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1.
bioRxiv ; 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38464274

RESUMO

Metabolism plays an important role in the maintenance of vigilance states (e.g. wake, NREM, and REM). Brain lactate fluctuations are a biomarker of sleep. Increased interstitial fluid (ISF) lactate levels are necessary for arousal and wake-associated behaviors, while decreased ISF lactate is required for sleep. ATP-sensitive potassium (K ATP ) channels couple glucose-lactate metabolism with neuronal excitability. Therefore, we explored how deletion of neuronal K ATP channel activity (Kir6.2-/- mice) affected the relationship between glycolytic flux, neuronal activity, and sleep/wake homeostasis. Kir6.2-/- mice shunt glucose towards glycolysis, reduce neurotransmitter synthesis, dampen cortical EEG activity, and decrease arousal. Kir6.2-/- mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-K ATP channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of each vigilance state and providing the metabolic flexibility to transition between states. Highlights: Glycolytic flux is necessary for neurotransmitter synthesis. In its absence, neuronal activity is compromised causing changes in arousal and vigilance states despite sufficient energy availability. With Kir6.2-K ATP channel deficiency, the ability to both maintain and shift between different vigilance states is compromised due to changes in glucose utilization. Kir6.2-K ATP channels are metabolic sensors under circadian control that gate arousal and sleep/wake transitions.

2.
Biomolecules ; 14(3)2024 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-38540695

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder affecting nearly one in nine older adults in the US. This number is expected to grow exponentially, thereby increasing stress on caregivers and health systems. While some risk factors for developing AD are genetic, an estimated 1/3 of AD cases are attributed to lifestyle. Many of these risk factors emerge decades before clinical symptoms of AD are detected, and targeting them may offer more efficacious strategies for slowing or preventing disease progression. This review will focus on two common risk factors for AD, metabolic dysfunction and sleep impairments, and discuss potential mechanisms underlying their relationship to AD pathophysiology. Both sleep and metabolism can alter AD-related protein production and clearance, contributing to an imbalance that drives AD progression. Additionally, these risk factors have bidirectional relationships with AD, where the presence of AD-related pathology can further disrupt sleep and worsen metabolic functioning. Sleep and metabolism also appear to have a bidirectional relationship with each other, indirectly exacerbating AD pathophysiology. Understanding the mechanisms involved in these relationships is critical for identifying new strategies to slow the AD cascade.


Assuntos
Doença de Alzheimer , Humanos , Idoso , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Sono , Emoções , Fatores de Risco
3.
J Extracell Vesicles ; 13(1): e12398, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38191961

RESUMO

Brain-derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. The internal cargo of EVs is protected from degradation, making EVs attractive AD biomarkers. However, it is unclear how circulating EVs relate to EVs isolated from disease-vulnerable brain regions. We developed a novel method for collecting EVs from the hippocampal interstitial fluid (ISF) of live mice. EVs (EVISF ) were isolated via ultracentrifugation and characterized by nanoparticle tracking analysis, immunogold labelling, and flow cytometry. Mass spectrometry and proteomic analyses were performed on EVISF cargo. EVISF were 40-150 nm in size and expressed CD63, CD9, and CD81. Using a model of cerebral amyloidosis (e.g., APPswe, PSEN1dE9 mice), we found protein concentration increased but protein diversity decreased with Aß deposition. Genotype, age, and Aß deposition modulated proteostasis- and immunometabolic-related pathways. Changes in the microglial EVISF proteome were sexually dimorphic and associated with a differential response of plaque associated microglia. We found that female APP/PS1 mice have more amyloid plaques, less plaque associated microglia, and a less robust- and diverse- EVISF microglial proteome. Thus, in vivo microdialysis is a novel technique for collecting EVISF and offers a unique opportunity to explore the role of EVs in AD.


Assuntos
Doença de Alzheimer , Vesículas Extracelulares , Placa Aterosclerótica , Feminino , Animais , Camundongos , Proteoma , Líquido Extracelular , Microglia , Proteômica , Hipocampo
4.
J Healthc Manag ; 69(1): 45-58, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38175534

RESUMO

GOAL: As of January 1, 2021, the Centers for Medicare & Medicaid Services requires most U.S. hospitals to publish pricing information on their website to help consumers make decisions regarding services and to transform negotiations with health insurers. For this study, we evaluated changes in hospitals' compliance with the federal price transparency rule after the first year of enactment, during which the Centers for Medicare & Medicaid Services increased the penalty for noncompliance. METHODS: Using a nationally representative random sample of 470 hospitals, we assessed compliance with both parts of the hospital transparency rule (publishing a machine-readable price database and a consumer shopping tool) in the first quarter of 2022 and compared its baseline level in the first quarter of 2021. Using data from the American Hospital Association and Clarivate, we next assessed how compliance varied by hospital factors (ownership, number of beds, system membership, teaching status, type of electronic health record system), market factors (hospital and insurer market concentration), and the estimated change in penalty for noncompliance. PRINCIPAL FINDINGS: By early 2022, 46% of hospitals had posted both machine-readable and consumer-shoppable data, an increase of 24% from the prior year. Almost 9 in 10 hospitals had complied with the consumer-shoppable data requirement by early 2022. Larger hospitals and public hospitals had lower probabilities of baseline compliance with the machine-readable and consumer-shoppable requirements, respectively, although public hospitals were significantly more likely to become compliant with the consumer-shoppable requirement by 2022. Higher hospital market concentration was also associated with higher baseline compliance for both the machine-readable and consumer-shoppable requirements. Furthermore, our analyses found that hospitals with certain electronic health record systems were more likely to comply with the consumer-shoppable requirement in 2021 and became increasingly compliant with the machine-readable requirement in 2022. Finally, we found that hospitals with a larger estimated penalty were more likely to become compliant with the machine-readable requirement. PRACTICAL APPLICATIONS: Longitudinal analyses of compliance with the federal price transparency rule are valuable for monitoring changes in hospitals' behavior and assessing whether compliance changes vary systematically for specific types of hospitals and/or market structures. Our results suggest a trend toward increased hospital compliance between 2021 and 2022. Although hospitals perceive the consumer-shopping tools as being the most impactful, the value of this information depends on whether it is comprehensible and comparable across hospitals. The new price transparency rule has facilitated the creation of new data that have the potential to significantly alter the competitive landscape for hospitals and may require hospital leaders to consider how their organizational strategies change concerning their engagement with payers and patients. Finally, greater price transparency is likely to bolster national policy discussions related to price variation, affordability, and the role of regulation in healthcare markets.


Assuntos
Hospitais Públicos , Medicare , Idoso , Estados Unidos , Humanos , American Hospital Association , Bases de Dados Factuais , Cooperação do Paciente
5.
JCI Insight ; 8(10)2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-37129980

RESUMO

Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-ß (Aß) release, offering a mechanistic link between type 2 diabetes and Alzheimer's disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice. Next, we explored whether eliminating neuronal KATP channel activity uncoupled the relationship between metabolism, excitability, and Aß pathology in a potentially novel mouse model of cerebral amyloidosis and neuronal KATP channel ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2-/- mouse). Using both acute and chronic paradigms, we demonstrate that Kir6.2-KATP channels are metabolic sensors that regulate hyperglycemia-dependent increases in interstitial fluid levels of Aß, amyloidogenic processing of APP, and amyloid plaque formation, which may be dependent on lactate release. These studies identify a potentially new role for Kir6.2-KATP channels in AD and suggest that pharmacological manipulation of Kir6.2-KATP channels holds therapeutic promise in reducing Aß pathology in patients with diabetes or prediabetes.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Hiperglicemia , Humanos , Camundongos , Animais , Canais KATP/metabolismo , Doença de Alzheimer/patologia , Diabetes Mellitus Tipo 2/complicações , Glucose , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo
6.
Health Aff (Millwood) ; 42(4): 498-507, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37011307

RESUMO

Financial distress among rural hospitals in the US has increased in recent years. Using national hospital data, we investigated how the decline in profitability has affected hospital survival, either independently or with a merger. The answer has direct implications for access to care and competition in rural markets. We assessed the rate of hospital closures and mergers in predominantly rural markets during the period 2010-18, focusing on hospitals that were unprofitable at baseline. A minority of unprofitable hospitals (7 percent) closed. A larger share (17 percent) merged, most commonly with organizations from outside of their local geographic market. Most unprofitable hospitals (77 percent) continued to operate through 2018 without closure or merger. About half of these hospitals returned to profitability. At the market level, 22 percent of markets served by unprofitable hospitals lost a competitor to closure or within-market merger. Out-of-market mergers affected 33 percent of markets with an unprofitable hospital. Overall, our results suggest that rural markets are experiencing meaningful rates of hospital closures and mergers, yet many hospitals have survived despite poor financial performance. Policies targeting access to care will continue to be important. Similar attention will be needed to address the competitive effects of hospital closures and mergers on prices and quality.


Assuntos
Fechamento de Instituições de Saúde , Instituições Associadas de Saúde , Humanos , Estados Unidos , Hospitais Rurais , População Rural , Competição Econômica
7.
bioRxiv ; 2023 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-36945515

RESUMO

Brain-derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. Circulating EVs are protected from degradation, making them attractive AD biomarkers. However, it is unclear how circulating EVs relate to EVs isolated from disease-vulnerable brain regions. We developed a novel method for collecting EVs from the hippocampal interstitial fluid (ISF) of live mice. EVs (EVISF) were isolated via ultracentrifugation and characterized by nanoparticle tracking analysis, immunogold labeling, and flow cytometry. Mass spectrometry and proteomic analyses were performed on EVISF cargo. EVISF were 40-150 nm in size and expressed CD63, CD9, and CD81. Using a model of cerebral amyloidosis (e.g. APPswe,PSEN1dE9 mice), we found protein concentration increased but protein diversity decreased with A deposition. Genotype, age, and Aß deposition modulated proteostasis- and immunometabolic-related pathways. Changes in the microglial EVISF proteome were sexually dimorphic and associated with a differential response of plaque associated microglia. We found that female APP/PS1 mice have more amyloid plaques, less plaque associated microglia, and a less robust- and diverse- EVISF microglial proteome. Thus, in vivo microdialysis is a novel technique for collecting EVISF and offers a unique opportunity to explore the role of EVs in AD.

8.
JAMA Oncol ; 9(3): 324-333, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36602811

RESUMO

Importance: Immunotherapies reflect an important breakthrough in cancer treatment, substantially improving outcomes for patients with a variety of cancer types, yet little is known about which practices have adopted this novel therapy or the pace of adoption. Objective: To assess adoption of immunotherapies across US oncology practices and examine variation in adoption by practice type. Design, Setting, and Participants: This cohort study used data from Medicare fee-for-service beneficiaries undergoing 6-month chemotherapy episodes between 2010 and 2017. Data were analyzed January 19, 2021, to September 28, 2022, for patients with cancer types for which immunotherapy was approved by the US Food and Drug Administration (FDA) during the study period: melanoma, kidney cancer, lung cancer, and head and neck cancer. Exposures: Oncology practice location (rural vs urban), affiliation type (academic system, nonacademic system, independent), and size (1 to 5 physicians vs 6 or more physicians). Main Outcomes and Measures: The primary outcome was whether a practice adopted immunotherapy. Adoption rates for each practice type were estimated using multivariate linear models that adjusted for patient characteristics (age, sex, race and ethnicity, cancer type, Charlson Comorbidity Index, and median household income). Results: Data included 71 659 episodes at 1732 oncology practices. Of these, 264 practices (15%) were rural, 900 (52%) were independent, and 492 (28%) had 1 to 5 physicians. Most practices adopted immunotherapy within 2 years of FDA approval, but there was substantial variation in adoption rates across practice types. After FDA approval, adoption of immunotherapy was 11 (95% CI, -16 to -6) percentage points lower at rural practices than urban practices and 27 (95% CI, -32 to -22) percentage points lower at practices with 1 to 5 physicians than practices with 6 or more physicians. Adoption rates were similar at independent practices and nonacademic systems; however, both practice types had lower adoption than academic systems (independent practice difference, -6 [95% CI, -9 to -3] percentage points; nonacademic systems difference, -9 [95% CI, -11 to -6] percentage points). Conclusions and Relevance: In this cohort study of Medicare claims, practice characteristics, especially practice size and rural location, were associated with adoption of immunotherapy. These findings suggest that there may be geographic disparities in access to important innovations for treating patients with cancer.


Assuntos
Neoplasias Pulmonares , Medicare , Humanos , Idoso , Estados Unidos , Estudos de Coortes , Imunoterapia , Terapias em Estudo
9.
Med Care Res Rev ; 80(2): 236-244, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-35848406

RESUMO

Since the summer of 2020, the rate of coronavirus cases in the United States has been higher in rural areas than in urban areas, raising concerns that patients with coronavirus disease 2019 (COVID-19) will overwhelm under-resourced rural hospitals. Using data from the University of Minnesota COVID-19 Hospitalization Tracking Project and the U.S. Department of Health and Human Services, we document disparities in COVID-19 hospitalization rates between rural and urban areas. We show that rural-urban differences in COVID-19 admission rates were minimal in the summer of 2020 but began to diverge in fall 2020. Rural areas had statistically higher hospitalization rates from September 2020 through early 2021, after which rural-urban admission rates re-converged. The insights in this article are relevant to policymakers as they consider the adequacy of hospital resources across rural and urban areas during the COVID-19 pandemic.


Assuntos
COVID-19 , Humanos , Estados Unidos/epidemiologia , COVID-19/epidemiologia , Pandemias , Hospitalização , População Rural , Hospitais Rurais , População Urbana
10.
Health Aff Sch ; 1(2): qxad020, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38769945

RESUMO

The postpartum period is critical for the health and well-being of birthing people, yet little is known about the range of health care services and supports needed during this time. Maternity care patients are often targeted for clinical interventions based on "low risk" or "high risk" designations, but dichotomized measures can be imprecise and may not reflect meaningful groups for understanding needed postpartum care. Using claims data from privately insured patients with childbirths between 2016 and 2018, this study identifies categories and predictors of postpartum care utilization, including the use of maternal care and other, nonmaternal, care (eg, respiratory, digestive). We then compare identified utilization-based categories with typical high- and low-risk designations. Among 269 992 patients, 5 categories were identified: (1) low use (55% of births); (2) moderate maternal care use, low other care use (25%); (3) moderate maternal, high other (8%); (4) high maternal, moderate other (7%); and (5) high maternal, high other (5%). Utilization-based categories were better at differentiating postpartum care use and were more consistent across patient profiles, compared with high- and low-risk dichotomies. Identifying categories of postpartum care need beyond a simple risk dichotomy is warranted and can assist in maternal health services research, policymaking, and clinical practice.


The time after childbirth is important for the health of a parent who has just given birth, and postpartum experiences and needs vary widely. We studied health care data for privately insured people who gave birth and identified 5 categories of health care use in the postpartum period. None of the categories we uncovered fit the common model of a single visit at 6 weeks postpartum as the sole care needed or used postpartum. Typically, patients are divided into high-risk and low-risk groups, but our research shows that this is insufficient and masks important differences among patients within these dichotomous groups. Using advanced statistical methods to identify categories of health care use after childbirth may improve postpartum health by better targeting resources to those who need them the most.

11.
JAMA Health Forum ; 3(10): e223292, 2022 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-36239954

RESUMO

Importance: Little is known about the quality of postpartum care or disparities in the content of postpartum care associated with health insurance, rural or urban residency, and race and ethnicity. Objectives: To examine receipt of recommended postpartum care content and to describe variations across health insurance type, rural or urban residence, and race and ethnicity. Design, Settings, and Participants: This cross-sectional survey of patients with births from 2016 to 2019 used data from the Pregnancy Risk Assessment Monitoring System (43 states and 2 jurisdictions). A population-based sample of patients conducted by state and local health departments in partnership with the Centers for Disease Control and Prevention were surveyed about maternal experiences 2 to 6 months after childbirth (mean weighted response rate, 59.9%). Patients who attended a postpartum visit were assessed for content at that visit. Analyses were performed November 2021 to July 2022. Exposures: Medicaid or private health insurance, rural or urban residence, and race and ethnicity (non-Hispanic White or racially minoritized groups). Main Outcomes and Measures: Receipt of 2 postpartum care components recommended by national quality standards (depression screening and contraceptive counseling), and/or other recommended components (smoking screening, abuse screening, birth spacing counseling, eating and exercise discussions) with estimated risk-adjusted predicted probabilities and percentage-point (pp) differences. Results: Among the 138 073 patient-respondents, most (59.5%) were in the age group from 25 to 34 years old; 59 726 (weighted percentage, 40%) were insured by Medicaid; 27 721 (15%) were rural residents; 9718 (6%) were Asian, 24 735 (15%) were Black, 22 210 (15%) were Hispanic, 66 323 (60%) were White, and fewer than 1% were Indigenous (Native American/Alaska Native) individuals. Receipt of both depression screening and contraceptive counseling both significantly lower for Medicaid-insured patients (1.2 pp lower than private; 95% CI, -2.1 to -0.3), rural residents (1.3 pp lower than urban; 95% CI, -2.2 to -0.4), and people of racially minoritized groups (0.8 pp lower than White individuals; 95% CI, -1.6 to -0.1). The highest receipt of these components was among privately insured White urban residents (80%; 95% CI, 79% to 81%); the lowest was among privately insured racially minoritized rural residents (75%; 95% CI, 72% to 78%). Receipt of all other components was significantly higher for Medicaid-insured patients (6.1 pp; 95% CI, 5.2 to 7.0), rural residents (1.1 pp; 95% CI, 0.1 to 2.0), and people of racially minoritized groups (8.5 pp; 95% CI, 7.7 to 9.4). The highest receipt of these components was among Medicaid-insured racially minoritized urban residents (34%; 95% CI, 33% to 35%), the lowest was among privately insured White urban residents (19%; 95% CI, 18% to 19%). Conclusions and Relevance: The findings of this cross-sectional survey of postpartum individuals in the US suggest that inequities in postpartum care content were extensive and compounded for patients with multiple disadvantaged identities. Examining only 1 dimension of identity may understate the extent of disparities. Future studies should consider the content of postpartum care visits.


Assuntos
Etnicidade , Cuidado Pós-Natal , Adulto , Anticoncepcionais , Estudos Transversais , Feminino , Geografia , Humanos , Seguro Saúde , Gravidez , Estados Unidos/epidemiologia
13.
Health Aff (Millwood) ; 41(4): 531-539, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35377761

RESUMO

Access to obstetric services has declined steadily during the past decade, driven by the closure of hospital-based obstetric units and of entire hospitals. A fundamental challenge to maintaining obstetric services is that they are frequently unprofitable for hospitals to operate, threatening hospital viability. Medicaid expansion has emerged as a possible remedy for obstetric service closure because it reduces uncompensated care and improves hospital finances. Using national hospital data from the period 2010-18, we assessed the relationship between Medicaid expansion and obstetric service closure in rural and urban communities. We found that expansion led to a large reduction in hospital closures; however, this effect was concentrated among hospitals that did not have obstetric units. Considering closure of obstetric units, we found that rural obstetric units were less likely to close immediately after expansion, but this effect faded within two years. Overall, our findings suggest that Medicaid expansion had little effect on the closure of obstetric services. Policies supporting access to obstetric care may need to directly address the financial challenges specific to this service line.


Assuntos
Medicaid , Cuidados de Saúde não Remunerados , Feminino , Fechamento de Instituições de Saúde , Hospitais , Humanos , Gravidez , Estados Unidos
14.
Violence Against Women ; 28(1): 255-276, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33577427

RESUMO

Rape victims often face secondary victimization by the criminal justice system, prompting their advocates to promote a variety of procedural changes, including the provision of an independent legal counsel for victims. Sweden implemented a legal counsel for victims of sexual assault and rape in the late 1980s, yet research about their role remains limited. This article draws upon interviews with victim-lawyers in Sweden and suggests that having access to an independent legal counsel can mitigate the risks for secondary victimization by empowering victims to access their rights and providing emotional support and connectedness in the criminal justice system.


Assuntos
Vítimas de Crime , Estupro , Vítimas de Crime/psicologia , Direito Penal , Humanos , Aplicação da Lei , Estupro/psicologia , Suécia
15.
Med Care Res Rev ; 79(3): 428-434, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34148382

RESUMO

As of January 1, 2021, most U.S. hospitals are required to publish pricing information on their website to promote more informed decision making by consumers regarding their care. In a nationally representative sample of 470 hospitals, we analyzed whether hospitals met price transparency information reporting requirements and the extent to which complete reporting was associated with ownership status, bed size category, system affiliation, and location in a metropolitan area. Fewer than one quarter of sampled hospitals met the price transparency information requirements of the new rule, which include five types of standard charges in machine-readable form and the consumer-shoppable display of 300 shoppable services. Our analyses of hospital reporting by organizational and market attributes revealed limited differences, with some exceptions for nonprofit and system-member hospitals demonstrating greater responsiveness with respect to the consumer-shoppable aspects of the rule.


Assuntos
Hospitais , Custos e Análise de Custo , Humanos , Estados Unidos
16.
Front Aging Neurosci ; 11: 258, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616284

RESUMO

Alzheimer's disease (AD) is the most common form of dementia and affects over 45 million people worldwide. Both type-2-diabetes (T2D), a metabolic condition associated with aging, and disrupted sleep are implicated in the pathogenesis of AD, but how sleep and metabolism interact to affect AD progression remains unclear. In the healthy brain, sleep/wake cycles are a well-coordinated interaction between metabolic and neuronal activity, but when disrupted, are associated with a myriad of health-related issues, including metabolic syndrome, cardiovascular disease, T2D, and AD. Therefore, this review will explore our current understanding of the relationship between metabolism, sleep, and AD-related pathology to identify the causes and consequences of disease progression in AD. Moreover, sleep disturbances and metabolic dysfunction could serve as potential therapeutic targets to mitigate the increased risk of AD in individuals with T2D or offer a novel approach for treating AD.

17.
Arterioscler Thromb Vasc Biol ; 39(9): 1747-1761, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31167565

RESUMO

OBJECTIVE: The role of hepatocyte Abca1 (ATP binding cassette transporter A1) in trafficking hepatic free cholesterol (FC) into plasma versus bile for reverse cholesterol transport (RCT) is poorly understood. We hypothesized that hepatocyte Abca1 recycles plasma HDL-C (high-density lipoprotein cholesterol) taken up by the liver back into plasma, maintaining the plasma HDL-C pool, and decreasing HDL-mediated RCT into feces. Approach and Results: Chow-fed hepatocyte-specific Abca1 knockout (HSKO) and control mice were injected with human HDL radiolabeled with 125I-tyramine cellobiose (125I-TC; protein) and 3H-cholesteryl oleate (3H-CO). 125I-TC and 3H-CO plasma decay, plasma HDL 3H-CO selective clearance (ie, 3H-125I fractional catabolic rate), liver radiolabel uptake, and fecal 3H-sterol were significantly greater in HSKO versus control mice, supporting increased plasma HDL RCT. Twenty-four hours after 3H-CO-HDL injection, HSKO mice had reduced total hepatic 3H-FC (ie, 3H-CO hydrolyzed to 3H-FC in liver) resecretion into plasma, demonstrating Abca1 recycled HDL-derived hepatic 3H-FC back into plasma. Despite similar liver LDLr (low-density lipoprotein receptor) expression between genotypes, HSKO mice treated with LDLr-targeting versus control antisense oligonucleotide had slower plasma 3H-CO-HDL decay, reduced selective 3H-CO clearance, and decreased fecal 3H-sterol excretion that was indistinguishable from control mice. Increased RCT in HSKO mice was selective for 3H-CO-HDL, since macrophage RCT was similar between genotypes. CONCLUSIONS: Hepatocyte Abca1 deletion unmasks a novel and selective FC trafficking pathway that requires LDLr expression, accelerating plasma HDL-selective CE uptake by the liver and promoting HDL RCT into feces, consequently reducing HDL-derived hepatic FC recycling into plasma.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/fisiologia , Colesterol/metabolismo , Hepatócitos/fisiologia , Lipoproteínas HDL/sangue , Receptores de LDL/fisiologia , Animais , Transporte Biológico , Feminino , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
18.
Sleep ; 42(5)2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30722054

RESUMO

Local sleep need within cortical circuits exhibits extensive interregional variability and appears to increase following learning during preceding waking. Although the biological mechanisms responsible for generating sleep need are unclear, this local variability could arise as a consequence of wake-dependent synaptic plasticity. To test whether cortical synaptic strength is a proximate driver of sleep homeostasis, we developed a novel experimental approach to alter local sleep need. One hour prior to light onset, we injected zeta-inhibitory peptide (ZIP), a pharmacological antagonist of protein kinase Mζ, which can produce pronounced synaptic depotentiation, into the right motor cortex of freely behaving rats. When compared with saline control, ZIP selectively reduced slow-wave activity (SWA; the best electrophysiological marker of sleep need) within the injected motor cortex without affecting SWA in a distal cortical site. This local reduction in SWA was associated with a significant reduction in the slope and amplitude of individual slow waves. Local ZIP injection did not significantly alter the amount of time spent in each behavioral state, locomotor activity, or EEG/LFP power during waking or REM sleep. Thus, local ZIP injection selectively produced a local reduction in sleep need; synaptic strength, therefore, may play a causal role in generating local homeostatic sleep need within the cortex.


Assuntos
Eletroencefalografia/métodos , Lipopeptídeos/administração & dosagem , Córtex Motor/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Animais , Peptídeos Penetradores de Células , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Injeções Intraventriculares , Masculino , Córtex Motor/fisiologia , Plasticidade Neuronal/fisiologia , Ratos , Ratos Sprague-Dawley , Sono/efeitos dos fármacos , Sono/fisiologia , Sono REM/fisiologia
19.
J Health Econ ; 61: 47-62, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30059822

RESUMO

We study how physicians respond to financial incentives imposed by episode-based payment (EBP), which encourages lower spending and improved quality for an entire episode of care. Specifically, we study the impact of the Arkansas Health Care Payment Improvement Initiative, a multi-payer program that requires providers to enter into EBP arrangements for perinatal care, covering the majority of births in the state. Unlike fee-for-service reimbursement, EBP holds physicians responsible for all care within a discrete episode, rewarding physicians for efficient use of their own services and for efficient management of other health care inputs. In a difference-in-differences analysis of commercial claims, we find that perinatal spending in Arkansas decreased by 3.8% overall under EBP, compared to surrounding states. The decrease was driven by reduced spending on non-physician health care inputs, specifically the prices paid for inpatient facility care. We additionally find a limited improvement in quality of care under EBP.


Assuntos
Planos de Pagamento por Serviço Prestado/economia , Gastos em Saúde , Aceitação pelo Paciente de Cuidados de Saúde , Assistência Perinatal/economia , Arkansas , Cuidado Periódico , Planos de Pagamento por Serviço Prestado/estatística & dados numéricos , Feminino , Gastos em Saúde/estatística & dados numéricos , Humanos , Modelos Econômicos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Assistência Perinatal/organização & administração , Assistência Perinatal/estatística & dados numéricos , Planos de Incentivos Médicos/economia , Planos de Incentivos Médicos/estatística & dados numéricos , Gravidez
20.
Prenat Diagn ; 34(12): 1127-32, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24947130

RESUMO

OBJECTIVE: The aim of this study was to evaluate outcomes for neonates with critical congenital heart disease (CHD) requiring emergent neonatal cardiac intervention (ENCI). METHODS: Neonates < 30 days of age that underwent ENCI at <48 h of age were retrospectively enrolled over a 2-year period. RESULTS: Forty-seven neonates met inclusion criteria for ENCI comprising nine cardiac defects that underwent 25 catheterizations and 22 cardiothoracic surgeries. The main groups were d-transposition of the great arteries (DTGA) and total anomalous pulmonary venous return (TAPVR). Prenatal detection was 38% overall: higher for single ventricle (86%) and heterotaxy (75%) than for DTGA (28%) or TAPVR (13%). Mortality was 11.1% (2/18) in prenatally diagnosed versus 13.8% (4/29) in postnatally diagnosed neonates (p = 0.86). Prenatal detection was associated with shorter mean hospital stay: 16.8 versus 30.3 days (p = 0.03). Prenatally diagnosed patients had lower preoperative inotropic scores (p = 0.02), less acidosis (pH; p = 0.09), but decreased likelihood of spontaneous labor (p = 0.01), lower gestational age (p = 0.01), and lower birth weight (p = 0.01). CONCLUSIONS: Fewer deaths occurred in neonates with prenatal detection of their critical CHD requiring ENCI. However, there was no statistical difference in survival demonstrated for prenatally diagnosed neonates in this small cohort. Prenatal detection did improve preoperative clinical status and shorten hospital length of stay.


Assuntos
Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/mortalidade , Diagnóstico Pré-Natal/estatística & dados numéricos , Serviços Médicos de Emergência , Cardiopatias Congênitas/terapia , Humanos , Recém-Nascido , Terapia Intensiva Neonatal/estatística & dados numéricos , Los Angeles/epidemiologia , Estudos Retrospectivos
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