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This study aims to identify opportunities to improve surgical equity by evaluating unmet social health needs by race, ethnicity, and insurance type.Although inequities in surgical care and outcomes based on race, ethnicity, and insurance have been well documented for decades, underlying drivers remain poorly understood.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, SES, and unmet social health needs on health status.Among a weighted sample of 14,471,501 surgical patients, 30% reported at least one unmet social health need. Compared to non-Hispanic White patients, non-Hispanic Black and Hispanic patients reported higher rates of unmet social health needs. Compared to 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 aOR 2.14 (95% 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).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.

Direct-acting antivirals (DAAs) offer an unprecedented opportunity to eliminate hepatitis C virus (HCV) infection, yet barriers among people who inject drugs (PWID) remain. Having pharmacists provide care through collaborative drug therapy agreements (CDTAs) offers a promising solution. We developed and piloted a Pharmacist, Physician, and Patient Navigator-Collaborative Care Model (PPP-CCM) which utilized pharmacists to directly deliver HCV care at community organizations serving PWID. We conducted formative evaluation of the PPP-CCM pilot to characterize implementation experiences.The PPP-CCM was implemented from November of 2020 through July of 2022. Formative evaluation team members observed implementation-related meetings and conducted multiple site visits, taking detailed fieldnotes. Fieldnotes were iteratively reviewed to identify barriers and facilitators to implementation and used to inform 7 key informant interviews conducted with programmatic staff at the end of the pilot. All data were analyzed using a Rapid Assessment Process (RAP) guided by the Consolidated Framework for Implementation Research (CFIR). The formative evaluation team shared results with program stakeholders (pharmacists, physicians, and other site staff) to verify and expand on learnings.Evaluation of PPP-CCM revealed 5 themes, encompassing all CFIR domains: 1) PPP-CCM was feasible but challenging to deliver efficiently; 2) the pharmacist role and characteristics (e.g., being flexible, available, and patient-centered) were key to PPP-CCM successes; 3) the PPP-CCM team met challenges engaging patients over time, but some team-based strategies helped; 4) community site characteristics (e.g., existing trusting relationships with PWID and physical space that enabled program visibility) were important contributors; and 5) financial barriers may limit PPP-CCM scale-up and sustainability.PPP-CCM is a novel and promising approach to HCV care delivery for PWID who may previously lack engagement in traditional care models, but careful attention needs to be paid to financial barriers to ensure scalability and sustainability.

Protein phosphorylation is a fundamental element of cell signaling. First discovered as a biochemical switch in glycogen metabolism, we now know that this posttranslational modification permeates all aspects of cellular behavior. In humans, over 540 protein kinases attach phosphate to acceptor amino acids, whereas around 160 phosphoprotein phosphatases remove phosphate to terminate signaling. Aberrant phosphorylation underlies disease, and kinase inhibitor drugs are increasingly used clinically as targeted therapies. Specificity in protein phosphorylation is achieved in part because kinases and phosphatases are spatially organized inside cells. A prototypic example is compartmentalization of the cyclic adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase A through association with A-kinase anchoring proteins. This configuration creates autonomous signaling islands where the anchored kinase is constrained in proximity to activators, effectors, and selected substates. This article primarily focuses on A kinase anchoring protein (AKAP) signaling in the heart with an emphasis on anchoring proteins that spatiotemporally coordinate excitation-contraction coupling and hypertrophic responses.

Background Mortality after stage 1 palliation of hypoplastic left heart syndrome remains significant. Both cardiac output (CO) and systemic vascular resistance (SVR) contribute to hemodynamic vulnerability. Simultaneous measures of mean arterial pressure and somatic regional near infrared spectroscopy saturation can classify complex hemodynamics into 4 distinct states, with a low-CO state of higher risk. We sought to identify interventions associated with low-CO state occupancy and transition. Methods Perioperative data were prospectively collected in an institutional review board–approved database. Hemodynamic state was classified as high CO, high SVR, low SVR, and low CO using bivariate analysis. Associations of static and dynamic support levels and state classifications over 48 postoperative hours were tested between states and across transitions using mixed regression methods in a quasi-experimental design. Results Data from 10,272 hours in 214 patients were analyzed. A low-CO state was observed in 142 patients for 1107 hours. Both low CO and extracorporeal membrane oxygenation had increased mortality risk. The low-CO state was characterized by lower milrinone but higher catecholamine dose. Successful transition out of low CO was associated with increased milrinone dose and hemoglobin concentration. Increasing milrinone and hemoglobin levels predicted reduced risk of low CO in future states. Conclusions Bivariate classification objectively defines hemodynamic states and transitions with distinct support profiles. Maintaining or increasing inodilator and hemoglobin levels were associated with improved hemodynamic conditions and were predictive of successful future transitions from the low-CO state.

WHO recommends training lay first responders (LFRs) as the first step toward formal emergency medical services development, yet no tool exists to evaluate LFR programs. We developed Prehospital Emergency Trauma Care Assessment Tool (PETCAT), a seven-question survey administered to first-line hospital-based healthcare providers, to independently assess LFR prehospital intervention frequency and quality. PETCAT surveys were administered one month pre-LFR program launch (June 2019) in Makeni, Sierra Leone and again 14 months post-launch (August 2020). Using a difference-in-differences approach, PETCAT was also administered in a control city (Kenema) with no LFR training intervention during the study period at the same intervals to control for secular trends. PETCAT measured change in both the experimental and control locations. Cronbach’s alpha, point bi-serial correlation, and inter-rater reliability using Cohen's Kappa assessed PETCAT reliability. PETCAT administration to 90 first-line, hospital-based healthcare providers found baseline prehospital intervention were rare in Makeni and Kenema prior to LFR program launch (1.2/10 vs. 1.8/10). Fourteen months post-LFR program implementation, PETCAT demonstrated prehospital interventions increased in Makeni with LFRs (5.2/10, p

This paper documents the importance of foreign patents for the technology transfer of inventions created in the laboratories of the U.S. federal agencies. First, we describe the patent portfolios of the 11 federal agencies with 98 percent of the research performed within the laboratories of all U.S. federal agencies. Second, we estimate the distributed lag function showing the effects on license revenue of an agency’s history of patent applications for inventions granted U.S. patents. The estimation shows that those effects depend on whether the agency also obtained foreign patent protection for its inventions. Third, we estimate a dynamic panel data model of license revenues as a function of the history of applications and granted patents. The evidence supports the view that an agency that obtains U.S. patents for its technologies but does not obtain foreign patent protection disadvantages the corporations that license the agency’s technologies and then face international competition from firms that copy those technologies and compete with lower costs because they do not incur full development costs or pay royalties for licensing the technologies. An increase in foreign patents would increase the willingness of companies to undertake the development costs necessary to have successful commercial products, and technology transfer—with more remuneration to U.S. taxpayers via license royalties—of inventions from the laboratories of U.S. federal agencies would increase.

OBJECTIVE The objective of this study was to develop a simple and practical guide for discussing and managing obesity in primary care settings. METHODS This study convened representatives from 12 primary care and obesity specialty organizations for a series of roundtable meetings to discuss the key components of obesity treatment in primary care. Attendees identified the need for a guide for primary care providers that outlined the key steps for discussing obesity with patients and managing their care while recognizing the significant time constraints on such provider/patient encounters. RESULTS Prevailing themes from the roundtable sessions suggested that the key components of addressing obesity in primary care settings are obtaining patient permission, addressing weight bias, providing a diagnosis, and emphasizing shared decision-making. A modified "6A" framework with the steps "Ask," "Assess," "Advise," "Agree," "Assist," and "Arrange" was deemed appropriate to organize the process of weight management in primary care. An algorithm was developed to provide a script for the patient/provider encounter. CONCLUSIONS The expert panel developed a short, accessible, practical, and informative guide for obesity management by primary care clinicians. Efforts are under way to disseminate the guide to primary care providers through the 11 participating organizations that have endorsed it.

Adult females of the blacklegged tick, Ixodes scapularis (Acari: Ixodidae), were collected from a North American porcupine, Erethizon dorsatum, in eastern Ontario, Canada. This porcupine parasitism indicates that an established population of I. scapularis is present in the local vicinity. This tick species is known to parasitize more than 150 different vertebrate hosts, including the North American porcupine. The presence of I. scapularis ticks parasitizing a North American porcupine constitutes a new tick-host record in Canada.

Hepatitis C virus (HCV) infection is common in the United States and leads to significant morbidity, mortality, and economic costs. Simplified screening recommendations and highly effective direct-acting antivirals for HCV present an opportunity to eliminate HCV. The objective of this study was to increase testing, linkage to care, treatment, and cure of HCV. This was an observational, prospective, population-based intervention program carried out between September 2014 and September 2018 and performed in three community health centers, three large multiclinic health care systems, and an HCV patient education and advocacy group in King County, WA. There were 232,214 patients included based on criteria of documented HCV-related diagnosis code, positive HCV laboratory test or prescription of HCV medication, and seen at least once at a participating clinical site in the prior year. Electronic health record (EHR) prompts and reports were created. Case management linked patients to care. Primary care providers received training through classroom didactics, an online curriculum, specialty clinic shadowing, and a telemedicine program. The proportion of baby boomer patients with documentation of HCV testing increased from 18% to 54% during the project period. Of 77,577 baby boomer patients screened at 87 partner clinics, 2,401 (3%) were newly identified HCV antibody positive. The number of patients staged for treatment increased by 391%, and those treated increased by 1,263%. Among the 79% of patients tested after treatment, 95% achieved sustained virologic response. Conclusion: A combination of EHR-based health care system interventions, active linkage to care, and clinician training contributed to a tripling in the number of patients screened and a more than 10-fold increase of those treated. The interventions are scalable and foundational to the goal of HCV elimination.

ImportancePrivately insured US children account for 40% of non–birth-related pediatric hospitalizations. However, there are no national data on the magnitude or correlates of out-of-pocket spending for these hospitalizations.ObjectiveTo estimate out-of-pocket spending for non–birth-related hospitalizations among privately insured children and identify factors associated with this spending.Design, Setting, and ParticipantsThis study is a cross-sectional analysis of the IBM MarketScan Commercial Database, which reports claims from 25 to 27 million privately insured enrollees annually. In the primary analysis, all non–birth-related hospitalizations of children 18 years and younger from 2017 through 2019 were included. In a secondary analysis focused on insurance benefit design, hospitalizations that could be linked to the IBM MarketScan Benefit Plan Design Database and were covered by plans with a family deductible and inpatient coinsurance requirements were analyzed.Main Outcomes and MeasuresIn the primary analysis, factors associated with out-of-pocket spending per hospitalization (sum of deductibles, coinsurance, and copayments) were identified using a generalized linear model. In the secondary analysis, variation in out-of-pocket spending was assessed by level of deductible and inpatient coinsurance requirements.ResultsAmong 183 780 hospitalizations in the primary analysis, 93 186 (50.7%) were for female children, and the median (IQR) age of hospitalized children was 12 (4-16) years. A total of 145 108 hospitalizations (79.0%) were for children with a chronic condition and 44 282 (24.1%) were covered by a high-deductible health plan. Mean (SD) total spending per hospitalization was $28 425 ($74 715). Mean (SD) and median (IQR) out-of-pocket spending per hospitalization were $1313 ($1734) and $656 ($0-$2011), respectively. Out-of-pocket spending exceeded $3000 for 25 700 hospitalizations (14.0%). Factors associated with higher out-of-pocket spending included hospitalization in quarter 1 compared with quarter 4 (average marginal effect [AME], $637; 99% CI, $609-$665) and lack of chronic conditions compared with having a complex chronic condition (AME, $732; 99% CI, $696-$767). The secondary analysis included 72 165 hospitalizations. Among hospitalizations covered by the least generous plans (deductible of $3000 or more and coinsurance of 20% or more) and most generous plans (deductible less than $1000 and coinsurance of 1% to 19%), mean (SD) out-of-pocket spending was $1974 ($1999) and $826 ($798), respectively (AME, $1123; 99% CI, $1069-$1179).Conclusions and RelevanceIn this cross-sectional study, out-of-pocket spending for non–birth-related pediatric hospitalizations were substantial, especially when they occurred early in the year, involved children without chronic conditions, or were covered by plans with high cost-sharing requirements.

Epistaxis is common, impacting more than half the population, and can require procedural intervention in approximately 10% of cases. With an aging population and increasing use of antiplatelets and anticoagulants, severe epistaxis is likely to increase in frequency significantly over the next two decades. Sphenopalatine artery embolization is rapidly becoming the most common type of procedural intervention. The efficacy of endovascular embolization is dependent on a refined understanding of the anatomy and collateral physiology of this circulation as well as the impact of temporizing measures such as nasal packing and inflation of a nasal balloon. Likewise, safety is dependent on a detailed appreciation of collateralization with the internal carotid artery and ophthalmic artery. Cone beam CT imaging has the resolution to enable a clear visualization of the anatomy and collateral circulation associated with the arterial supply to the nasal cavity, in addition to assisting with hemorrhage localization. We present a review of epistaxis treatment, a detailed description of anatomic and physiologic considerations informed by cone beam CT imaging, and a proposed protocol for sphenopalatine embolization for which there is currently no standard.

The widespread adoption of written constitutions is one of the most notable developments in institutional design in politics over the past 250 years. The American states offer a rich place to study constitutional innovation and imitation as being among the first political bodies to adopt constitutions and also given that they often replaced them, in both cases innovating and learning from one another. In this paper, we use quantitative text analysis to identify constitutional innovation and to investigate patterns of imitation. First, we find substantial textual borrowing between state constitutions. On average, 20 percent of a state’s constitutional language was borrowed directly from another state constitution. Second, states were more likely to borrow text from geographically proximate states, from temporally proximate state constitutions, and from states that shared similar partisan profiles. Finally, we offer a brief discussion of the most influential constitutions as an exploratory example for extending our approach of identifying textual innovation and imitation. These findings offer new contributions to both the study of constitutional design and institutional diffusion.

In this paper, we focus on scientific publications as an innovative output from the research efforts at U.S. federal laboratories. The data used relate to Federally Funded Research and Development Centers (FFRDCs). The relationship between R&D expenditures at these federal laboratories and their peer-reviewed scientific publications allows us to make inferences about the return to public-sector R&D. We examine two complementary statistical models. From the first model, we find that a 10% increase in constant dollar public-sector R&D is associated with between a 15.5 and 21.5% increase in scientific publications. From the second model, we find that the annual rate of return generated by an additional $1 million of R&D-based knowledge stock varies across the FFRDCs, averaging about 93 additional scientific publications, with the statistically significant values ranging from about 1 to as many as about 400 additional scientific publications.

Purpose of Review This review summarizes HIV care delivered via telemedicine before and during the COVID-19 pandemic and highlights areas of study to inform optimal usage of telemedicine in HIV clinical practice in the future. Recent Findings To address barriers to care created by the COVID-19 pandemic, regulatory agencies and payors waived longstanding restrictions, which enabled rapid expansion of telemedicine across the country. Preliminary data show that providers and persons with HIV (PWH) view telemedicine favorably. Some data suggest telemedicine has facilitated retention in care, but other studies have found increasing numbers of PWH lost to follow-up and worsened virologic suppression rates despite offering video and/or telephone visits. Summary The COVID-19 pandemic has exacerbated gaps in the HIV care continuum. To help mitigate the impact, most clinics have adopted new virtual care options and are now evaluating usage, impact, and concerns. Further research into the effects of telemedicine on HIV care and continued work towards universal access are needed.

For mass culture of photosynthetic green microalgae, industrial flue gases can represent a low-cost resource of CO2. However, flue gases are often avoided, because they often also contain high levels of SO2 and/or NO2, which cause significant acidification of media to below pH 3 due to production of sulfuric and nitric acid. This creates an unsuitable environment for the neutrophilic microalgae commonly used in large-scale commercial production. To address this issue, we have looked at selecting acid-tolerant microalgae via growth at pH 2.5 carried out with samples bioprospected from an active smelter site. Of the eight wild samples collected, one consisting mainly of Coccomyxa sp. grew at pH 2.5 and achieved a density of 640 mg L−1. Furthermore, three previously bioprospected green microalgae from acidic waters (pH 3–4.5) near abandoned mine sites were also re-acclimated down to their in-situ pH environment after approximately 4 years spent at neutral pH. Of those three, an axenic culture of Coccomyxa sp. was the most successful at re-acclimating and achieved the highest density of 293.1 mg L−1 and maximum daily productivity of 38.8 mg L−1 day−1 at pH 3. Re-acclimation of acid-tolerant species is, therefore, achievable when directly placed at their original pH, but gradual reduction in pH is recommended to give the cells time to acclimate.

Government Royalties on Sales of Pharmaceutical and Other Biomedical Products Developed with Substantial Public Funding: Illustrated with the Technology Transfer of the Drug-Eluting Coronary Stent

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.

Regulatory enzymes often have different roles in distinct subcellular compartments. Yet, most drugs indiscriminately saturate the cell. Thus, subcellular drug-delivery holds promise as a means to reduce off-target pharmacological effects. A-kinase anchoring proteins (AKAPs) sequester combinations of signaling enzymes within subcellular microdomains. Targeting drugs to these ‘signaling islands’ offers an opportunity for more precise delivery of therapeutics. Here, we review mechanisms that bestow protein kinase A (PKA) versatility inside the cell, appraise recent advances in exploiting AKAPs as platforms for precision pharmacology, and explore the impact of methodological innovations on AKAP research.

Ion beams are used routinely for processing of semiconductors, particularly sputtering, ion implantation and direct-write fabrication of nanostructures. However, the utility of ion beam techniques is limited by crystal damage and surface roughening. Damage can be reduced or eliminated by performing irradiation at elevated temperatures. However, at these conditions, surface roughening is highly problematic due to thermal mobility of adatoms and surface vacancies. Here we solve this problem using hydrogen gas, which we use to stabilize surface mass flow and suppress roughening during ion bombardment of elemental and compound semiconductors. We achieve smooth surfaces during ion-beam processing, and show that the method can be enhanced by radicalizing H2 gas using a remote plasma source. Our approach is broadly applicable, and expands the utility of ion beam techniques for the processing and fabrication of functional materials and nanostructures., 14 pages, 5 figures

The U.S. National Library of Medicine’s (NLM) Environmental Health Information Partnership (EnHIP) collaborates with Historically Black Colleges and Universities (HBCUs) and other minority-serving academic institutions to enhance their capacity to reduce health disparities through the access, use, and delivery of environmental health information on their campuses and in their communities. The partnership began in 1991 as the Toxicology Information Outreach Panel (TIOP) pilot project, and through successive iterations it is NLM’s longest running outreach activity. EnHIP’s continued relevance today as an information outreach and training program testifies to the prescience of NLM director, Donald A.B. Lindberg M.D’s initial support for the program. Dr. Lindberg’s seeing to its continued success to benefit participating institutions and help achieve the societal goals of environmental justice serve as well to benefit NLM by increasing its visibility, and use of its resources in the classroom, for research, and in community outreach. NLM envisions an expanding role for EnHIP in advancing health equity as the impact of environmental exposure, climate change, and increasing zoonotic diseases disproportionately impact their communities.

The prior article in this series delved into measuring cost in acute care surgery, and this subsequent work explains in detail how quality is measured. Specifically, objective quality is based on outcome measures, both from administrative and clinical registry databases from a multitude of sources. Risk stratification is key in comparing similar populations across diseases and procedures. Importantly, a move toward focusing on subjective outcomes like patient-reported outcomes measures and financial well-being are vital to evolving surgical quality measures for the 21st century.

Background MAT9001 is an omega‐3 free fatty acid (FFA) formulation containing mainly eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA). Compared with icosapent ethyl (EPA‐ethyl esters [EE]), EPA+DPA‐FFA previously showed enhanced triglyceride lowering and higher plasma EPA when both were administered once daily with a very–low fat diet. This trial compared pharmacodynamic responses and plasma omega‐3 levels following twice daily dosing, with meals, of EPA+DPA‐FFA and EPA‐EE in hypertriglyceridemic subjects consuming a Therapeutic Lifestyle Changes diet. Methods and Results This open‐label, randomized, 2‐way crossover trial, with 28‐day treatment periods separated by ≥28‐day washout, was conducted at 8 US centers and included 100 subjects with fasting triglycerides 1.70 to 5.64 mmol/L (150–499 mg/dL) (median 2.31 mmol/L [204 mg/dL]; 57% women, average age 60.3 years). The primary end point was least squares geometric mean percent change from baseline plasma triglycerides. In the 94 subjects with analyzable data for both treatment periods, EPA+DPA‐FFA and EPA‐EE reduced least squares geometric mean triglycerides from baseline: 20.9% and 18.3%, respectively ( P =not significant). EPA+DPA‐FFA reduced least squares geometric mean high‐sensitivity C‐reactive protein by 5.8%; EPA‐EE increased high‐sensitivity C‐reactive protein by 8.5% ( P =0.034). EPA+DPA‐FFA increased least squares geometric mean plasma EPA, DPA, and total omega‐3 (EPA+docosahexaenoic acid+DPA) concentrations by 848%, 177%, and 205%, respectively, compared with corresponding changes with EPA‐EE of 692%, 140%, and 165% (all P P =0.011). Lipoprotein cholesterol and apolipoprotein responses did not differ between treatments. Conclusions EPA+DPA‐FFA raised plasma EPA, DPA, and total omega‐3 significantly more than did EPA‐EE. EPA+DPA‐FFA also reduced triglycerides and high‐sensitivity C‐reactive protein without increasing low‐density lipoprotein cholesterol. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04177680.

Despite early studies linking calcium-calmodulin protein kinase kinase 2 (CAMKK2) to prostate cancer cell migration and invasion, the role of CAMKK2 in metastasis in vivo remains unclear. Moreover, while CAMKK2 is known to regulate systemic metabolism, whether CAMKK2's effects on whole-body metabolism would impact prostate cancer progression and/or related comorbidities is not known. Here, we demonstrate that germline ablation of

Background Emergency general surgery (EGS) encompasses a heterogeneous population of acutely ill patients, and standardized methods for determining disease severity are essential for comparative effectiveness research and quality improvement initiatives. The American Association for the Surgery of Trauma (AAST) has developed a grading system for the anatomic severity of 16 EGS conditions; however, little is known regarding how well these AAST EGS grades can be approximated by diagnosis codes in administrative databases. Methods We identified adults admitted for 16 common EGS conditions in the 2012 to 2017q3 National Inpatient Sample. Disease severity strata were assigned using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes based on AAST EGS anatomic severity grades. We evaluated whether assigned EGS severity (multiple strata or dichotomized into less versus more complex) were associated with in-hospital mortality, complications, length of stay, discharge disposition, and costs. Analyses were adjusted for age, sex, comorbidities, hospital traits, geography, and year. Results We identified 10,886,822 EGS admissions. The number of anatomic severity strata derived from ICD-9/10-CM codes varied by EGS condition and by year. Four conditions mapped to four strata across all years. Two conditions mapped to four strata with ICD-9-CM codes but only two or three strata with ICD-10-CM codes. Others mapped to three or fewer strata. When dichotomized into less versus more complex disease, patients with more complex disease had worse outcomes across all 16 conditions. The addition of multiple strata beyond a binary measure of complex disease, however, showed inconsistent results. Conclusion Classification of common EGS conditions according to anatomic severity is feasible with International Classification of Diseases codes. No condition mapped to five distinct severity grades, and the relationship between increasing grade and outcomes was not consistent across conditions. However, a standardized measure of severity, even if just dichotomized into less versus more complex, can inform ongoing efforts aimed at optimizing outcomes for EGS patients across the nation. Level of evidence Prognostic, level III.

The calcium-calmodulin–dependent protein kinase kinase-2 (CaMKK2) is a key regulator of cellular and whole-body energy metabolism. It is known to be activated by increases in intracellular Ca(2+), but the mechanisms by which it is inactivated are less clear. CaMKK2 inhibition protects against prostate cancer, hepatocellular carcinoma, and metabolic derangements induced by a high-fat diet; therefore, elucidating the intracellular mechanisms that inactivate CaMKK2 has important therapeutic implications. Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues. PKA-dependent phosphorylation of Ser(495) directly impairs calcium-calmodulin activation, whereas phosphorylation of Ser(100) and Ser(511) mediate recruitment of 14-3-3 adaptor proteins that hold CaMKK2 in the inactivated state by preventing dephosphorylation of phospho-Ser(495). We also report the crystal structure of 14-3-3ζ bound to a synthetic diphosphorylated peptide that reveals how the canonical (Ser(511)) and noncanonical (Ser(100)) 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.

BackgroundThe WHO recommends training lay first responders (LFRs) as the first step towards establishing emergency medical services (EMS) in low-income and middle-income countries. Understanding social and financial benefits associated with responder involvement is essential for LFR programme continuity and may inform sustainable development.MethodsA mixed-methods follow-up study was conducted in July 2019 with 239 motorcycle taxi drivers, including 115 (75%) of 154 initial participants in a Ugandan LFR course from July 2016, to evaluate LFR training on participants. Semi-structured interviews and surveys were administered to samples of initial participants to assess social and economic implications of training, and non-trained motorcycle taxi drivers to gauge interest in LFR training. Themes were determined on a per-question basis and coded by extracting keywords from each response until thematic saturation was achieved.ResultsThree years post-course, initial participants reported new knowledge and skills, the ability to help others, and confidence gain as the main benefits motivating continued programme involvement. Participant outlook was unanimously positive and 96.5% (111/115) of initial participants surveyed used skills since training. Many reported sensing an identity change, now identifying as first responders in addition to motorcycle taxi drivers. Drivers reported they believe this led to greater respect from the Ugandan public and a prevailing belief that they are responsible transportation providers, increasing subsequent customer acquisition. Motorcycle taxi drivers who participated in the course reported a median weekly income value that is 24.39% higher than non-trained motorcycle taxi counterparts (pConclusionsA simultaneous delivery of sustained social and perceived financial benefits to LFRs are likely to motivate continued voluntary participation. These benefits appear to be a potential mechanism that may be leveraged to contribute to the sustainability of future LFR programmes to deliver basic prehospital emergency care in resource-limited settings.

The L-type Ca2+ channel CaV1.2 is essential for arterial myocyte excitability, gene expression and contraction. Elevations in extracellular glucose (hyperglycemia) potentiate vascular L-type Ca2+ channel via PKA, but the underlying mechanisms are unclear. Here, we find that cAMP synthesis in response to elevated glucose and the selective P2Y11 agonist NF546 is blocked by disruption of A-kinase anchoring protein 5 (AKAP5) function in arterial myocytes. Glucose and NF546-induced potentiation of L-type Ca2+ channels, vasoconstriction and decreased blood flow are prevented in AKAP5 null arterial myocytes/arteries. These responses are nucleated via the AKAP5-dependent clustering of P2Y11/ P2Y11-like receptors, AC5, PKA and CaV1.2 into nanocomplexes at the plasma membrane of human and mouse arterial myocytes. Hence, data reveal an AKAP5 signaling module that regulates L-type Ca2+ channel activity and vascular reactivity upon elevated glucose. This AKAP5-anchored nanocomplex may contribute to vascular complications during diabetic hyperglycemia., Molecular mechanisms by which glucose modulates L-type Ca2+ channel activity and vascular reactivity are unclear. Here the authors report a nanocomplex orchestrated by AKAP5 that facilitates local purinergic stimulation of L-type Ca2+ channels and vasoconstriction during diabetic hyperglycemia.