cAMP signaling: a remarkably regional affair.

Louis Pasteur once famously said 'in the fields of observation chance favors only the prepared mind'. Much of chance is being in the right place at the right time. This is particularly true in the crowded molecular environment of the cell where being in the right place is often more important than timing. Although Brownian motion argues that enzymes will eventually bump into substrates, this probability is greatly enhanced if both molecules reside in the same subcellular compartment. However, activation of cell signaling enzymes often requires the transmission of chemical signals from extracellular stimuli to intracellular sites of action. This review highlights new developments in our understanding of cAMP generation and the 3D utilization of this second messenger inside cells.

Signalling scaffolds and local organization of cellular behaviour.

Cellular responses to environmental cues involve the mobilization of GTPases, protein kinases and phosphoprotein phosphatases. The spatial organization of these signalling enzymes by scaffold proteins helps to guide the flow of molecular information. Allosteric modulation of scaffolded enzymes can alter their catalytic activity or sensitivity to second messengers in a manner that augments, insulates or terminates local cellular events. This Review examines the features of scaffold proteins and highlights examples of locally organized groups of signalling enzymes that drive essential physiological processes, including hormone action, heart rate, cell division, organelle movement and synaptic transmission.

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

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

Methylprednisolone for Heart Surgery in Infants - A Randomized, Controlled Trial.

BACKGROUND: Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass is unknown. METHODS: We conducted a multicenter, prospective, randomized, placebo-controlled, registry-based trial involving infants (<1 year of age) undergoing heart surgery with cardiopulmonary bypass at 24 sites participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Registry data were used in the evaluation of outcomes. The infants were randomly assigned to receive prophylactic methylprednisolone (30 mg per kilogram of body weight) or placebo, which was administered into the cardiopulmonary-bypass pump-priming fluid. The primary end point was a ranked composite of death, heart transplantation, or any of 13 major complications. Patients without any of these events were assigned a ranked outcome based on postoperative length of stay. In the primary analysis, the ranked outcomes were compared between the trial groups with the use of odds ratios adjusted for prespecified risk factors. Secondary analyses included an unadjusted odds ratio, a win ratio, and safety outcomes. RESULTS: A total of 1263 infants underwent randomization, of whom 1200 received either methylprednisolone (599 infants) or placebo (601 infants). The likelihood of a worse outcome did not differ significantly between the methylprednisolone group and the placebo group (adjusted odds ratio, 0.86; 95% confidence interval [CI], 0.71 to 1.05; P = 0.14). Secondary analyses (unadjusted for risk factors) showed an odds ratio for a worse outcome of 0.82 (95% CI, 0.67 to 1.00) and a win ratio of 1.15 (95% CI, 1.00 to 1.32) in the methylprednisolone group as compared with the placebo group, findings suggestive of a benefit with methylprednisolone; however, patients in the methylprednisolone group were more likely than those in the placebo group to receive postoperative insulin for hyperglycemia (19.0% vs. 6.7%, P<0.001). CONCLUSIONS: Among infants undergoing surgery with cardiopulmonary bypass, prophylactic use of methylprednisolone did not significantly reduce the likelihood of a worse outcome in an adjusted analysis and was associated with postoperative development of hyperglycemia warranting insulin in a higher percentage of infants than placebo. (Funded by the National Center for Advancing Translational Sciences and others; STRESS ClinicalTrials.gov number, NCT03229538.).

Drugs That Regulate Local Cell Signaling: AKAP Targeting as a Therapeutic Option.

Cells respond to environmental cues by mobilizing signal transduction cascades that engage protein kinases and phosphoprotein phosphatases. Correct organization of these enzymes in space and time enables the efficient and precise transmission of chemical signals. The cyclic AMP-dependent protein kinase A is compartmentalized through its association with A-kinase anchoring proteins (AKAPs). AKAPs are a family of multivalent scaffolds that constrain signaling enzymes and effectors at subcellular locations to drive essential physiological events. More recently, it has been recognized that defective signaling in certain endocrine disorders and cancers proceeds through pathological AKAP complexes. Consequently, pharmacologically targeting these macromolecular complexes unlocks new therapeutic opportunities for a growing number of clinical indications. This review highlights recent findings on AKAP signaling in disease, particularly in certain cancers, and offers an overview of peptides and small molecules that locally regulate AKAP-binding partners.

Evidence of the Monopolar-Dipolar Crossover Regime: A Multiscale Study of Ferroelastic Domains by In Situ Microscopy Techniques.

The elastic interaction between kinks (and antikinks) within domain walls plays a pivotal role in shaping the domain structure, and their dynamics. In bulk materials, kinks interact as elastic monopoles, dependent on the distance between walls (d-1) and typically characterized by a rigid and straight domain configuration. In this work the evolution of the domain structure is investigated, as the sample size decreases, by the means of in situ heating microscopy techniques on free-standing samples. As the sample size decreases, a significant transformation is observed: domain walls exhibit pronounced curvature, accompanied by an increase in both domain wall and junction density. This transformation is attributed to the pronounced influence of kinks, inducing sample warping, where "dipole-dipole" interactions are dominant (d-2). Moreover, a critical thickness range that delineates a crossover between the monopolar and dipolar regimens is experimentally identified and corroborated by atomic simulations. These findings are relevant for in situ TEM studies and for the development of novel devices based on free-standing ferroic thin films and nanomaterials.

CaMKK2 as an emerging treatment target for bipolar disorder.

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

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

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

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

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

Classification of Cushing's syndrome PKAc mutants based upon their ability to bind PKI.

Cushing's syndrome is an endocrine disorder caused by excess production of the stress hormone cortisol. Precision medicine strategies have identified single allele mutations within the PRKACA gene that drive adrenal Cushing's syndrome. These mutations promote perturbations in the catalytic core of protein kinase A (PKAc) that impair autoinhibition by regulatory subunits and compartmentalization via recruitment into AKAP signaling islands. PKAcL205R is found in ∼45% of patients, whereas PKAcE31V, PKAcW196R, and L198insW and C199insV insertion mutants are less prevalent. Mass spectrometry, cellular, and biochemical data indicate that Cushing's PKAc variants fall into two categories: those that interact with the heat-stable protein kinase inhibitor PKI, and those that do not. In vitro activity measurements show that wild-type PKAc and W196R activities are strongly inhibited by PKI (IC50 < 1 nM). In contrast, PKAcL205R activity is not blocked by the inhibitor. Immunofluorescent analyses show that the PKI-binding variants wild-type PKAc, E31V, and W196R are excluded from the nucleus and protected against proteolytic processing. Thermal stability measurements reveal that upon co-incubation with PKI and metal-bound nucleotide, the W196R variant tolerates melting temperatures 10°C higher than PKAcL205. Structural modeling maps PKI-interfering mutations to a ∼20 Šdiameter area at the active site of the catalytic domain that interfaces with the pseudosubstrate of PKI. Thus, Cushing's kinases are individually controlled, compartmentalized, and processed through their differential association with PKI.

Discovery and In Vitro Characterization of BAY 2686013, an Allosteric Small Molecule Antagonist of the Human Pituitary Adenylate Cyclase-Activating Polypeptide Receptor.

The human pituitary adenylate cyclase-activating polypeptide receptor (hPAC1-R), a class B G-protein-coupled receptor (GPCR) identified almost 30 years ago, represents an important pharmacological target in the areas of neuroscience, oncology, and immunology. Despite interest in this target, only a very limited number of small molecule modulators have been reported for this receptor. We herein describe the results of a drug discovery program aiming for the identification of a potent and selective hPAC1-R antagonist. An initial high-throughput screening (HTS) screen of 3.05 million compounds originating from the Bayer screening library failed to identify any tractable hits. A second, completely revised screen using native human embryonic kidney (HEK)293 cells yielded a small number of hits exhibiting antagonistic properties (4.2 million compounds screened). BAY 2686013 (1) emerged as a promising compound showing selective antagonistic activity in the submicromolar potency range. In-depth characterization supported the hypothesis that BAY 2686013 blocks receptor activity in a noncompetitive manner. Preclinical, pharmacokinetic profiling indicates that BAY 2686013 is a valuable tool compound for better understanding the signaling and function of hPAC1-R. SIGNIFICANCE STATEMENT: Although the human pituitary adenylate cyclase-activating polypeptide receptor (hPAC1-R) is of major significance as a therapeutic target with a well documented role in pain signaling, only a very limited number of small-molecule (SMOL) compounds are known to modulate its activity. We identified and thoroughly characterized a novel, potent, and selective SMOL antagonist of hPAC1-R (acting in an allosteric manner). These characteristics make BAY 2686013 an ideal tool for further studies.

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

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

Surgical Procedures at Critical Access Hospitals Within Hospital Networks.

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

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

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

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

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

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

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

Phosphorylation, compartmentalization, and cardiac function.

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.

Utilizing CO2 in industrial off-gas for microalgae cultivation: considerations and solutions.

The utilization of microalgae to treat carbon dioxide (CO2)-rich industrial off-gas has been suggested as both beneficial for emissions reduction and economically favorable for the production of microalgal products. Common sources of off-gases include coal combustion (2-15% CO2), cement production (8-15% CO2), coke production (18-23% CO2), and ore smelting (6-7% CO2). However, industrial off-gas also commonly contains other acid gas components [typically nitrogen oxides (NOX) and sulfur dioxide (SO2)] and metals that could inhibit microalgae growth and productivity. To utilize industrial off-gas effectively in microalgae cultivation systems, a number of solutions have been proposed to overcome potential inhibitions. These include bioprospecting to identify suitable strains, genetic modification to improve specific cellular characteristics, chemical additions, and bioreactor designs and operating procedures.In this review, results from microalgae experiments related to utilizing off-gas are presented, and the outcomes of different conditions discussed along with potential solutions to resolve limitations associated with the application of off-gas.

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

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

Financial outcomes after pediatric critical illness among commercially insured families.

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