Sleep Apnea Physiological Burdens and Cardiovascular Morbidity and Mortality.

Rationale: Obstructive sleep apnea is characterized by frequent reductions in ventilation, leading to oxygen desaturations and/or arousals. Objectives: In this study, association of hypoxic burden with incident cardiovascular disease (CVD) was examined and compared with that of "ventilatory burden" and "arousal burden." Finally, we assessed the extent to which the ventilatory burden, visceral obesity, and lung function explain variations in hypoxic burden. Methods: Hypoxic, ventilatory, and arousal burdens were measured from baseline polysomnograms in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Osteoporotic Fractures in Men (MrOS) studies. Ventilatory burden was defined as event-specific area under ventilation signal (mean normalized, area under the mean), and arousal burden was defined as the normalized cumulative duration of all arousals. The adjusted hazard ratios for incident CVD and mortality were calculated. Exploratory analyses quantified contributions to hypoxic burden of ventilatory burden, baseline oxygen saturation as measured by pulse oximetry, visceral obesity, and spirometry parameters. Measurements and Main Results: Hypoxic and ventilatory burdens were significantly associated with incident CVD (adjusted hazard ratio [95% confidence interval] per 1 SD increase in hypoxic burden: MESA, 1.45 [1.14, 1.84]; MrOS, 1.13 [1.02, 1.26]; ventilatory burden: MESA, 1.38 [1.11, 1.72]; MrOS, 1.12 [1.01, 1.25]), whereas arousal burden was not. Similar associations with mortality were also observed. Finally, 78% of variation in hypoxic burden was explained by ventilatory burden, whereas other factors explained only <2% of variation. Conclusions: Hypoxic and ventilatory burden predicted CVD morbidity and mortality in two population-based studies. Hypoxic burden is minimally affected by measures of adiposity and captures the risk attributable to ventilatory burden of obstructive sleep apnea rather than a tendency to desaturate.

Redesign of the American Board of Radiology Diagnostic Radiology Certifying Examination.

On April 13, 2023, the American Board of Radiology (ABR) announced plans to replace the current computer-based diagnostic radiology (DR) certifying examination with a new oral examination to be administered remotely, beginning in 2028. This article describes the planned changes and the process that led to those changes. In keeping with its commitment to continuous improvement, the ABR gathered input regarding the DR initial certification process. Respondents generally agreed that the qualifying (core) examination was satisfactory but expressed concerns regarding the computer-based certifying examination's effectiveness and impact on training. Examination redesign was conducted using input from key groups with a goal of effectively evaluating competence and incentivizing study behaviors that best prepare candidates for radiology practice. Major design elements included examination structure, breadth and depth of content, and timing. The new oral examination will focus on critical findings as well as common and important diagnoses routinely encountered in all diagnostic specialties, including radiology procedures. Candidates will first be eligible for the examination in the calendar year after residency graduation. Additional details will be finalized and announced in coming years. The ABR will continue to engage with interested parties throughout the implementation process.

Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study.

AIMS: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF). METHODS AND RESULTS: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking. CONCLUSION: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.

Associations between emphysema-like lung on CT and incident airflow limitation: a general population-based cohort study.

Emphysema on CT is associated with accelerated lung function decline in heavy smokers and patients with COPD; however, in the general population, it is not known whether greater emphysema-like lung on CT is associated with incident COPD. We used data from 2045 adult participants without initial prebronchodilator airflow limitation, classified by FEV1/FVC<0.70, in the Multi-Ethnic Study of Atherosclerosis. Emphysema-like lung on baseline cardiac CT, defined as per cent low attenuation areas<-950HU>upper limit of normal, was associated with increased odds of incident airflow limitation at 5-year follow-up on both prebronchodilator (adjusted OR 2.62, 95% CI 1.47 to 4.67) and postbronchodilator (adjusted OR 4.38, 95% CI 1.63 to 11.74) spirometry, independent of smoking history. These results support investigation into whether emphysema-like lung could be informative for COPD risk stratification.

Identification of potent and selective retinoic acid receptor gamma (RARγ) antagonists for the treatment of osteoarthritis pain using structure based drug design.

A series of triaryl pyrazoles were identified as potent pan antagonists for the retinoic acid receptors (RARs) α, ß and γ. X-ray crystallography and structure-based drug design were used to improve selectivity for RARγ by targeting residue differences in the ligand binding pockets of these receptors. This resulted in the discovery of novel antagonists which maintained RARγ potency but were greater than 500-fold selective versus RARα and RARß. The potent and selective RARγ antagonist LY2955303 demonstrated good pharmacokinetic properties and was efficacious in the MIA model of osteoarthritis-like joint pain. This compound demonstrated an improved margin to RARα-mediated adverse effects.

LLY-2707, a novel nonsteroidal glucocorticoid antagonist that reduces atypical antipsychotic-associated weight gain in rats.

Weight gain and diabetes have been reported during treatment with atypical antipsychotic drugs (AAPDs). Patients treated with the glucocorticoid receptor antagonist (GRA) and the progesterone receptor antagonist (PRA) mifepristone [estra-4,9-dien-3-one, 11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-(11ß,17ß)-(9CI)] experienced significant reduction in the weight gain observed when patients were treated with olanzapine or risperidone. To understand the pharmacology responsible for this finding, we discovered LLY-2707 [N-(5-(tert-butyl)-3-(2-fluoro-5-methylpyridin-4-yl)-2-methyl-1H-indol-7-yl)methanesulfonamide], a novel and selective GRA, and evaluated its utility in preclinical models of AAPD-associated weight gain and diabetes. In vitro, LLY-2707 was a highly selective and potent GRA. GR occupancy in vivo was assessed using ex vivo binding where LLY-2707 inhibited [(3)H]dexamethasone binding to the liver. Modest but statistically significant decreases in brain ex vivo binding were observed with high doses of CORT-108297 [(R)-4α-(ethoxymethyl)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline] and LLY-2707, but mifepristone inhibited at all doses. Central activity of the GRAs was confirmed by their ability to suppress amphetamine-induced increases in locomotor activity. The increases in the body weight of female rats treated with olanzapine (2 mg/kg PO) over 14 days were reduced in a dose-dependent manner by coadministration of LLY-2707. Similar decreases, although less robust, in body weight were seen with mifepristone and CORT-108297. In addition, sGRAs prevented the glucose excursion after intragastric olanzapine infusions consistent with a direct effect on the hyperglycemia observed during treatment with AAPDs. At doses effectively preventing weight gain, LLY-2707 did not substantially interfere with the dopamine D2 receptor occupancy by olanzapine. Therefore, GRA coadministration may provide a novel treatment modality to prevent the weight gain and diabetes observed during treatment with AAPDs.

Prediction of the tissue-specificity of selective estrogen receptor modulators by using a single biochemical method.

Here, we demonstrate that a single biochemical assay is able to predict the tissue-selective pharmacology of an array of selective estrogen receptor modulators (SERMs). We describe an approach to classify estrogen receptor (ER) modulators based on dynamics of the receptor-ligand complex as probed with hydrogen/deuterium exchange (HDX) mass spectrometry. Differential HDX mapping coupled with cluster and discriminate analysis effectively predicted tissue-selective function in most, but not all, cases tested. We demonstrate that analysis of dynamics of the receptor-ligand complex facilitates binning of ER modulators into distinct groups based on structural dynamics. Importantly, we were able to differentiate small structural changes within ER ligands of the same chemotype. In addition, HDX revealed differentially stabilized regions within the ligand-binding pocket that may contribute to the different pharmacology phenotypes of the compounds independent of helix 12 positioning. In summary, HDX provides a sensitive and rapid approach to classify modulators of the estrogen receptor that correlates with their pharmacological profile.

Contextualizing the first-round failure of the AHCA: down but not out.

On 8 November 2016 the American electorate voted Donald Trump into the Presidency and a majority of Republicans into both houses of Congress. Since many Republicans ran for elected office on the promise to 'repeal and replace' Obamacare, this election result came with an expectation that campaign rhetoric would result in legislative action on healthcare. The American Health Care Act (AHCA) represented the Republican effort to repeal and replace the Affordable Care Act (ACA). Key elements of the AHCA included modifications of Medicaid expansion, repeal of the individual mandate, replacement of ACA subsidies with tax credits, and a broadening of the opportunity to use healthcare savings accounts. Details of the bill and the political issues which ultimately impeded its passage are discussed here.

Benzopyrans are selective estrogen receptor beta agonists with novel activity in models of benign prostatic hyperplasia.

Benzopyran selective estrogen receptor beta agonist-1 (SERBA-1) shows potent, selective binding and agonist function in estrogen receptor beta (ERbeta) in vitro assays. X-ray crystal structures of SERBA-1 in ERalpha and beta help explain observed beta-selectivity of this ligand. SERBA-1 in vivo demonstrates involution of the ventral prostate in CD-1 mice (ERbeta effect), while having no effect on gonadal hormone levels (ERalpha effect) at 10x the efficacious dose, consistent with in vitro properties of this molecule.

A peroxisome proliferator-activated receptor alpha/gamma dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia.

LSN862 is a novel peroxisome proliferator-activated receptor (PPAR)alpha/gamma dual agonist with a unique in vitro profile that shows improvements on glucose and lipid levels in rodent models of type 2 diabetes and dyslipidemia. Data from in vitro binding, cotransfection, and cofactor recruitment assays characterize LSN862 as a high-affinity PPARgamma partial agonist with relatively less but significant PPARalpha agonist activity. Using these same assays, rosiglitazone was characterized as a high-affinity PPARgamma full agonist with no PPARalpha activity. When administered to Zucker diabetic fatty rats, LSN862 displayed significant glucose and triglyceride lowering and a significantly greater increase in adiponectin levels compared with rosiglitazone. Expression of genes involved in metabolic pathways in the liver and in two fat depots from compound-treated Zucker diabetic fatty rats was evaluated. Only LSN862 significantly elevated mRNA levels of pyruvate dehydrogenase kinase isozyme 4 and bifunctional enzyme in the liver and lipoprotein lipase in both fat depots. In contrast, both LSN862 and rosiglitazone decreased phosphoenol pyruvate carboxykinase in the liver and increased malic enzyme mRNA levels in the fat. In addition, LSN862 was examined in a second rodent model of type 2 diabetes, db/db mice. In this study, LSN862 demonstrated statistically better antidiabetic efficacy compared with rosiglitazone with an equivalent side effect profile. LSN862, rosiglitazone, and fenofibrate were each evaluated in the humanized apoA1 transgenic mouse. At the highest dose administered, LSN862 and fenofibrate reduced very low-density lipoprotein cholesterol, whereas, rosiglitazone increased very low-density lipoprotein cholesterol. LSN862, fenofibrate, and rosiglitazone produced maximal increases in high-density lipoprotein cholesterol of 65, 54, and 30%, respectively. These findings show that PPARgamma full agonist activity is not necessary to achieve potent and efficacious insulin-sensitizing benefits and demonstrate the therapeutic advantages of a PPARalpha/gamma dual agonist.

The Burwell roadmap.

In January 2015 the current Secretary of the Department of Health and Human Services (HHS) outlined a bold initiative to shape the delivery of healthcare through a set of strategies aimed at improving the quality of care and reducing the growth of healthcare costs. The strategies include increasing payment incentives tied to higher value care, increasing care coordination and integration, and increasing access to information to guide patients and clinicians. Significantly, the proposal includes specific goals for alternative payment models and value-based payments for the first time in the history of the Medicare program.

The Bundled Payments for Care Improvement Initiative.

The Affordable Care Act enters its fifth year firmly entrenched in our national consciousness. One method that has entered the vernacular for achieving cost savings is accountable care. There are other approaches that are less well known. The Bundled Payments for Care Improvement Initiative has the potential to significantly impact neurointerventionalists. We review that initiative here.

MACRA: background, opportunities and challenges for the neurointerventional specialist.

The legislative branch of government took many by surprise when it announced the Medicare Access and CHIP Reauthorization Act of 2015. Once the Act was passed, President Obama quickly signed this bipartisan, bicameral effort into law. A foundational element of this legislation was the permanent repeal of the sustainable growth rate formula. Physicians and their patients were appropriately enthusiastic about this development. The Medicare Access and CHIP Reauthorization Act of 2015 included additional elements of considerable interest to neurointerventional specialists.

Bilateral disk edema with unilateral macular serous fluid secondary to neurocysticercosis.

PURPOSE: The purpose of this article is to document a case of neurocysticercosis that manifested clinically with bilateral disk edema and serous fluid accumulation in the macula of the left eye. We also describe the recovery of visual-field loss (O.D.) and diminution of bilateral disk edema following anti-helminthic treatment. CASE REPORT: A 41-year-old woman reporting headaches came to us with bilateral disk edema and co-existing serous macular fluid in the left eye. RESULTS: Magnetic resonance imaging (MRI) revealed the presence of large multi-septated cysts that exhibited peripheral enhancement, with minimal surrounding edema at the posterior left temporal lobe. Scattered punctate lesions, suggesting areas of calcification, were also observed within both temporal lobes. The optic chiasm appeared compressed. This presentation was considered characteristic of neurocysticercosis and the patient was prescribed a regimen of 200mg albendazole b.i.d. The patient responded well to the treatment, with progressive resolution of the bilateral disk edema and macular fluid. CONCLUSION: Although rare, cases of cysticercosis and neurocysticercosis may still be encountered in industrialized nations, where the parasite has been almost eradicated. Ocular signs of disk edema and macular serous fluid secondary to neurocysticercosis may correspond to optic nerve, parenchymal, or extraparenchymal disease.

Current procedural terminology; a primer.

In 1966, The American Medical Association (AMA) working with multiple major medical specialty societies developed an iterative coding system for describing medical procedures and services using uniform language, the Current Procedural Terminology (CPT) system. The current code set, CPT IV, forms the basis of reporting most of the services performed by healthcare providers, physicians and non-physicians as well as facilities allowing effective, reliable communication among physician and other providers, third parties and patients. This coding system and its maintenance has evolved significantly since its inception, and now goes well beyond its readily perceived role in reimbursement. Additional roles include administrative management, tracking new and investigational procedures, and evolving aspects of 'pay for performance'. The system also allows for local, regional and national utilization comparisons for medical education and research. Neurointerventional specialists use CPT category I codes regularly--for example, 36,215 for first-order cerebrovascular angiography, 36,216 for second-order vessels, and 37,184 for acute stroke treatment by mechanical means. Additionally, physicians add relevant modifiers to the CPT codes, such as '-26' to indicate 'professional charge only,' or '-59' to indicate a distinct procedural service performed on the same day.

Indole Glucocorticoid Receptor Antagonists Active in a Model of Dyslipidemia Act via a Unique Association with an Agonist Binding Site.

To further elucidate the structural activity correlation of glucocorticoid receptor (GR) antagonism, the crystal structure of the GR ligand-binding domain (GR LBD) complex with a nonsteroidal antagonist, compound 8, was determined. This novel indole sulfonamide shows in vitro activity comparable to known GR antagonists such as mifepristone, and notably, this molecule lowers LDL (-74%) and raises HDL (+73%) in a hamster model of dyslipidemia. This is the first reported crystal structure of the GR LBD bound to a nonsteroidal antagonist, and this article provides additional elements for the design and pharmacology of clinically relevant nonsteroidal GR antagonists that may have greater selectivity and fewer side effects than their steroidal counterparts.

Design and synthesis of a potent and selective triazolone-based peroxisome proliferator-activated receptor alpha agonist.

A new series of hPPARalpha agonists containing a 2,4-dihydro-3H-1,2,4-triazol-3-one (triazolone) core is described leading to the discovery of 5 (LY518674), a highly potent and selective PPARalpha agonist.

Vitreal pathogenic role in optic pit foveolar retinoschisis and central serous retinopathy.

PURPOSE: To expand on current theories concerning the vitreal-induced mechanism underlying the development of foveolar retinoschisis and macular sensory detachments associated with optic nerve head pits. To propose the notion that vitreal traction may contribute to the pathogenesis of serous detachments in central serous chorioretinopathy (CSC). REPORTS: We describe two patients, one with macular retinoschisis and the other with central serous detachment. The first patient, a 45-year-old Hispanic female, presented with a temporally located optic nerve head pit, foveolar retinoschisis and schisis retinal spaces extending to the surrounding macula and to the disc. The second patient, a 43-year-old Haitian male, developed a central serous retinal detachment OS with decreased visual acuity one day following in-office administration of Apraclonidine (0.5 per cent Iopidine, Alcon) and Dorzolamide-Timolol Maleate (Cosopt, Merck) to lower elevated intraocular pressure (IOP). Macular retinal pigment mottling and epiretinal membrane sheen OU had been observed on his initial visit. Visual acuity improved within a three-day period with resolution of the serous detachment. CONCLUSION: We suggest that the persistence of Cloquet's canal may permit fluid leakage into the proximal vitreous in cases of congenital optic nerve head pits. Tangential vitreal traction may promote the opening of a fistula at the optic pit and additionally thrust vitreal fluid into the pit and retinal space inducing the formation of schisis spaces, foveolar-schisis and underlying sensory serous detachment. We question whether a reduction in vitreous volume, induced by initial administration of anti-glaucoma medications, may contribute to the development and/or recurrence of central serous choroidopathy in predisposed individuals.

Melanocytoma inducing compressive optic neuropathy: the ocular morbidity potential of an otherwise invariably benign lesion.

PURPOSE: The purpose of this article is to document a case of melanocytoma of the optic nerve head inducing compressive optic neuropathy; to provide a summarized clinical review; and to reflect on the potential ocular morbidity aspects of this relatively benign insult. METHODS: We present a case report of a 32-year-old Hispanic woman with constant esotropia, inert tractional Toxacara granuloma in the right eye, and a jet-black lesion engulfing the left eye optic nerve head, with accompanying disk edema. RESULTS: A diagnosis of melanocytoma of the optic nerve with secondary compressive optic neuropathy was made on the basis of the clinical presentation. Patient education and quarterly follow-up visits to monitor the lesion were the recommended management. CONCLUSION: Although optic nerve head melanocytoma can be considered benign, it has the underlying potential to promote ocular morbidity. Our case report highlights the potential impact of melanocytoma on optic nerve head anatomy. The potential for even subtle changes in the visual fields from this condition becomes significant in a monocular patient. This is exemplified in this case, by the presence of a co-existing Toxacara granuloma and related amblyopia in the contralateral eye.