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Calcium (Ca2+) ions are ubiquitous and indispensable signaling messengers that regulate virtually every cell function. The unique ability of Ca2+ to regulate so many different processes yet cause stimulus specific changes in cell function requires sensing and decoding of Ca2+ signals. Ca2+-sensing proteins, such as calmodulin, decode Ca2+ signals by binding and modifying the function of a diverse range of effector proteins. These effectors include the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme, which is the core component of a signaling cascade that plays a key role in important physiological and pathophysiological processes, including brain function and cancer. In addition to its role as a Ca2+ signal decoder, CaMKK2 also serves as an important junction point that connects Ca2+ signaling with energy metabolism. By activating the metabolic regulator AMP-activated protein kinase (AMPK), CaMKK2 integrates Ca2+ signals with cellular energy status, enabling the synchronization of cellular activities regulated by Ca2+ with energy availability. Here, we review the structure, regulation, and function of CaMKK2 and discuss its potential as a treatment target for neurological disorders, metabolic disease, and cancer., (© 2024 The Author(s).)

Objective: To quantify recent trends in access to timely, high-quality, affordable surgical care in the US., Background: Insufficient access to surgical care remains an ongoing concern in the US. Previous attempts to understand and quantify barriers in access to surgical care in the US lack a comprehensive, policy-relevant lens., Methods: This observational cross-sectional study evaluates multiple domains of access to surgical care across the US from 2011-2015 and 2016-2020. Our stepwise model included timeliness (<60-minute drive time), quality (surgically capable hospital with ≥3 CMS stars), and affordability (neither uninsured nor underinsured) of access to surgical care using a novel combination of data from the American Hospital Association, Medicare claims, CMS's Five-Star Quality Rating System, the American Community Survey, and the Medical Expenditure Panel Survey., Results: The number of Americans lacking access to timely, high-quality, affordable surgical care increased from 97.7 million in 2010-2015 to 98.7 million in 2016-2020. Comparing these two periods, we found improvements in the number of Americans lacking access due to being uninsured (decrease from 38.5 to 26.5 million). However, these improvements were offset by increasing numbers of Americans for whom timeliness (increase from 9.5 to 14.1 million), quality (increase from 3.4 to 4.9 million), and underinsured status (increase from 46.3 to 53.1 million) increased as barriers to access. Multiple sensitivity analyses using alternative thresholds for each access domain demonstrated similar trends. Those with insufficient access to care tended to be more rural (6.7% vs. 2.0%, P<0.001), lower income (40.7% vs. 30.0%, P<0.001), and of Hispanic ethnicity (35.9% vs. 15.8%, P<0.001)., Conclusions: Nearly one-in-three Americans lack access to surgical care that is timely, high-quality, and affordable. This study identifies the multiple actionable drivers of access to surgical care that notably can each be addressed with specific policy interventions., Competing Interests: Financial disclosures and funding: Dr. Dimick is a cofounder of ArborMetrix, Inc, a company that makes software for profiling hospital quality and efficiency. The authors have no conflicts of interest pertaining to the work herein. Dr. Ibrahim receives funding from the Agency for Healthcare Research and Quality (AHRQ) as principal investigator on grant R01-HS028606-01A1, from AHRQ as a co-investigator on grant R18-HS028963, and from the National Institutes of Health (NIH) as a co-principal investigator on grant R0-1DK137466. Dr. Scott receives funding from AHRQ as principal investigator on grant K08-HS028672 and from the NIH as a co-principal investigator on grant R0-1DK137466., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Although the precise underlying cause(s) of autism spectrum disorder remain unclear, more than 1000 rare genetic variations are associated with the condition. For a large number of people living with profound autism, this genetic heterogeneity has impeded the identification of common biological targets for therapy development for core and comorbid traits that include significant impairments in social communication, and repetitive and restricted behaviors. A substantial number of genes associated with autism encode proteins involved in signal transduction and synaptic transmission that are critical for brain development and function. CAMK4 is an emerging risk gene for autism spectrum disorder that encodes the Ca 2+ -calmodulin-dependent protein kinase-4 (CaMK4) enzyme. CaMK4 is a key component of a Ca 2+ -activated signaling pathway that regulates neurodevelopment and synaptic plasticity. In this review, we discuss three genetic variants of CAMK4 found in individuals with hyperkinetic movement disorder and comorbid neurological symptoms including autism spectrum disorder that are likely pathogenic with monogenic effect. We also comment on four other genetic variations in CAMK4 that display associations with autism spectrum disorder, as well as twelve examples of autism-associated variations in other genes that impact CaMK4 signaling pathways. Finally, we highlight three environmental risk factors that impact CaMK4 signaling based on studies in preclinical models of autism and/or clinical cohorts. Overall, we review molecular, genetic, physiological, and environmental evidence that suggest defects in the CaMK4 signaling pathway may play an important role in a common autism pathogenesis network across numerous patient groups, and propose CaMK4 as a potential therapeutic target., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Community-level disadvantage is associated with reduced quality of life after burn injury. We evaluated the association between community-level disadvantage and return to work after burn injury., Methods: A multicenter burn injury database was queried from 1998-2021. Participants 18-65 years old with documented employment status and ZIP codes were included. Exposures were community distress (Distressed Communities Index, DCI), patient demographics, and burn characteristics. The primary outcome was odds of employment 6 months after burn injury using stepwise logistic regression models, first with patient-level variables, then DCI. An interaction term was included to evaluate the modification of DCI and post-injury employment by race., Results: 1960 participants were included, with a median age of 39.2 years (IQR 29.2, 49.3); 81 % were White, 75 % male, and 74 % were working at the time of injury. Participants unemployed 6 months post-injury were more often older, female, non-White, and unemployed at injury, with larger burn sizes and longer hospitalizations. 59 % of participants unemployed at 6 months were employed at the time of injury. Residence in the highest distress ZIP codes was associated with 2.21 (95 % CI 1.39-3.52) odds of 6 month unemployment. Older age, larger burn size, more operations, Black race, and pre-injury unemployment were associated with the greatest odds of unemployment. The interaction between race and DCI was not statistically significant., Conclusion: Patients from the highest distress communities have twice the odds of unemployment 6 months after injury. This association did not vary by race. Screening for DCI by ZIP code may be a useful tool to focus vocational rehabilitation resources., Competing Interests: Declaration of Competing Interest The authors have no financial conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Introduction: There is a growing body of literature that shows geographic social vulnerability, which seeks to measure the resiliency of a community to withstand unforeseen disasters, may be associated with negative outcomes after traumatic injury. For motor vehicle collisions (MVCs) specifically, it is unknown how the resources of a patient's home environment may interact with resources of the environment where the crash occurred., Methods: We merged publicly available crash data from the state of Michigan with the Michigan Trauma Quality Improvement dataset. A social vulnerability index (SVI) score was calculated for each ZIP code and was then cross-referenced between the location of the MVC (Crash-SVI) and the patient's home address (Home-SVI). SVI was divided into quintiles, with higher numbers indicating greater vulnerability. Adjusted logistic regression models using least absolute shrinkage and selection operator for feature selection and regularization were performed sequentially using patient, vehicular, and environmental variables to identify associations between Home-SVI and Crash-SVI, with mortality and injury severity score (ISS) greater than 15 (ISS15)., Results: Between January 2020 and December 2022, a total of 14,706 patients were identified. Most MVCs (75.3% of all patients) occurred in the second through fourth quintiles of SVI. In all cases, Crash-SVI occurred most frequently within the same quintile as the patient's Home-SVI. Average crash speed limits showed a significant negative association with increasing SVI. On adjusted logistic regression, there were significantly increased odds of mortality for the fifth quintile of Home-SVI in comparison to the first quintile when adjusted for patient factors; but this lost significance after the addition of vehicular or environmental variables. In contrast, there were decreased odds of ISS15 for the highest quintiles of Crash-SVI in all logistic regression models., Conclusions: Geographic social vulnerability markers were associated with lower MVC-associated injury severity, perhaps in part because of the association with lower speed limit in these areas., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Trauma patients are at increased risk for venous thromboembolism events (VTEs). The decision of when to initiate VTE chemoprophylaxis (VTEP) and with what agent remains controversial in patients with severe traumatic brain injury (TBI)., Methods: This comparative effectiveness study evaluated the impact of timing and agent for VTEP on outcomes for patients with severe TBI (Abbreviated Injury Scale head score of 3, 4, or 5). Data were collected at 35 Level 1 and 2 trauma centers from January 1, 2017, to June 1, 2022. Patients were placed into analysis cohorts: no VTEP, low-molecular-weight heparin (LMWH) ≤48 hours, LMWH >48 hours, heparin ≤48 hours, and heparin >48 hours. Propensity score matching accounting for patient factors and injury characteristics was used with logistic regression modeling to evaluate in-hospital mortality, VTEs, and discharge disposition. Neurosurgical intervention after initiation of VTEP was used to evaluate extension of intracranial hemorrhage., Results: Of 12,879 patients, 32% had no VTEP, 36% had LMWH, and 32% had heparin. Overall mortality was 8.3% and lowest among patients receiving LMWH ≤48 hours (4.1%). Venous thromboembolism event rates were lower with use of LMWH (1.6% vs. 4.5%; odds ratio, 2.98; 95% confidence interval, 1.40-6.34; p = 0.005) without increasing mortality or neurosurgical interventions. Venous thromboembolism event rates were lower with early prophylaxis (2.0% vs. 3.5%; odds ratio, 1.76; 95% confidence interval, 1.15-2.71; p = 0.01) without increasing mortality ( p = 1.0). Early VTEP was associated with more nonfatal intracranial operations ( p < 0.001). However, patients undergoing neurosurgical intervention after VTEP initiation had no difference in rates of mortality, withdrawal of care, or unfavorable discharge disposition ( p = 0.7, p = 0.1, p = 0.5)., Conclusion: In patients with severe TBI, LMWH usage was associated with lower VTE incidence without increasing mortality or neurosurgical interventions. Initiation of VTEP ≤48 hours decreased VTE incidence and increased nonfatal neurosurgical interventions without affecting mortality. Low-molecular-weight heparin is the preferred VTEP agent for severe TBI, and initiation ≤48 hours should be considered in relation to these risks and benefits., Level of Evidence: Therapeutic/Care Management; Level III., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Prompt acetylcysteine treatment with standard doses (300 mg/kg over 21 h in divided doses) is almost universally effective in preventing hepatotoxicity after paracetamol (acetaminophen) overdose. However, hepatotoxicity is reported despite early treatment when paracetamol concentrations exceed 300 mg/L (1,985 μmol/L) at 4 h. Prior studies evaluating high-dose acetylcysteine to treat high-risk ingestions have shown mixed results. We compared outcomes in patients with high-risk ingestions receiving standard or high-dose acetylcysteine., Methods: Records from a single poison center were reviewed from 1 January 2017 to 31 December 2022. We included cases of acute paracetamol ingestion treated with intravenous acetylcysteine with an initial paracetamol concentration above the "300 mg/L" (1,985 μmol/L) line on the Rumack-Matthew nomogram. We compared standard and high-dose acetylcysteine groups by odds ratios and multivariable logistic regression. We defined hepatotoxicity as aminotransferase activity >1,000 U/L., Results: We included 190 cases. Fifty-six percent received standard-dose acetylcysteine while 44% received high-dose acetylcysteine. Treatment within 8 h yielded no difference in hepatotoxicity between groups (odds ratio 1.67, 95% CI 0.067-42.3). Among patients treated after 8 h, hepatoxicity was more common in the high-dose group (odds ratio 3.39, 95% CI 1.25-9.2) though odds of liver failure were similar (odds ratio 2.78, 95% CI 0.89-8.69). Eighty-eight percent of patients with hepatotoxicity had elevated aminotransferase activity at presentation. No patient died or received a liver transplant., Discussion: Rates of hepatotoxicity were low in patients treated within 8 h regardless of acetylcysteine dose. Unexpectedly, high-dose acetylcysteine treatment was associated with an increased odds of hepatoxicity in those treated after 8 h, but most had abnormal aminotransferase activities at presentation and there was no difference in rates of liver failure. Limitations include the use of retrospective, voluntarily reported poison center data., Conclusions: Prompt treatment with acetylcysteine, regardless of dose, prevented hepatotoxicity in high-risk paracetamol ingestion.

Trauma activation fees are intended to help trauma centers cover the costs of providing lifesaving care at all times, but they have fallen under greater scrutiny because of a lack of regulation and wide variability in charges. We leveraged the federal Hospital Price Transparency rule to systematically describe trauma activation fees as captured in the Turquoise Health database for all Level I-III trauma centers nationally and across payer types. As of April 18, 2023, a total of 38 percent of US trauma centers published trauma activation fees. These fees varied widely by payer type. The minimum fee charged was $40 (for a Medicaid contract); the maximum fees charged were $28,356 (self-pay) and $28,893 (commercial payers). Trauma centers that were larger, metropolitan, located in the West, and associated with proprietary (investor-owned, for-profit) hospitals had higher trauma activation fees. Proprietary hospitals posted fees that were 60 percent higher than those published by public, nonfederal hospitals. Unmerited variation in trauma activation fees may suggest that the current funding strategy is equitable neither for trauma centers nor for the severely injured patients who rely on them for lifesaving care.

Abstract: Acute care surgery (ACS) patients are frequently faced with significant long-term recovery and financial implications that extend far beyond their hospitalization. While major injury and emergency general surgery (EGS) emergencies are often viewed solely as acute moments of crisis, the impact on patients can be lifelong. Financial outcomes after major injury or emergency surgery have only begun to be understood. The Healthcare Economics Committee from the American Association for the Surgery of Trauma previously published a conceptual overview of financial toxicity in ACS, highlighting the association between financial outcomes and long-term physical recovery. The aims of second-phase financial toxicity review by the Healthcare Economics Committee of the American Association for the Surgery of Trauma are to (1) understand the unique impact of financial toxicity on ACS patients; (2) delineate the current limitations surrounding measurement domains of financial toxicity in ACS; (3) explore the "when, what and how" of optimally capturing financial outcomes in ACS; and (4) delineate next steps for integration of these financial metrics in our long-term patient outcomes. As acute care surgeons, our patients' recovery is often contingent on equal parts physical, emotional, and financial recovery. The ACS community has an opportunity to impact long-term patient outcomes and well-being far beyond clinical recovery., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Trauma survivors are susceptible to experiencing financial toxicity (FT). Studies have shown the negative impact of FT on chronic illness outcomes. However, there is a notable lack of data on FT in the context of trauma. We aimed to better understand prevalence, risk factors, and impact of FT on trauma long-term outcomes., Methods: Adult trauma patients with an Injury Severity Score (ISS) ≥9 treated at Level I trauma centers were interviewed 6 months to 14 months after discharge. Financial toxicity was considered positive if patients reported any of the following due to the injury: income loss, lack of care, newly applied/qualified for governmental assistance, new financial problems, or work loss. The Impact of FT on Patient Reported Outcome Measure Index System (PROMIS) health domains was investigated., Results: Of 577 total patients, 44% (254/567) suffered some form of FT. In the adjusted model, older age (odds ratio [OR], 0.4; 95% confidence interval [95% CI], 0.2-0.81) and stronger social support networks (OR, 0.44; 95% CI, 0.26-0.74) were protective against FT. In contrast, having two or more comorbidities (OR, 1.81; 95% CI, 1.01-3.28), lower education levels (OR, 1.95; 95% CI, 95%, 1.26-3.03), and injury mechanisms, including road accidents (OR, 2.69; 95% CI, 1.51-4.77) and intentional injuries (OR, 4.31; 95% CI, 1.44-12.86) were associated with higher toxicity. No significant relationship was found with ISS, sex, or single-family household. Patients with FT had worse outcomes across all domains of health. There was a negative linear relationship between the severity of FT and worse mental and physical health scores., Conclusion: Financial toxicity is associated with long-term outcomes. Incorporating FT risk assessment into recovery care planning may help to identify patients most in need of mitigative interventions across the trauma care continuum to improve trauma recovery. Further investigations to better understand, define, and address FT in trauma care are warranted., Level of Evidence: Prognostic and Epidemiological; Level III., (Copyright © 2024 American Association for the Surgery of Trauma.)

Background: Knowing the mechanical properties of trabecular bone is critical for many branches of orthopaedic research. Trabecular bone is anisotropic and the principal trabecular direction is usually aligned with the load it transmits. It is therefore critical that the mechanical properties are measured as close as possible to this direction, which is often perpendicular to a curved articulating surface., Methods: This study presents a method to extract trabecular bone cores perpendicular to a curved articulating surface of the distal femur. Cutting guides were generated from computed tomography scans of 12 human distal femora and a series of cutting tools were used to release cylindrical bone cores from the femora. The bone cores were then measured to identify the angle between the bone core axis and the principal trabecular axis., Findings: The method yielded an 83% success rate in core extraction over 10 core locations per distal femur specimen. In the condyles, 97% of extracted cores were aligned with the principal trabecular direction., Interpretation: This method is a reliable way of extracting trabecular bone specimens perpendicular to a curved articular surface and could be useful across the field of orthopaedic research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Emergency general surgery conditions are common, costly, and highly morbid. The proportion of excess morbidity due to variation in health systems and processes of care is poorly understood. We constructed a collaborative quality initiative for emergency general surgery to investigate the emergency general surgery care provided and guide process improvements., Methods: We collected data at 10 hospitals from July 2019 to December 2022. Five cohorts were defined: acute appendicitis, acute gallbladder disease, small bowel obstruction, emergency laparotomy, and overall aggregate. Processes and inpatient outcomes investigated included operative versus nonoperative management, mortality, morbidity (mortality and/or complication), readmissions, and length of stay. Multivariable risk adjustment accounted for variations in demographic, comorbid, anatomic, and disease traits., Results: Of the 19,956 emergency general surgery patients, 56.8% were female and 82.8% were White, and the mean (SD) age was 53.3 (20.8) years. After accounting for patient and disease factors, the adjusted aggregate mortality rate was 3.5% (95% confidence interval [CI], 3.2-3.7), morbidity rate was 27.6% (95% CI, 27.0-28.3), and the readmission rate was 15.1% (95% CI, 14.6-15.6). Operative management varied between hospitals from 70.9% to 96.9% for acute appendicitis and 19.8% to 79.4% for small bowel obstruction. Significant differences in outcomes between hospitals were observed with high- and low-outlier performers identified after risk adjustment in the overall cohort for mortality, morbidity, and readmissions. The use of a Gastrografin challenge in patients with a small bowel obstruction ranged from 10.7% to 61.4% of patients. In patients who underwent initial nonoperative management of acute cholecystitis, 51.5% had a cholecystostomy tube placed. The cholecystostomy tube placement rate ranged from 23.5% to 62.1% across hospitals., Conclusion: A multihospital emergency general surgery collaborative reveals high morbidity with substantial variability in processes and outcomes among hospitals. A targeted collaborative quality improvement effort can identify outliers in emergency general surgery care and may provide a mechanism to optimize outcomes., Level of Evidence: Therapeutic/Care Management; Level III., (Copyright © 2024 American Association for the Surgery of Trauma.)

Introduction: Early operative intervention in orthopaedic injuries is associated with decreased morbidity and mortality. Relevant process measures (e.g. femoral shaft fixation <24 hours) are used in trauma quality improvement programs to evaluate performance. Currently, there is no mechanism to account for patients who are unable to undergo surgical intervention (i.e. physiologically unstable). We characterized the factors associated with patients who did not meet these orthopaedic process measures., Methods: A retrospective cohort study of patients from 35 ACS-COT verified Level 1 and Level 2 trauma centers was performed utilizing quality collaborative data (2017-2022). Inclusion criteria were adult patients (≥18 years), ISS ≥5, and a closed femoral shaft or open tibial shaft fracture classified via the Abbreviated Injury Scale version 2005 (AIS2005). Relevant factors (e.g. physiologic) associated with a procedural delay >24 hours were identified through a multivariable logistic regression and the effect of delay on inpatient outcomes was assessed. A sub-analysis characterized the rate of delay in "healthy patients"., Results: We identified 5,199 patients with a femoral shaft fracture and 87.5% had a fixation procedure, of which 31.8% had a delay, and 47.1% of those delayed were "healthy." There were 1,291 patients with an open tibial shaft fracture, 92.2% had fixation, 50.5% had an irrigation and debridement and 11.2% and 18.7% were delayed, respectively. High ISS, older age and multiple medical comorbidities were associated with a delay in femur fixation, and those delayed had a higher incidence of complications., Conclusions: There is a substantial incidence of surgical delays in some orthopaedic trauma process measures that are predicted by certain patient characteristics, and this is associated with an increased rate of complications. Understanding these factors associated with a surgical delay, and effectively accounting for them, is key if these process measures are to be used appropriately in quality improvement programs., Level of Evidence: Level III; Therapeutic/Care Management., Competing Interests: Conflict of Interest: All Journal of Trauma and Acute Care Surgery disclosure forms have been supplied and are provided as supplemental digital content (http://links.lww.com/TA/D763)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

There are places on earth that are considered to possess extreme physico-chemical characteristics as they relate to life. Surprisingly, there are microbes that have adapted various strategies that enable them to form robust communities in these environments. The microbes that live in these environments, called extremophiles, are described as being thermophilic, psychrophilic, halophilic, acidophilic, alkaliphilic, barophilic, and so on. Given that extremophiles were not discovered until relatively recently due to a view point that the environments in which they inhabited were not conducive to life, it is reasonable to conclude that the concept of extremophiles may be hard to grasp for students. Herein is described a laboratory exercise adapted from laboratory exercises that use mesophilic catalase enzymes to illustrate the influence of physico-chemical parameters on enzyme activity. Catalase is an enzyme that accelerates the degradation of hydrogen peroxide to water and oxygen gas. In addition to mesophilic catalases, the catalase from Pyrobaculum calidifontis , a hyperthermophile with an optimal growth temperature of 90°C, is used to highlight the adaptation of an enzyme to an extreme environment. A visual comparison of bubble production by the hyperthermophilic and mesophilic enzymes after heating at high temperatures dramatically illustrates differences in thermostability that will likely reinforce concepts that are given in a pre-laboratory lecture that discusses not only the extremophiles themselves but also their applications in biotechnology and possible role in the field of astrobiology., Competing Interests: The authors declare no conflict of interest.

Importance: Access-sensitive surgical conditions, such as abdominal aortic aneurysm, ventral hernia, and colon cancer, are ideally treated with elective surgery, but when left untreated have a natural history requiring an unplanned operation. Patients' health insurance status may be a barrier to receiving timely elective care, which may be associated with higher rates of unplanned surgery and worse outcomes., Objective: To evaluate the association between patients' insurance status and rates of unplanned surgery for these 3 access-sensitive surgical conditions and postoperative outcomes., Design, Setting, and Participants: This cross-sectional cohort study examined a geographically broad patient sample from the Healthcare Cost and Utilization Project State Inpatient Databases, including data from 8 states (Arizona, Colorado, Florida, Kentucky, Maryland, North Carolina, Washington, and Wisconsin). Participants were younger than 65 years who underwent abdominal aortic aneurysm repair, ventral hernia repair, or colectomy for colon cancer between 2016 and 2020. Patients were stratified into groups by insurance status. Data were analyzed from June 1 to July 1, 2023., Exposure: Health insurance status (private insurance, Medicaid, or no insurance)., Main Outcomes and Measures: The primary outcome was the rate of unplanned surgery for these 3 access-sensitive conditions. Secondary outcomes were rates of postoperative outcomes including inpatient mortality, any hospital complications, serious complications (a complication with a hospital length of stay longer than the 75th percentile for that procedure), and hospital length of stay., Results: The study included 146 609 patients (mean [SD] age, 50.9 [10.3] years; 73 871 females [50.4%]). A total of 89 018 patients (60.7%) underwent elective surgery while 57 591 (39.3%) underwent unplanned surgery. Unplanned surgery rates varied significantly across insurance types (33.14% for patients with private insurance, 51.46% for those with Medicaid, and 72.60% for those without insurance; P < .001). Compared with patients with private insurance, patients without insurance had higher rates of inpatient mortality (1.29% [95% CI, 1.04%-1.54%] vs 0.61% [0.57%-0.66%]; P < .001), higher rates of any complications (19.19% [95% CI, 18.33%-20.05%] vs 12.27% [95% CI, 12.07%-12.47%]; P < .001), and longer hospital stays (7.27 [95% CI, 7.09-7.44] days vs 5.56 [95% CI, 5.53-5.60] days, P < .001)., Conclusions and Relevance: Findings of this cohort study suggest that uninsured patients more often undergo unplanned surgery for conditions that can be treated electively, with worse outcomes and longer hospital stays compared with their counterparts with private health insurance. As efforts are made to improve insurance coverage, tracking elective vs unplanned surgery rates for access-sensitive surgical conditions may be a useful measure to assess progress.

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Rural hospitals are closing at unprecedented rates, with hundreds more at risk of closure in the coming 2 years. Multiple federal policies are being developed and implemented without a salient understanding of the emerging literature evaluating rural hospital closures and its impacts. We conducted a scoping review to understand the impacts of rural hospital closure to inform ongoing policy debates and research., Methods: A comprehensive search strategy was devised by library faculty to collate publications using the PRISMA extension for scoping reviews. Two coauthors then independently performed title and abstract screening, full text review, and study extraction., Findings: We identified 5054 unique citations and assessed 236 full texts for possible inclusion in our narrative synthesis of the literature on the impacts of rural hospital closure. Twenty total original studies were included in our narrative synthesis. Key domains of adverse impacts related to rural hospital closure included emergency medical service transport, local economies, availability and utilization of emergency care and hospital services, availability of outpatient services, changes in quality of care, and workforce and community members. However, significant heterogeneity existed within these findings., Conclusions: Given the significant heterogeneity within our findings across multiple domains of impact, we advocate for a tailored approach to mitigating the impacts of rural hospital closures for policymakers. We also discuss crucial knowledge gaps in the evidence base-especially with respect to quality measures beyond mortality. The synthesis of these findings will permit policymakers and researchers to understand, and mitigate, the harms of rural hospital closure., (© 2023 National Rural Health Association.)

Primary care physicians are often the first to screen and identify patients with access-sensitive surgical conditions that should be treated electively. These conditions require surgery that is preferably planned (elective), but, when access is limited, treatment may be delayed and worsening symptoms lead to emergency surgery (for example, colectomy for cancer, abdominal aortic aneurysm repair, and incisional hernia repair). We evaluated the rates of elective versus emergency surgery for patients with three access-sensitive surgical conditions living in primary care Health Professional Shortage Areas during 2015-19. Medicare beneficiaries in more severe primary care shortage areas had higher rates of emergency surgery compared with rates in the least severe shortage areas (37.8 percent versus 29.9 percent). They were also more likely to have serious complications (14.9 percent versus 11.7 percent) and readmissions (15.7 percent versus 13.5 percent). When we accounted for areas with a shortage of surgeons, the findings were similar. Taken together, these findings suggest that residents of areas with greater primary care workforce shortages may also face challenges in accessing elective surgical care. As policy makers consider investing in Health Professional Shortage Areas, our findings underscore the importance of primary care access to a broader range of services.

Superfluid 3 He is a paradigm for odd-parity Cooper pairing, ranging from neutron stars to uranium-based superconducting compounds. Recently it has been shown that 3 He, imbibed in anisotropic silica aerogel with either positive or negative strain, preferentially selects either the chiral A-phase or the time-reversal-symmetric B-phase. This control over basic order parameter symmetry provides a useful model for understanding imperfect unconventional superconductors. For both phases, the orbital quantization axis is fixed by the direction of strain. Unexpectedly, at a specific temperature T x , the orbital axis flops by 90 ∘ , but in reverse order for A and B-phases. Aided by diffusion limited cluster aggregation simulations of anisotropic aerogel and small angle X-ray measurements, we are able to classify these aerogels as either "planar" and "nematic" concluding that the orbital-flop is caused by competition between short and long range structures in these aerogels., (© 2024. The Author(s).)

We evaluated the association between childbirth and having medical debt in collections and examined differences by neighborhood socioeconomic status. Among a statewide cohort of commercially insured pregnant (n=14,560) and postpartum (n=12,157) adults, having medical debt in collections was more likely among postpartum individuals compared with pregnant individuals (adjusted odds ratio [aOR] 1.36, 95% CI 1.27-1.46) and those in lowest-income neighborhoods compared with all others (aOR 2.18, 95% CI 2.02-2.35). Postpartum individuals in lowest-income neighborhoods had the highest predicted probabilities of having medical debt in collections (28.9%, 95% CI 27.5-30.3%), followed by pregnant individuals in lowest-income neighborhoods (23.2%, 95% CI 22.0-24.4%), followed by all other postpartum and pregnant people (16.1%, 95% CI 15.4-16.8% and 12.5%, 95% CI 11.9-13.0%, respectively). Our findings suggest that current peripartum out-of-pocket costs are objectively more than many commercially insured families can afford, leading to medical debt. Policies to reduce maternal-infant health care spending among commercially insured individuals may mitigate financial hardship and improve birth equity., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite the growing awareness of the negative financial impact of traumatic injury on patients' lives, the association between financial toxicity and long-term health-related quality of life (hrQoL) among trauma survivors remains poorly understood., Methods: Patients from nine trauma centers participating in a statewide trauma quality collaborative had responses from longitudinal survey data linked to inpatient trauma registry data. Financial toxicity was defined based on patient-reported survey responses regarding medical debt, work or income loss, nonmedical financial strain, and forgone care due to costs. A financial toxicity score ranging from 0 to 4 was calculated. Health-related quality of life was assessed using the EuroQol 5 Domain tool. Multivariable regression models evaluated the association between financial toxicity and hrQoL outcomes while adjusting for patient demographics, injury severity and inpatient treatment intensity, and health systems variables., Results: Among the 403 patients providing 510 completed surveys, rates of individual financial toxicity elements ranged from 21% to 46%, with 65% of patients experiencing at least one element of financial toxicity. Patients with any financial toxicity had worse summary measures of hrQoL and higher rates of problems in all five EuroQol 5 Domain domains ( p < 0.05 for all). Younger age, lower household income, lack of insurance, more comorbidities, discharge to a facility, and air ambulance transportation were independently associated with higher odds of financial toxicity ( p < 0.05 for all). Injury traits and inpatient treatment intensity were not independently associated with financial toxicity., Conclusion: A majority of trauma survivors in this study experienced some level of financial toxicity, which was independently associated with worse risk-adjusted health outcomes across all hrQoL measures. Risk factors for financial toxicity are not related to injury severity or treatment intensity but rather to sociodemographic variables and measures of prehospital and posthospital health care resource utilization. Targeted interventions and policies are needed to address financial toxicity and ensure optimal recovery for trauma survivors., Level of Evidence: Prognostic and Epidemiological; Level III., (Copyright © 2023 American Association for the Surgery of Trauma.)

Introduction: In 2015, the United States moved from the International Classification of Diseases, Ninth Revision ( ICD-9 ), to the International Classification of Diseases, Tenth Revision ( ICD-10 ), coding system. The American Association for the Surgery of Trauma Committee on Severity Assessment and Patient Outcomes previously established a list of ICD-9 diagnoses to define the field of emergency general surgery (EGS). This study evaluates the general equivalence mapping (GEM) crosswalk to generate an equivalent list of ICD-10 -coded EGS diagnoses., Methods: The GEM was used to generate a list of ICD-10 codes corresponding to the American Association for the Surgery of Trauma ICD-9 EGS diagnosis codes. These individual ICD-9 and ICD-10 codes were aggregated by surgical area and diagnosis groups. The volume of patients admitted with these diagnoses in the National Inpatient Sample in the ICD-9 era (2013-2014) was compared with the ICD-10 volumes to generate observed to expected ratios. The crosswalk was manually reviewed to identify the causes of discrepancies between the ICD-9 and ICD-10 lists., Results: There were 485 ICD-9 codes, across 89 diagnosis categories and 11 surgical areas, which mapped to 1,206 unique ICD-10 codes. A total of 196 (40%) ICD-9 codes have an exact one-to-one match with an ICD-10 code. The median observed to expected ratio among the diagnosis groups for a primary diagnosis was 0.98 (interquartile range, 0.82-1.12). There were five key issues identified with the ability of the GEM to crosswalk ICD-9 EGS diagnoses to ICD-10 : (1) changes in admission volumes, (2) loss of necessary modifiers, (3) lack of specific ICD-10 code, (4) mapping to a different condition, and (5) change in coding nomenclature., Conclusion: The GEM provides a reasonable crosswalk for researchers and others to use when attempting to identify EGS patients in with ICD-10 diagnosis codes. However, we identify key issues and deficiencies, which must be accounted for to create an accurate patient cohort. This is essential for ensuring the validity of policy, quality improvement, and clinical research work anchored in ICD-10 coded data., Level of Evidence: Diagnostic Test/Criteria; Level III., (Copyright © 2023 American Association for the Surgery of Trauma.)

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 Ca 2+ -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., (© 2023. The Author(s).)

Background: Excessive opioid prescribing has resulted in opioid diversion and misuse. In July 2018, Michigan's Public Act 251 established a state-wide policy limiting opioid prescriptions for acute pain to a 7-day supply. Traumatic injury increases the risk for new persistent opioid use, yet the impact of prescribing policy in trauma patients remains unknown. To determine the relationship between policy enactment and prescribing in trauma patients, we compared oral morphine equivalents prescribed at discharge before and after implementation of Public Act 251., Methods: In this cross-sectional study, adult patients who received any oral opioids at discharge from a Level 1 trauma center between January 1, 2016, and June 30, 2021, were identified. The exposure was patients admitted starting July 1, 2018. Inpatient oral morphine equivalents per day 48 hours before discharge and discharge prescription oral morphine equivalents per day were calculated. Student's t test and an interrupted time series analysis were performed to compare mean oral morphine equivalents per day pre- and post-policy. Multivariable risk adjustment accounted for patient/injury factors and inpatient oral morphine equivalent use., Results: A total of 3,748 patients were included in the study (pre-policy n = 1,685; post-policy n = 2,063). Implementation of the prescribing policy was associated with a significant decrease in mean discharge oral morphine equivalents per day (34.8 ± 49.5 vs 16.7 ± 32.3, P < .001). After risk adjustment, post-policy discharge prescriptions differed by -19.2 oral morphine equivalents per day (95% CI -21.7 to -16.8, P < .001). The proportion of patients obtaining a refill prescription 30 days post-discharge did not increase after implementation (0.38 ± 0.48 vs 0.37 ± 0.48, P = .7)., Conclusion: Discharge prescription amounts for opioids in trauma patients decreased by approximately one-half after the implementation of opioid prescribing policies, and there was no compensatory increase in subsequent refill prescriptions. Future work is needed to evaluate the effect of these policies on the adequacy of pain management and functional recovery after injury., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Gains in inpatient survival over the last five decades have shifted the burden of major injuries and surgical emergencies from the acute phase to their long-term sequelae. More attention has been placed on evaluation and optimization of long-term physical and mental health; however, the impact of major injuries and surgical emergencies on long-term financial well-being remains a critical blind spot for clinicians and researchers. The concept of financial toxicity encompasses both the objective financial consequences of illness and medical care as well as patients' subjective financial concerns. In this review, representatives of the Healthcare Economics Committee from the American Association for the Surgery of Trauma (1) provide a conceptual overview of financial toxicity after trauma or emergency surgery, (2) outline what is known regarding long-term economic outcomes among trauma and emergency surgery patients, (3) explore the bidirectional relationship between financial toxicity and long-term physical and mental health outcomes, (4) highlight policies and programs that may mitigate financial toxicity, and (5) identify the current knowledge gaps and critical next steps for clinicians and researchers engaged in this work., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Biosolids and sewage effluent application to agricultural fields is becoming a win-win practice as both an economical waste management strategy and a source of nutrients and organic matter for plant growth. However, these organic wastes contain a variety of trace chemicals of environmental concern such as pharmaceuticals and personal care products (PPCPs), which may pose a risk to agricultural fields and ecosystems. This work aims to investigate the sorption of sitagliptin on four agricultural soils, evaluate the effects of biosolids and sewage effluent application, and elucidate the main sorption mechanism of the pharmaceutical on soils. The sorption study revealed that the sorption capacities of sitagliptin on different soils were positively related to the contents of soil organic matter and negatively associated with soil pH values. The application of biosolids and sewage effluent decreased the sorption capacity of sitagliptin, which may be attributed to the loading of dissolved organic matter derived from organic wastes. The Freundlich isotherm model demonstrated that the addition of biosolids from 0 to 100 % (W/W) consistently decreased the sorption affinity (K f ) of sitagliptin from 1.69 × 10 2 to 3.82 × 10 1  mg (1-n) L n kg -1 . Sewage application at 0, 10, 50, and 100 % (V/V) also reduced the K f values from 1.69 × 10 2 to 9.17 × 10 1  mg (1-n) L n kg -1 . Attenuated Total Reflection (ATR)-Infrared (IR) spectroscopy analyses suggested that electrostatic interactions between carbonyl and amino groups of sitagliptin and the negatively charged soil surface are the main sorption mechanisms. In a co-solute system, the sorption affinity of sitagliptin on the soil decreased with increasing metformin concentrations, suggesting that competitive sorption may reduce the sorption capacity of individual contaminants in soil systems containing multiple PPCPs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)