caregivers may be at higher risk for poor financial status following their child's critical illness.

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

The AMP-activated protein kinase (AMPK) αßγ 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 an opportunity for new strategies to treat type 2 diabetes and insulin resistance, with recent genetic and pharmacological studies indicating the α2ß2γ1 isoform combination as the heterotrimer complex primarily responsible. With the goal of developing α2ß2-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 ß2 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 α2ß2γ1 AMPK with one order of magnitude greater potency than the pan AMPK activator MK-8722. A crystal structure of MSG011 complexed to AMPK α2ß1γ1 revealed a similar binding mode to SC4 and the potential importance of an interaction between the SC4 2-hydroxyl group and α2-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 α2ß2-selective AMPK activators, that we hypothesise may avoid off-target complications associated with indiscriminate activation of AMPK throughout the body.

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

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.

Emergency Surgery Rates Among Medicare Beneficiaries With Access Sensitive Surgical Conditions.

INTRODUCTION: Access sensitive surgical conditions should be treated electively with optimal access but result in emergency operations when access is limited. However, the rates of emergency procedures for these conditions are unknown. METHODS: Cross-sectional retrospective review of Medicare beneficiaries who underwent access sensitive surgical procedures (abdominal aortic aneurysm repair, colectomy for colorectal cancer, or incisional hernia repair) between 2014 and 2018. Risk-adjusted outcomes using a multivariable logistical regression that adjusted for patient factors (age, sex, race, and Elixhauser comorbidities), hospital characteristics (ownership, size, geographic region, surgical volume) and type of operation were compared between planned and emergency (urgent and emergent) surgical procedures. Outcome measures were rates of emergency procedures as well as associated postoperative outcomes. RESULTS: Of the 744,818 Medicare beneficiaries undergoing access sensitive surgical procedures, 259,541 (34.9%) were done in the emergency setting. Risk-adjusted rates of emergency surgery varied widely across hospital service areas from 23.28% (lowest decile) to 54.88% (highest decile) (Odds Ratio 4.74; P < 0.001). Emergency procedures were associated with significantly higher rates of 30-d mortality (8.15% versus 3.65%, P < 0.001) and readmissions (16.28% versus 12.88%, P < 0.001) compared to elective procedures. Sensitivity analysis with younger and healthier beneficiaries demonstrated persistently high rates (23.3%) of emergency surgery with wide regional variation and worse patient outcomes. CONCLUSIONS: Emergency surgery for access sensitive surgical conditions is extremely common and varied almost fivefold across United States hospital service areas. This suggests there are opportunities to improve access for these common surgical conditions.

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

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.

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

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.

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

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 Ca2+, 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 Ser495 directly impairs calcium-calmodulin activation, whereas phosphorylation of Ser100 and Ser511 mediate recruitment of 14-3-3 adaptor proteins that hold CaMKK2 in the inactivated state by preventing dephosphorylation of phospho-Ser495 We also report the crystal structure of 14-3-3ζ bound to a synthetic diphosphorylated peptide that reveals how the canonical (Ser511) and noncanonical (Ser100) 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.

Is Initial Board Certification Associated With Better Early Career Surgical Outcomes?

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 versus noncertified early career general surgeons. METHODS: We identified Medicare patients who underwent a partial colectomy between 2008 and 2016 and were operated on by a non-subspecialty trained surgeon within their first 5 years of practice. Surgeon certification status was determined using the 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 = 4239) versus noncertified (n = 191) early-career general surgeons was 9.1% versus 10.7% (odds ratio 0.83, P = 0.03). Adjusted mortality rate for certified versus noncertified early-career general surgeons was 4.9% versus 6.1% (odds ratio 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.

The Affordable Care Act at 10 Years: Evaluating the Evidence and Navigating an Uncertain Future.

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.