Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice.

Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain.

A Roadmap for Successful State Sepsis Regulations-Lessons From New York.

New York state implemented the first state-level sepsis regulations in 2013. These regulations were associated with improved mortality, leading other states to consider similar steps. Our objective was to provide insight into New York state's sepsis policy making process, creating a roadmap for policymakers in other states considering similar regulations. DESIGN: Qualitative study using semistructured interviews. SETTING: We recruited key stakeholders who had knowledge of the New York state sepsis regulations. SUBJECTS: Thirteen key stakeholders from three groups included four New York state policymakers and seven clinicians and hospital association leaders involved in the creation and implementation of the 2013 New York state sepsis regulations, as well as two members of patient advocacy groups engaged in sepsis advocacy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used iterative, inductive thematic analysis to identify themes related to participant perceptions of the New York state sepsis policy, factors that influenced the policy's perceived successes, and opportunities for improvement. We identified several factors that facilitated success. Among these were that policymakers engaged a diverse array of stakeholders in development, allowing them to address potential barriers to implementation and create early buy-in. Policymakers also paid specific attention to the balance between the desire for comprehensive reporting and the burden of data collection, narrowly focusing on "essential" sepsis-related data elements to reduce the burden on hospitals. In addition, the regulations touched on all three major domains of sepsis quality-structure, process, and outcomes-going beyond a data collection to give hospitals tools to improve sepsis care. CONCLUSIONS: We identified factors that distinguish the New York sepsis regulations from less successful sepsis polices at the federal level. Ultimately, lessons from New York state provide valuable guidance to policymakers and hospital officials seeking to develop and implement policies that will improve sepsis quality.

Holmium laser ureterocele excision with transurethral incision of the prostate

ABSTRACT Introduction: Ureteroceles present a diagnostic and treatment challenge in adults (1). With an estimated prevalence of 1/500 to 1/4000, it is not uncommon for any urologist to encounter ureteroceles in clinical practice (2). The incidence of prolapsed ureteroceles in adults is unknown (3). Materials and Methods: We present an interesting case of a 53-year-old male with a 20-year history of obstructive voiding symptoms who presented with urinary retention with a Foley catheter in place. Pre-operative evaluation included a transrectal ultrasound of the prostate which revealing prostate volume of 20cc. Urodynamics revealed a high-pressure, low flow voiding pattern with a functional detrusor muscle. Cystourethroscopy was performed revealing an orthotopic ureterocele on the left side that was prolapsed into the prostatic urethra, and the bladder neck was elevated. The patient then underwent holmium laser ureterocele excision with transurethral incision of the prostate (TUIP). Using MOSES technology and laser settings of 30Hz and 1.5J, the ureterocele was completely excised and a TUIP was performed. Results: The patient was discharged home on the day of surgery with a Foley catheter in place. On post-operative day 1 he passed a voiding trial with a post-void residual volume of 25cc. Renal ultrasonography was performed 3 months postoperatively revealing no hydronephrosis. His postoperative International Prostate Symptom Score of 2 was improved compared to his preoperative score of 34. Conclusion: Holmium laser ureterocele excision with a TUIP is an effective treatment modality in the management of a prolapsed orthotopic ureterocele causing bladder outlet obstruction in a male patient.

Advanced Practice Provider-inclusive Staffing Models and Patient Outcomes in Pediatric Critical Care.

BACKGROUND: Pediatric intensive care units (PICUs) are increasingly staffed with advanced practice providers (APPs), supplementing traditional physician staffing models. OBJECTIVES: We evaluate the effect of APP-inclusive staffing models on clinical outcomes and resource utilization in US PICUs. RESEARCH DESIGN: Retrospective cohort study of children admitted to PICUs in 9 states in 2016 using the Healthcare Cost and Utilization Project's State Inpatient Databases. PICU staffing models were assessed using a contemporaneous staffing survey. We used multivariate regression to examine associations between staffing models with and without APPs and outcomes. MEASURES: The primary outcome was in-hospital mortality. Secondary outcomes included odds of hospital acquired conditions and ICU and hospital lengths of stay. RESULTS: The sample included 38,788 children in 40 PICUs. Patients admitted to PICUs with APP-inclusive staffing were younger (6.1±5.9 vs. 7.1±6.2 y) and more likely to have complex chronic conditions (64% vs. 43%) and organ failure on admission (25% vs. 22%), compared with patients in PICUs with physician-only staffing. There was no difference in mortality between PICU types [adjusted odds ratio (AOR): 1.23, 95% confidence interval (CI): 0.83-1.81, P=0.30]. Patients in PICUs with APP-inclusive staffing had lower odds of central line-associated blood stream infections (AOR: 0.76, 95% CI: 0.59-0.98, P=0.03) and catheter-associated urinary tract infections (AOR: 0.73, 95% CI: 0.61-0.86, P<0.001). There were no differences in lengths of stay. CONCLUSIONS: Despite being younger and sicker, children admitted to PICUs with APP-inclusive staffing had no increased odds of mortality and lower odds of some hospital acquired conditions compared with those in PICUs with physician-only staffing. Further research can inform APP integration strategies which optimize outcomes.

Physical fitness of Latin America children and adolescents: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Physical fitness (PF) is an important indicator of health in children and adolescents. Internationally, test batteries have been used to assess overall PF. In Latin America, however, while PF has been widely measured, there is no accepted test battery, making it difficult to monitor and/or compare the PF levels of Latin children. The aim of this study, therefore, is to systematically review and potentially meta-analyse the peer-reviewed literature regarding the assessment of PF in Latin American children and adolescents. METHODS AND ANALYSIS: This systematic review and meta-analysis will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols statement. The systematic literature search will be performed in MEDLINE, Scopus, SciELO, EMBASE, Cochrane Library, Web of Science, SPORTDiscus, LILACS and Latindex (Spanish) to locate articles published up to April 2021. Eligible studies will include both descriptive and analytic study designs. Meta-analyses are planned for sufficiently homogeneous PF outcomes with regard to statistical and methodological characteristics. Narrative syntheses are planned for PF outcomes that are considered to be too heterogeneous. The statistical program STATA V.15 will be used for meta-analyses, with subgroup analyses performed according to the characteristics of included studies. ETHICS AND DISSEMINATION: This systematic review and meta-analysis protocol is designed to provide updated evidence on the PF of Latin American children and adolescents. Findings from this review may be useful for teachers, researchers and other professionals responsible for paediatric fitness and health promotion/surveillance. The results will be disseminated through peer-reviewed scientific publications, conferences, educational talks and infographics. PROSPERO REGISTRATION NUMBER: CRD42020189892.

Activation of PKCε-ALDH2 axis prevents 4-HNE-induced pain in mice / A ativação do eixo PKCε-ALDH2 previne a dor induzida por 4-HNE em camundongos

Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain.

Activation of PKCε-ALDH2 axis prevents 4-HNE-induced pain in mice

Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain.

Economic Analysis of Mandated Protocolized Sepsis Care in New York Hospitals.

OBJECTIVES: Initial evidence suggests that state-level regulatory mandates for sepsis quality improvement are associated with decreased sepsis mortality. However, sepsis mandates require financial investments on the part of hospitals and may lead to increased spending. We evaluated the effects of the 2013 New York State sepsis regulations on the costs of care for patients hospitalized with sepsis. DESIGN: Retrospective cohort study using state discharge data from the U.S. Healthcare Costs and Utilization Project and a comparative interrupted time series analytic approach. Costs were calculated from admission-level charge data using hospital-specific cost-to-charge ratios. SETTING: General, short stay, acute care hospitals in New York, and four control states: Florida, Massachusetts, Maryland, and New Jersey. PATIENTS: All patients hospitalized with sepsis between January 1, 2011, and September 30, 2015. INTERVENTIONS: The 2013 New York mandate that all hospitals develop and implement protocols for sepsis identification and treatment, educate staff, and report performance data to the state. MEASUREMENTS AND MAIN RESULTS: The analysis included 1,026,664 admissions in 520 hospitals. Mean unadjusted costs per hospitalization in New York State were $42,036 ± $60,940 in the pre-regulation period and $39,719 ± $59,063 in the post-regulation period, compared with $34,642 ± $52,403 pre-regulation and $31,414 ± $48,155 post-regulation in control states. In the comparative interrupted time series analysis, the regulations were not associated with a significant difference in risk-adjusted mean cost per hospitalization (p = 0.12) or risk-adjusted mean cost per hospital day (p = 0.44). For example, in the 10th quarter after implementation of the regulations, risk-adjusted mean cost per hospitalization was $3,627 (95% CI, -$681 to $7,934) more than expected in New York State relative to control states. CONCLUSIONS: Mandated protocolized sepsis care was not associated with significant changes in hospital costs in patients hospitalized with sepsis in New York State.

Relationship Between State Policy and Anesthesia Provider Supply in Rural Communities.

BACKGROUND: There is a significant geographic variation in anesthesia provider supply. Lower supply in rural communities raises concerns about access to procedures that require anesthesia in rural areas. State policies related to certified registered nurse anesthetist (CRNA) practice may help to alleviate rural supply concerns. OBJECTIVES: To estimate the association between state CRNA policy and anesthesia provider supply especially in rural communities. RESEARCH DESIGN: Repeated cross-sectional design using ordinary least squares and 2-stage least squares regressions. SUBJECTS: All counties in the United States from 2010 to 2015. MEASURES: Dependent variables include anesthesia provider counts per 100,000 people, calculated separately for anesthesiologists, CRNAs, and their sum. Key variables of interest include state-level CRNA policy based on scope of practice (SOP) regulations and Medicare opt-out status. RESULTS: Opt-out status and less restrictive SOP regulations were consistently correlated with a greater supply of CRNAs, especially in rural counties. Furthermore, we found that anesthesiologists and CRNAs tend to be complements to each other, but less restrictive SOP and opt-out status tend to weaken the importance of this relationship. CONCLUSIONS: State regulations may lead to increased supply of CRNAs in rural communities. However, the design of our study makes causality difficult to assert. So, it is also possible that states set CRNA policy as a response to counts of anesthesia providers in rural areas. Furthermore, given supply of anesthesiologists and CRNAs are complementary to one another, improving access to anesthesia services may require addressing issues pertaining to the supply of all anesthesia provider types.

Estimating Associations Between Medical Home Adoption, Utilization, and Quality: A Comparison of Evaluation Approaches.

BACKGROUND: Methodological differences between evaluations of medical home adoption might complicate readers' ability to draw conclusions across studies. OBJECTIVES: To study whether associations between medical home adoption and patient care are affected by methodological choices. DESIGN, SETTING, AND SUBJECTS: Among 71 practices participating in the Pennsylvania Chronic Care Initiative (a medical home pilot), we estimated cross-sectional and longitudinal associations between 4 definitions of "medical home adoption" [National Committee on Quality Assurance (NCQA) recognition in year 3, Medical Home Index scores at baseline and 3, and within-practice changes in Medical Home Index scores between baseline and year 3] and utilization and quality. MEASUREMENTS: Six utilization and 6 quality measures. RESULTS: In cross-sectional analyses at year 3, NCQA recognition was associated with higher rates of nephropathy monitoring (7.23 percentage points; confidence interval, 0.45-14.02), breast cancer screening (7.48; 2.11-12.86), and colorectal cancer screening (8.43; 2.44-14.42). In longitudinal analyses, NCQA recognition was associated with increases in hospitalization rates (2.75 per 1000 patient-months; 0.52-4.98). In baseline cross-sectional analyses, higher Medical Home Index scores were associated with fewer ambulatory care-sensitive hospitalizations (-0.61 per 1000 patient per month; -1.11 to -0.11), all-cause emergency department visits (-6.80; -12.28 to -1.32), and ambulatory care-sensitive emergency department visits (-5.60; 10.32 to -0.88). There were no statistically significant associations between any other measure of medical home adoption and quality or utilization. CONCLUSIONS: The findings of medical home evaluations are sensitive to methodological choices. Meta-analyses, narrative reviews, and other syntheses of medical home studies should consider subdividing their findings by analytic approach.

Creating Unidimensional Global Measures of Physician Practice Quality Based on Health Insurance Claims Data.

OBJECTIVE: To explore the extent to which commonly used claims-based process quality indicators can be used to create an internally valid global composite measure of physician practice quality. DATA SOURCES: Health insurance claims data (October 2007-May 2010) from 134 physician practices in Seattle, WA. STUDY DESIGN: We use confirmatory and exploratory factor analysis to develop theory- and empirically driven internally valid composite measures based on 19 quality indicators. DATA COLLECTION METHODS: Health insurance claims data from nine insurance companies and self-funded employers were collected and aggregated by third-party organization. PRINCIPAL FINDINGS: Our results did not support a single global measure using the entire set of quality indicators. We did identify an acceptable multidimensional model (RMSEA = 0.059; CFI = 0.934; TLI = 0.910). The four dimensions in our data were diabetes, depression, preventive care, and generic drug prescribing. CONCLUSIONS: Our study demonstrates that commonly used process indicators can be used to create a small set of useful composite measures. However, the lack of an internally valid single unidimensional global measure has important implications for policy approaches meant to improve quality by rewarding "high-quality physicians."

Abundance and characteristics of microplastics in beach sediments: Insights into microplastic accumulation in northern Gulf of Mexico estuaries.

Microplastics (plastic debris smaller than 5mm) represent a growing concern worldwide due to increasing amounts of discarded trash. We investigated microplastic debris on sandy shorelines at seven locations in a northern Gulf of Mexico estuary (Mobile Bay, AL) during the summer of 2014. Microplastics were ubiquitous throughout the area studied at concentrations 66-253× larger than reported for the open ocean. The polymers polypropylene and polyethylene were most abundant, with polystyrene, polyester and aliphatic polyamide also present but in lower quantities. There was a gradient in microplastic abundance, with locations more directly exposed to marine currents and tides having higher microplastic abundance and diversity, as well as a higher contribution by denser polymers (e.g. polyester). These results indicate that microplastic accumulation on shorelines in the northern Gulf of Mexico may be a serious concern, and suggest that exposure to inputs from the Gulf is an important determinant of microplastic abundance.

An Examination of Hospital Nurse Staffing and Patient Experience with Care: Differences between Cross-Sectional and Longitudinal Estimates.

OBJECTIVE: To study the association between hospital nurse staffing and Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores. DATA SOURCES: State hospital financial and utilization reports, Healthcare Cost and Utilization Project State Inpatient Databases, HCAHPS survey, and American Hospital Association Annual Survey of Hospitals. STUDY DESIGN: Retrospective study using cross-sectional and longitudinal models to estimate the effect of nurse staffing levels and skill mix on seven HCAHPS measures. DATA COLLECTION/EXTRACTION METHODS: Hospital-level data measuring nurse staffing, patient experience, and hospital characteristics from 2009 to 2011 for 341 hospitals (977 hospital years) in California, Maryland, and Nevada. PRINCIPAL FINDINGS: Nurse staffing level (i.e., number of licensed practical nurses and registered nurses per 1,000 inpatient days) was significantly and positively associated with all seven HCAHPS measures in cross-sectional models and three of seven measures in longitudinal models. Nursing skill mix (i.e., percentage of all staff who are registered nurses) was significantly and negatively associated with scores on one measure in cross-sectional models and none in longitudinal models. CONCLUSIONS: After controlling for unobserved hospital characteristics, the positive influences of increased nurse staffing levels and skill mix were relatively small in size and limited to a few measures of patients' inpatient experience.

Compatible GLRaV-3 viral infections affect berry ripening decreasing sugar accumulation and anthocyanin biosynthesis in Vitis vinifera.

Virus infections in grapevine cause important economic losses and affect fruit quality worldwide. Although the phenotypic symptoms associated to viral infections have been described, the molecular plant response triggered by virus infection is still poorly understood in Vitis vinifera. As a first step to understand the fruit changes and mechanisms involved in the compatible grapevine-virus interaction, we analyzed the berry transcriptome in two stages of development in the red wine cultivar Cabernet Sauvignon infected with Grapevine leaf-roll-associated virus-3 (GLRaV-3). Analysis of global gene expression patterns indicate incomplete berry maturation in infected berries as compared to uninfected fruit suggesting viral infection interrupts the normal berry maturation process. Genes with altered expression in berries harvested from GLRaV-3-infected vines as compared to uninfected tissue include anthocyanin biosynthesis and sugar metabolism genes. The reduction in transcript accumulation for sugar and anthocyanin metabolism during fruit development is consistent with a dramatic reduction in anthocyanin biosynthesis as well as reduced sugar levels in berries, a hallmark phenotypic change observed in virus infected grapevines. Analysis of key regulatory factors provides a mechanism for the observed gene expression changes. Our results provide insight into commonly observed phenotypic alterations in virus infected vines and the molecular mechanisms associated with the plant response to the virus during berry ripening.