Xanthine oxidase mediates chronic stress-induced cerebrovascular dysfunction and cognitive impairment.

Xanthine oxidase (XO) mediates vascular function. Chronic stress impairs cerebrovascular function and increases the risk of stroke and cognitive decline. Our study determined the role of XO on stress-induced cerebrovascular dysfunction and cognitive decline. We measured middle cerebral artery (MCA) function, free radical formation, and working memory in 6-month-old C57BL/6 mice who underwent 8 weeks of control conditions or unpredictable chronic mild stress (UCMS) with or without febuxostat (50 mg/L), a XO inhibitor. UCMS mice had an impaired MCA dilation to acetylcholine vs. controls (p < 0.0001), and increased total free radical formation, XOR protein levels, and hydrogen peroxide production in the liver compared to controls. UCMS increased hydrogen peroxide production in the brain and cerebrovasculature compared to controls. Working memory, using the y-maze test, was impaired (p < 0.05) in UCMS mice compared to control mice. However, blocking XO using febuxostat prevented the UCMS-induced impaired MCA response, while free radical production and hydrogen peroxide levels were similar to controls in the liver and brain of UCMS mice treated with febuxostat. Further, UCMS + Feb mice did not have a significant reduction in working memory. These data suggest that the cerebrovascular dysfunction associated with chronic stress may be driven by XO, which leads to a reduction in working memory.

Vulnerable Child Syndrome in the International Community.

Vulnerable child syndrome (VCS) is a condition in which a caregiver perceives a child as inherently frail and consequently employs health care services disproportionate to medical need. Historically, VCS has been described after a medical event or diagnosis in developed countries. There is little to no literature on VCS outside of well-resourced countries. Cases from a medium-resource setting are presented to illustrate risks for development of VCS, including impaired feeding practices and the potential consequences of coronavirus disease 2019 (COVID-19). Exploring VCS through this different lens offers insights to providers working with immigrant populations on the United States mainland, including guidance on how to foster more resilience and less hypervigilance among their patients' parents. [Pediatr Ann. 2022;51(12):e469-e473.].

Do Financial Incentives Affect Utilization for Chronically Ill Medicare Beneficiaries?

OBJECTIVE: The objective of this study was to examine the price sensitivity for provider visits among Medicare Advantage beneficiaries. DATA SOURCES: We used Medicare Advantage encounter data from 2014 to 2017 accessed as part of an evaluation for the Center for Medicare & Medicaid Innovation. STUDY DESIGN: We analyzed the effect of cost-sharing on the utilization of 2 outcome categories: number of visits (specialist and primary care) and the probability of any visit (specialist and primary care). Our main independent variable was the size of the copayment for the visit, which we regressed on the outcomes with several beneficiary-level and plan-level control variables. DATA COLLECTION/EXTRACTION METHODS: We included beneficiaries with at least 1 of 4 specific chronic conditions and matched comparison beneficiaries. We did not require beneficiaries to be continuously enrolled from 2014 to 2017, but we required a full year of data for each year they were observed. This resulted in 371,140 beneficiary-year observations. PRINCIPAL FINDINGS: Copay reductions were associated with increases in utilization, although the changes were small, with elasticities <-0.2. We also found evidence of substitution effects between primary care provider (PCP) and specialist visits, particularly cardiology and endocrinology. When PCP copays declined, visits to these specialists also declined. CONCLUSIONS: We find that individuals with chronic conditions respond to changes in copays, although these responses are small. Reductions in PCP copays lead to reduced use of some specialists, suggesting that lowering PCP copays could be an effective way to reduce the use of specialist care, a desirable outcome if specialists are overused.

Undergoing transformation to the patient centered medical home in safety net health centers: perspectives from the front lines.

OBJECTIVES: Safety net health centers (SNHCs), which include federally qualified health centers (FQHCs) provide primary care for underserved, minority and low income patients. SNHCs across the country are in the process of adopting the patient centered medical home (PCMH) model, based on promising early implementation data from demonstration projects. However, previous demonstration projects have not focused on the safety net and we know little about PCMH transformation in SNHCs. DESIGN: This qualitative study characterizes early PCMH adoption experiences at SNHCs. SETTING AND PARTICIPANTS: We interviewed 98 staff (administrators, providers, and clinical staff) at 20 of 65 SNHCs, from five states, who were participating in the first of a five-year PCMH collaborative, the Safety Net Medical Home Initiative. MAIN MEASURES: We conducted 30-45 minute, semi-structured telephone interviews. Interview questions addressed benefits anticipated, obstacles encountered, and lessons learned in transition to PCMH. RESULTS: Anticipated benefits for participating in the PCMH included improved staff satisfaction and patient care and outcomes. Obstacles included staff resistance and lack of financial support for PCMH functions. Lessons learned included involving a range of staff, anticipating resistance, and using data as frequent feedback. CONCLUSIONS: SNHCs encounter unique challenges to PCMH implementation, including staff turnover and providing care for patients with complex needs. Staff resistance and turnover may be ameliorated through improved health care delivery strategies associated with the PCMH. Creating predictable and continuous funding streams may be more fundamental challenges to PCMH transformation.

Satisfaction with electronic health records is associated with job satisfaction among primary care physicians.

OBJECTIVE: To evaluate the association between electronic health record (EHR) satisfaction and job satisfaction in primary care physicians (PCPs). METHOD: Cross-sectional survey of PCPs at 825 primary care practices in North Carolina. RESULTS: Surveys were returned from 283 individuals across 214 practices (26% response rate for practices), of whom 122 were physicians with EHRs and no missing information. We found that for each point increase in EHR satisfaction, job satisfaction increased by ∼0.36 points both in an unadjusted and an adjusted model (ß 0.359 unadjusted, 0.361 adjusted; p < 0.001 for both models). CONCLUSION: We found that EHR satisfaction was associated with job satisfaction in a cross-sectional survey of PCPs. Our conclusions are limited by suboptimum survey response rate, but if confirmed may have substantial implications for how EHR vendors develop their product to support the needs of PCPs.

Factors influencing intermethod agreement between goldmann applanation, pascal dynamic contour, and ocular response analyzer tonometry.

PURPOSE: To examine factors that influence intraocular pressure (IOP) measurement agreement between Goldmann applanation (GAT), Ocular Response Analyzer (ORA), and Pascal Dynamic Contour tonometers (DCT). PATIENTS AND METHODS: In subjects who were diagnosed with primary open-angle glaucoma, ocular hypertension, glaucoma suspect, and normal, we used ORA, DCT, and GAT to obtain corneal hysteresis (CH), corneal resistance factor (CRF), ocular pulse amplitude, and 4 IOP values (ORA-IOPcc; ORA-IOPg; DCT-IOP; and GAT-IOP.) We also obtained corneal curvature, corneal thickness, axial length, retinal nerve fiber layer thickness, visual field parameters, diabetes diagnostic status, and topical IOP-lowering treatment data. Analysis of variance, Bland-Altman, and regression analyses were used to examine IOP agreement and associated factors. RESULTS: In 243 eyes of the 243 subjects, mean DCT-IOP (18.73±4.92) was not different from mean ORA-IOPcc (18.96±5.41) but both were significantly higher than ORA-IOPg (16.97±5.49) and GAT-IOP (16.37±4.97). In multivariate regression models, intermethod differences between IOPg, IOPcc, and DCT-IOP were explained almost completely by variations in CH, CRF, and level of IOP (r(2)=0.98 to 0.99); conversely, intermethod variability between GAT-IOP and the other 3 IOP metrics was only partially explained by the factors evaluated in this study (r(2)=0.31 to 0.65). CONCLUSIONS: Consistent with other studies, we found that the 4 IOP variables examined in this study are not interchangeable. The most consistent confounders of IOP measurement agreement were the ORA-measured corneal parameters, CH and CRF. Thus, accounting for these factors may be important in efforts to obtain accurate transcorneal estimates of IOP.

Patient-centered medical home characteristics and staff morale in safety net clinics.

BACKGROUND: We sought to determine whether perceived patient-centered medical home (PCMH) characteristics are associated with staff morale, job satisfaction, and burnout in safety net clinics. METHODS: Self-administered survey among 391 providers and 382 clinical staff across 65 safety net clinics in 5 states in 2010. The following 5 subscales measured respondents' perceptions of PCMH characteristics on a scale of 0 to 100 (0 indicates worst and 100 indicates best): access to care and communication with patients, communication with other providers, tracking data, care management, and quality improvement. The PCMH subscale scores were averaged to create a total PCMH score. RESULTS: Six hundred three persons (78.0%) responded. In multivariate generalized estimating equation models, a 10% increase in the quality improvement subscale score was associated with higher morale (provider odds ratio [OR], 2.64; 95% CI, 1.47-4.75; staff OR, 3.62; 95% CI, 1.84-7.09), greater job satisfaction (provider OR, 2.45; 95% CI, 1.42-4.23; staff OR, 2.55; 95% CI 1.42-4.57), and freedom from burnout (staff OR, 2.32; 95% CI, 1.31-4.12). The total PCMH score was associated with higher staff morale (OR, 2.63; 95% CI, 1.47-4.71) and with lower provider freedom from burnout (OR, 0.48; 95% CI, 0.30-0.77). A separate work environment covariate correlated highly with the quality improvement subscale score and the total PCMH score, and PCMH characteristics had attenuated associations with morale and job satisfaction when included in models. CONCLUSIONS: Providers and staff who perceived more PCMH characteristics in their clinics were more likely to have higher morale, but the providers had less freedom from burnout. Among the PCMH subscales, the quality improvement subscale score particularly correlated with higher morale, greater job satisfaction, and freedom from burnout.

Development of a safety net medical home scale for clinics.

BACKGROUND: Existing tools to measure patient-centered medical home (PCMH) adoption are not designed for research evaluation in safety-net clinics. OBJECTIVE: Develop a scale to measure PCMH adoption in safety-net clinics. RESEARCH DESIGN: Cross-sectional survey. SUBJECTS: Sixty-five clinics in five states. MAIN MEASURES: Fifty-two-item Safety Net Medical Home Scale (SNMHS). The total score ranges from 0 (worst) to 100 (best) and is an average of multiple subscales (0-100): Access and Communication, Patient Tracking and Registry, Care Management, Test and Referral Tracking, Quality Improvement, and External Coordination. The scale was tested for internal consistency reliability and tested for convergent validity using The Assessment of Chronic Illness Care (ACIC) and the Patient-Centered Medical Home Assessment (PCMH-A). The scale was applied to centers in the sample. In addition, linear regression models were used to measure the association between clinic characteristics and medical home adoption. RESULTS: The SNMHS had high internal consistency reliability (Cronbach's alpha = 0.84). The SNMHS score correlated moderately with the ACIC score (r = 0.64, p < 0.0001) and the PCMH-A (r = 0.56, p < 0.001). The mean SNMHS score was 61 ± SD 13. Among the subscales, External Coordination (66 ± 16) and Access and Communication (65 ± 14) had the highest mean scores, while Quality Improvement (55 ± 17) and Care Management (55 ± 16) had lower mean scores. Clinic characteristics positively associated with total SNMHS score were having more providers (ß 15.8 95% CI 8.1-23.4 >8 provider FTEs compared to <4 FTEs) and participation in financial incentive programs (ß 8.4 95% 1.6-15.3). CONCLUSION: The SNMHS demonstrated reliability and convergent validity for measuring PCMH adoption in safety-net clinics. Some clinics have significant PCMH adoption. However, room for improvement exists in most domains, especially for clinics with fewer providers.

Comparative analysis of the HV1 and HV2 regions of human mitochondrial DNA by denaturing high-performance liquid chromatography.

Denaturing high-performance liquid chromatography (DHPLC) was evaluated as a sequencing-independent means of detecting the presence of sequence differences in pair-wise mixtures of nonconcordant amplicons of human mitochondrial DNA (mtDNA). A total of 920 pair-wise combinations of HV1 and HV2 mtDNA amplicons from 95 individuals were assayed by DHPLC for sequence concordance/nonconcordance. For the 72 combinations of amplicons from different individuals who shared identical DNA sequences, DHPLC assays consistently indicated sequence concordance between the samples. This was in 100% agreement with sequencing data. For the 849 combinations of amplicons which differed in sequence, DHPLC detected the presence of sequence nonconcordance in all but 13 assays to yield 98.5% concordance with sequencing. Thus, DHPLC can be used to detect a diversity of sequence differences (transitions, transversions, insertions, and deletions) in the mtDNA D-loop. Accordingly, DHPLC may have utility as a presumptive indicator of mtDNA sequence concordance samples, as a screen for heteroplasmy/situational mixtures, and as a means for the physical fractionation of the individual contributors to an mtDNA mixture prior to sequencing.

Gpi19, the Saccharomyces cerevisiae homologue of mammalian PIG-P, is a subunit of the initial enzyme for glycosylphosphatidylinositol anchor biosynthesis.

Glycosylphosphatidylinositols (GPIs) are attached to the C termini of some glycosylated secretory proteins, serving as membrane anchors for many of those on the cell surface. Biosynthesis of GPIs is initiated by the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol. This reaction is carried out at the endoplasmic reticulum (ER) by an enzyme complex called GPI-N-acetylglucosaminyltransferase (GPI-GlcNAc transferase). The human enzyme has six known subunits, at least four of which, GPI1, PIG-A, PIG-C, and PIG-H, have functional homologs in the budding yeast Saccharomyces cerevisiae. The uncharacterized yeast gene YDR437w encodes a protein with some sequence similarity to human PIG-P, a fifth subunit of the GPI-GlcNAc transferase. Here we show that Ydr437w is a small but essential subunit of the yeast GPI-GlcNAc transferase, and we designate its gene GPI19. Similar to other mutants in the yeast enzyme, temperature-sensitive gpi19 mutants display cell wall defects and hyperactive Ras phenotypes. The Gpi19 protein associates with the yeast GPI-GlcNAc transferase in vivo, as judged by coimmuneprecipitation with the Gpi2 subunit. Moreover, conditional gpi19 mutants are defective for GPI-GlcNAc transferase activity in vitro. Finally, we present evidence for the topology of Gpi19 within the ER membrane.

Triglyceride accumulation protects against fatty acid-induced lipotoxicity.

Excess lipid accumulation in non-adipose tissues is associated with insulin resistance, pancreatic beta-cell apoptosis and heart failure. Here, we demonstrate in cultured cells that the relative toxicity of two common dietary long chain fatty acids is related to channeling of these lipids to distinct cellular metabolic fates. Oleic acid supplementation leads to triglyceride accumulation and is well tolerated, whereas excess palmitic acid is poorly incorporated into triglyceride and causes apoptosis. Unsaturated fatty acids rescue palmitate-induced apoptosis by channeling palmitate into triglyceride pools and away from pathways leading to apoptosis. Moreover, in the setting of impaired triglyceride synthesis, oleate induces lipotoxicity. Our findings support a model of cellular lipid metabolism in which unsaturated fatty acids serve a protective function against lipotoxicity though promotion of triglyceride accumulation.

Oligomerization of the murine fatty acid transport protein 1.

The 63-kDa murine fatty acid transport protein 1 (FATP1) was cloned on the basis of its ability to augment fatty acid import when overexpressed in mammalian cells. The membrane topology of this integral plasma membrane protein does not resemble that of polytopic membrane transporters for other substrates. Western blot analysis of 3T3-L1 adipocytes that natively express FATP1 demonstrate a prominent 130-kDa species as well as the expected 63-kDa FATP1, suggesting that this protein may participate in a cell surface transport protein complex. To test whether FATP1 is capable of oligomerization, we expressed functional FATP1 molecules with different amino- or carboxyl-terminal epitope tags in fibroblasts. These epitope-tagged proteins also form apparent higher molecular weight species. We show that, when expressed in the same cells, differentially tagged FATP1 proteins co-immunoprecipitate. The region between amino acid residues 191 and 475 is sufficient for association of differentially tagged truncated FATP1 constructs. When wild type FATP1 and the non-functional s250a FATP1 mutant are co-expressed in COS7 cells, mutant FATP1 has dominant inhibitory function in fatty acid uptake assays. Taken together, these results are consistent with a model in which FATP1 homodimeric complexes play an important role in cellular fatty acid import.

FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation.

X-linked mental retardation (XLMR) is an inherited condition that causes failure to develop cognitive abilities, owing to mutations in a gene on the X chromosome. The latest XLMR update lists up to 136 conditions leading to 'syndromic', or 'specific', mental retardation (MRXS) and 66 entries leading to 'nonspecific' mental retardation (MRX). For 9 of the 66 MRX entries, the causative gene has been identified. Our recent discovery of the contiguous gene deletion syndrome ATS-MR (previously known as Alport syndrome, mental retardation, midface hypoplasia, elliptocytosis, OMIM #300194), characterized by Alport syndrome (ATS) and mental retardation (MR), indicated Xq22.3 as a region containing one mental retardation gene. Comparing the extent of deletion between individuals with ATS-MR and individuals with ATS alone allowed us to define a critical region for mental retardation of approximately 380 kb, containing four genes. Here we report the identification of two point mutations, one missense and one splice-site change, in the gene FACL4 in two families with nonspecific mental retardation. Analysis of enzymatic activity in lymphoblastoid cell lines from affected individuals of both families revealed low levels compared with normal cells, indicating that both mutations are null mutations. All carrier females with either point mutations or genomic deletions in FACL4 showed a completely skewed X-inactivation, suggesting that the gene influences survival advantage. FACL4 is the first gene shown to be involved in nonspecific mental retardation and fatty-acid metabolism.