The anatomical distribution of genetic associations.

Deeper understanding of the anatomical intermediaries for disease and other complex genetic traits is essential to understanding mechanisms and developing new interventions. Existing ontology tools provide functional, curated annotations for many genes and can be used to develop mechanistic hypotheses; yet information about the spatial expression of genes may be equally useful in interpreting results and forming novel hypotheses for a trait. Therefore, we developed an approach for statistically testing the relationship between gene expression across the body and sets of candidate genes from across the genome. We validated this tool and tested its utility on three applications. First, we show that the expression of genes in associated loci from GWA studies implicates specific tissues for 57 out of 98 traits. Second, we tested the ability of the tool to identify novel relationships between gene expression and phenotypes. Specifically, we experimentally confirmed an underappreciated prediction highlighted by our tool: that white blood cell count--a quantitative trait of the immune system--is genetically modulated by genes expressed in the skin. Finally, using gene lists derived from exome sequencing data, we show that human genes under selective constraint are disproportionately expressed in nervous system tissues.

The effect of supplemental medical and prescription drug coverage on health care spending for Medicare beneficiaries with cancer.

OBJECTIVES: To examine whether patients with newly diagnosed cancer respond differently to supplemental coverage than the general Medicare population. METHODS: A cohort of newly diagnosed cancer patients (n = 1,799) from the 1997-2007 Medicare Current Beneficiary Survey and a noncancer cohort (n = 9,726) were identified and matched by panel year. Two-year total medical care spending was estimated by using generalized linear models with gamma distribution and log link-including endogeneity-corrected models. Interactions between cancer and type of insurance allowed testing for differential effects of a cancer diagnosis. RESULTS: The cancer cohort spent an adjusted $15,605 more over 2 years than did the noncancer comparison group. Relative to those without supplemental coverage, beneficiaries with employer-sponsored insurance, other private with prescription drug coverage, and public coverage had significantly higher total spending ($3,510, $2,823, and $4,065, respectively, for main models). For beneficiaries with cancer, supplemental insurance effects were similar in magnitude yet negative, suggesting little net effect of supplemental insurance for cancer patients. The endogeneity-corrected models produced implausibly large main effects of supplemental insurance, but the Cancer × Insurance interactions were similar in both models. CONCLUSIONS: Medicare beneficiaries with cancer are less responsive to the presence and type of supplemental insurance than are beneficiaries without cancer. Proposed restrictions on the availability of supplemental insurance intended to reduce Medicare spending would be unlikely to limit expenditures by beneficiaries with cancer, but would shift the financial burden to those beneficiaries. Policymakers should consider welfare effects associated with coverage restrictions.

Use of and spending on supportive care medications among Medicare beneficiaries with cancer.

PURPOSE: The study objective was to provide population-based estimates of supportive care medication (SCM) use among Medicare beneficiaries with cancer and determine factors related to SCM receipt. METHODS: This retrospective cohort study of community-based Medicare beneficiaries used the Medicare Current Beneficiary Survey (1997­2007). Dependent variables comprised use and spending on SCMs for three medication classes: opioids, antidepressants/sedative/hypnotics (ASH), and antiemetics. Independent variables of interest were supplemental insurance coverage, cancer site, and treatment. Multivariate models determined factors affecting receipt of, and spending on, SCMs. We also compared SCM use and spending among beneficiaries with and without cancer in order to understand what portion of SCM use and spending could be attributed to cancer as opposed to other comorbid conditions. RESULTS: A total of 1,836 Medicare beneficiaries with cancer and 9,898 beneficiaries without cancer were eligible for the study. Beneficiaries with cancer were more likely to receive opioids, ASH, and antiemetics compared to non-cancer beneficiaries. Adjusted annual payments for antiemetics were on average $637 higher in with cancer versus without cancer (p<0.01), while ASH payments were $184 lower (p<0.01). Opioid spending was similar among cancer and non-cancer users. Relative to colon cancer, beneficiaries with prostate cancer were least likely to receive any of the three SCM classes. Receipt of antineoplastic treatment increased the probability of use of all three classes of SCMs. Insurance coverage did not influence the use of or spending on opioids or antiemetics, but was associated with both outcomes for ASH. The use of all three SCM classes was significantly lower during years before Part D implementation of the new Medicare Part D prescription drug benefit and was higher after implementation of Part D. CONCLUSION: This study provides population-based information on SCM use among Medicare beneficiaries with cancer. Cancer site and treatment modality were important predictors of SCM use.

Affordability and adherence gains for Medicare Part D low-income subsidy recipients when low-income subsidy benefits expanded in 2024.

BACKGROUND: The lowest-income beneficiaries enrolled in the Medicare Part D prescription drug program receive "full subsidies" that waive the premium and deductible and impose minimal copayments. Those with slightly higher incomes and assets may be eligible for "partial subsidies." Prior to 2024, individuals receiving partial subsidies faced reduced Part D premiums and deductibles and paid 15% coinsurance. Under provisions of the Inflation Reduction Act, recipients of partial subsidies were upgraded to full subsidies beginning in 2024. The objective of this pilot study was to assess whether the new policy is likely to reduce cost-related nonadherence to prescribed medications- a common problem faced by older adults even among those receiving subsidies. OBJECTIVE: To compare cost-related nonadherence among partial- vs full-subsidy recipients with similar characteristics. METHODS: We used 2019 Medicare Current Beneficiary Survey data for the study. The Medicare Current Beneficiary Survey is uniquely suited for this work because it contains administrative data on low-income subsidy enrollment plus extensive survey-based information on financial resources necessary to establish program eligibility and rates of cost-related nonadherence. Explanatory variables included sociodemographic characteristics, economic resources, work status, and health variables. RESULTS: We found that the partial-subsidy group reported significantly more cost-related nonadherence (39% vs 22%; P = 0.01) arising both from a lower propensity to fill some prescriptions (23% vs 12%; P = 0.03) and to more delays in filling others (29% vs 8%; P = 0.03). The differences were more pronounced for women and racial and ethnic minority groups in contrast to men and majority populations, respectively. Because the study samples were small, we could not conduct a detailed regression analysis. CONCLUSIONS: The magnitude of cost-related nonadherence effects associated with partial-subsidy cost sharing suggests that the Inflation Reduction Act policy to expand low-income subsidies may boost medication adherence, most notably among women and racial and ethnic minority groups.

Equine rhabdomyolysis.

A 1.5-year-old Quarter Horse gelding with a history of chronic nasal discharge and leukocytosis presented with signs of increased lethargy and muscular pain. The horse quickly became recumbent and unable to rise and was euthanized due to a poor prognosis. At necropsy, severe bilateral guttural pouch empyema was observed, as well as numerous well-demarcated areas of pallor within the skeletal muscles of all major muscle groups. Polymerase chain reaction testing of the guttural pouch exudate confirmed an infection with Streptococcus equi subsp. equi, and an S. equi-associated immune-mediated rhabdomyolysis was initially considered to be the most likely diagnosis. This report briefly discusses the various etiologies that should be considered in cases of equine myopathy, and it demonstrates the complexity of these poorly understood muscular disorders.

Inhibition of Ly-6A antigen expression prevents T cell activation.

Antisense oligonucleotides complementary to the 5' end of the mRNA encoding the Ly-6A protein were used to block the expression of that protein. Using this approach we could inhibit the expression of Ly-6A by 60-80% in antigen-primed lymph node (LN) T cells as well as in the D10 T cell clone. Inhibition of Ly-6 expression resulted in the inability to restimulate in vitro, antigen-primed T cells. It also blocked the activation of normal spleen cells by Con A, monoclonal antibody (mAb) to CD3, and mAb to Ly-6. In contrast, stimulation of normal spleen cells with the pharmacological agents PMA + ionomycin were unaffected by the inhibition of Ly-6 expression. Similar results were obtained with the D10 T cell clone; stimulation with Con A + interleukin 1 (IL-1), antigen-presenting cells (APC), or the clonotypic antibody + IL-1 was greatly reduced in the presence of antisense oligonucleotides to Ly-6. Stimulation with PMA + ionomycin was again unaffected. We also studied the effect of antisense oligonucleotides on stimulation of preactivated D10 cells. Preactivation of D10 cells with Con A + IL-1 renders them receptive to secondary stimulation by other lymphokines. In this case, antisense oligonucleotides to Ly-6 had no effect on secondary activation with IL-2, IL-4 + IL-1, or PMA + ionomycin. We conclude from these studies that Ly-6 expression is required for T cell receptor (TCR)-mediated T cell activation.

An interesting case of adenoviral hepatitis in a cardiac transplant recipient.

Adenoviral infections are commonly described in pediatric transplant populations. However, much less information is available regarding the incidence of infection and clinical spectrum of disease in adult transplant recipients. Moreover, this infection usually manifests as involvement of the transplanted organ in one pathologic form or the other, in addition to other systemic manifestations. We present a case of adenoviral infection of a nontransplanted organ in a solid organ transplant recipient.

Actinomycete: isolation and identification of agent responsible for musty odors.

A compound produced by certain actinomycete cultures is responsible for a persistent musty odor. It has been isolated in high purity and identified by chemical and spectroscopic properties. Possible structures are discussed.

Pulmonary and circulatory adjustments determining the limits of depths in breathhold diving.

Data on pulmonary gas exchange were collected in breathhold dives to 90 feet in a tank and in open-sea breathhold dives to depths of 217.5 and 225 feet. Thoracic blood volume displacements were measured at depths of 25, 50, 90, and 130 feet, by use of the impedance plethysmograph. The open-sea dives were carried out with an average speed of descent of 3.95 feet per second and an average rate of ascent of 3.50 feet per second. End-dive alveolar oxygen tensions did not fall below 36 millimeters of mercury, while alveolar carbon dioxide tension did not rise above 40 millimeters of mercury except in one case. These findings indicate that for diver Croft, who has unusual lung capacity, neither hypoxia nor hypercapnia determined the depth limits under those conditions. At depths of 90 and 130 feet blood was forced into the thorax, amounting to 1047 and 850 milliliters respectively.

Medication adherence as a measure of the quality of care provided by physicians.

OBJECTIVES: To assess the extent to which medication adherence in congestive heart failure (CHF) and diabetes may serve as a measure of physician-level quality. STUDY DESIGN: A retrospective analysis of Medicare data from 2007 to 2009, including parts A (inpatient), B (outpatient), and D (pharmacy). METHODS: For each disease, we assessed the correlation between medication adherence and health outcomes at the physician level. We controlled for selection bias by first regressing patient-level outcomes on a set of covariates including comorbid conditions, demographic attributes, and physician fixed effects. We then classified physicians into 3 levels of average patient medication adherence-low, medium, and high-and compared health outcomes across these groups. RESULTS: There is a clear relationship between average medication adherence and patient health outcomes as measured at the physician level. Within the diabetes sample, among physicians with high average adherence and controlling for patient characteristics, 26.3 per 1000 patients had uncontrolled diabetes compared with 45.9 per 1000 patients among physicians with low average adherence. Within the CHF sample, also controlling for patient characteristics, the average rate of CHF emergency care usage among patients seen by physicians with low average adherence was 16.3% compared with 13.5% for doctors with high average adherence. CONCLUSIONS: This study's results establish a physician-level correlation between improved medication adherence and improved health outcomes in the Medicare population. Our findings suggest that medication adherence could be a useful measure of physician quality, at least for chronic conditions for which prescription medications are an important component of treatment.

Impact of early initiation of antihypertensive medications for patients with hypertension or elevated blood pressure.

OBJECTIVES: The 2017 American College of Cardiology/American Heart Association High Blood Pressure Guidelines lowered high blood pressure (BP) threshold, recommending earlier treatment to prevent cardiovascular disease. This study estimated the impact of initiating early antihypertensive medications on the risk of acute myocardial infarction (AMI), stroke, death, and on healthcare costs in patients potentially qualifying for antihypertensive treatment under the 2017 guidelines. METHODS: High-risk patients qualifying for antihypertensive medications under the 2017 guidelines were identified using Optum data. Patients with a diagnosis of elevated BP were also assumed eligible for hypertension treatment under the new guidelines. Patients were defined to have initiated early treatment if they initiated treatment before experiencing a cardiovascular event postdiagnosis. RESULTS: A total of 916 633 patients met eligibility requirements and all other study inclusion criteria. Of those, 66% initiated treatment during 2007-2016. Initiating early antihypertensive treatment decreased the likelihood of having AMI by 59%, stroke by 60% and death by 9%. Patients with only an 'elevated BP' diagnosis experienced reduced risk of stroke once they initiated medications. Treatment reduced the risk of AMI or stroke for patients with diabetes, chronic renal disease and obesity and also significantly lowered all-cause healthcare costs in the first postindex year. CONCLUSION: Initiating antihypertensive medications before experiencing a cardiovascular disease-related clinical event was associated with reduced risk of AMI, stroke and death for all hypertensive patients identified in the new guidelines. However, early treatment had a significantly smaller effect for patients with only 'elevated' BP, who experienced just a lower risk of stroke once treated.

A genetic analysis of neural progenitor differentiation.

Genetic mechanisms regulating CNS progenitor function and differentiation are not well understood. We have used microarrays derived from a representational difference analysis (RDA) subtraction in a heterogeneous stem cell culture system to systematically study the gene expression patterns of CNS progenitors. This analysis identified both known and novel genes enriched in progenitor cultures. In situ hybridization in a subset of clones demonstrated that many of these genes were expressed preferentially in germinal zones, some showing distinct ventricular or subventricular zone labeling. Several genes were also enriched in hematopoietic stem cells, suggesting an overlap of gene expression in neural and hematopoietic progenitors. This combination of methods demonstrates the power of using custom microarrays derived from RDA-subtracted libraries for both gene discovery and gene expression analysis in the central nervous system.

Primary Prevention Using Cholesterol-Lowering Medications in Patients Meeting New Treatment Guidelines: A Retrospective Cohort Analysis.

BACKGROUND: The American College of Cardiology and American Heart Association (ACC/AHA) issued new cholesterol treatment guidelines in 2013. Two of the groups designated for primary prevention were analyzed: patients with a low-density lipoprotein cholesterol (LDL-C) level ≥ 190 mg per dL and diabetic patients aged 40-75 years. OBJECTIVE: To estimate the effects of primary prevention as specified in the 2013 guidelines on cardiovascular event risk and cost. METHODS: Primary prevention patients were identified using laboratory and diagnostic data for Humana members from 2007 to 2013. Potential study patients were classified into 3 risk groups: elevated LDL-C, diabetes, and elevated LDL-C and diabetes. Patients receiving cholesterol-lowering medications before their index date were excluded. Eligible patients were divided into 2 treatment groups: (1) primary prevention patients who initiated treatment before experiencing any cardiovascular disease (CVD)-related event, and (2) patients who either did not initiate treatment until after experiencing a CVD event or never initiated treatment. The associations between initiating cholesterol-lowering medications for primary prevention and the risk for acute myocardial infarction, stroke, coronary angioplasty, or coronary artery bypass graft surgery were estimated using Cox proportional hazards models. The effect of primary prevention on health care costs was estimated using generalized linear models. RESULTS: 91,066 patients met study selection criteria. Primary prevention rates were the lowest in diabetic patients (35%), who were newly designated for treatment in the 2013 guidelines. Primary prevention rates were higher for patients designated for treatment under earlier guidelines: 65% for patients with elevated LDL-C and 78% for the combined LDL-C and diabetes group. Primary prevention treatment was associated with significant reductions in cardiovascular event risk (up to 37%) and lower total all-cause costs (by $673) in the first post-index year. CONCLUSIONS: Initiating cholesterol-lowering medications for primary prevention, as specified in the ACC/AHA 2013 guidelines, for patients with high LDL-C and diabetes is associated with reduced CVD event risks and lower health care costs. DISCLOSURES: No outside funding supported this study. Han received fellowship support from the Pharmaceutical Research and Manufacturers Association Foundation (PhRMA) during the conduct of this study. Dougherty is employed by PhRMA. The authors have nothing to disclose.

Medication Synchronization Programs Improve Adherence To Cardiovascular Medications And Health Care Use.

Medication synchronization programs based in pharmacies simplify the refill process by enabling patients to pick up all of their medications on a single visit. This can be especially important for improving medication adherence in patients with complex chronic diseases. We evaluated the impact of two synchronization programs on adherence, cardiovascular events, and resource use among Medicare beneficiaries treated between 2011 and 2014 for two or more chronic conditions-at least one of which was hypertension, hyperlipidemia, or diabetes. Among nearly 23,000 patients matched by propensity score, the mean proportion of days covered (a measure of medication adherence) for the control group of patients without a synchronization program was 0.84 compared to 0.87 for synchronized patients-a gain of 3 percentage points. Adherence improvement in synchronized versus control patients was three times greater in patients with low baseline adherence, compared to those with higher baseline adherence. Rates of hospitalization and emergency department visits and rates of outpatient visits were 9 percent and 3 percent lower in the synchronized group compared to the control group, respectively, while cardiovascular event rates were similar. Synchronization programs were associated with improved adherence for patients with cardiovascular disease, especially those with low baseline adherence.

The effect of insulin upon glucose metabolism by adipose cells of different size. Influence of cell lipid and protein content, age, and nutritional state.

Glucose metabolism and insulin sensitivity of isolated rat epididymal fat cells and of their delipidated derivatives ("ghosts") was studied as a function of cellular lipid content (fat cell size), cellular protein content, animal age, and state of nutrition in an effort to examine the relationship of adipose cell size to adipose tissue insulin sensitivity.In ad libitum-fed rats, basal rates of glucose-1-(14)C incorporation into CO(2) and triglyceride are similar over a wide range of adipose cell size. In contrast, the insulin sensitivity of intact fat cells from rats fed ad libitum is inversely related to their lipid content: the larger the cell, the less the response to insulin. This "resistance" of the enlarged adipose cell to the action of insulin was demonstrated by a reduction in the per cent rise above the basal rate as well as in the absolute rate of glucose oxidation and lipogenesis caused by insulin. The protein content of fat cells was found to be relatively constant over a wide range of fat cell size. Thus, enlarged insulin "resistant" fat cells contained the same amount of protein as smaller insulin "sensitive" cells. These relationships between insulin sensitivity and cellular lipid or protein content were true regardless of whether cells of different sizes were obtained from animals of different body weights and ages, or from different portions of the epididymal fat pads of animals of the same weight and age.Acute delipidation of intact fat cells did not appear to alter these relationships between basal glucose metabolism, insulin sensitivity, and cell size. "Ghosts" prepared from fat cells of widely different sizes metabolized glucose to CO(2) and triglyceride at similar rates. The insulin sensitivity of the fat cell "ghost" appeared to be inversely related to the size of the intact cell from which it was derived: the larger the intact cell the less insulin sensitive its "ghost."Although the insulin "resistance" of adipose tissue was reversed by weight loss and reduction of fat cell size, these studies also demonstrate that the insulin sensitivity of adipose cells of similar sizes can vary widely depending upon the state of nutrition and growth of the animal. Thus, factors other than cell size can also influence the insulin sensitivity of the adipose tissue.

The mouse immunoglobulin heavy-chain gene enhancer contains sequences that inhibit transcription in vitro in HeLa cell extracts.

The effect of the cell-specific mouse immunoglobulin heavy-chain gene (IgH) enhancer on transcription from heterologous promoter elements was studied in vitro with a HeLa whole-cell extract. No stimulation of transcription could be seen under conditions in which an activation was observed with the simian virus 40 enhancer. We found, however, that a specific segment of the IgH enhancer region contains sequences which inhibit transcription in vitro.

High mutation rate of a spleen necrosis virus-based retrovirus vector.

Spleen necrosis virus (SNV) is an avian retrovirus that efficiently infects some mammalian cells (e.g., dog and rat cells). We constructed an SNV-based vector, which contains less than 1 kilobase (kb) of the retrovirus sequence, and a number of derivatives containing selectable markers. We obtained high-titer virus stocks, over 10(6) transforming units per ml, with a vector whose genomic RNA consists of 1,850 bases (full-length SNV RNA is 7.7 kb). We also studied two vectors that both carry two genes which should be expressed from a single promoter, one gene from unspliced mRNA and the other gene from spliced mRNA. In one vector, both genes were efficiently expressed as expected. However, in the other vector, expression of the gene 3' to the splice acceptor was inhibited. When we selected for expression of the 3' gene is this latter case, we found that the resistant cells contained mutant proviruses in which the 3' gene could be expressed. Furthermore, we found that mutations were generated during a single round of virus replication (provirus to provirus) at a rate of approximately 0.5% mutations per cycle.

Does the offer of free prescriptions increase generic prescribing?

OBJECTIVES: To test if offering zero generic co-pays for oral antidiabetic drugs (OADs) and statins increases generic dispensing for low-income subsidy (LIS) recipients with diabetes enrolled in Medicare Part D. STUDY DESIGN: We analyzed a natural experiment in which LIS recipients were randomized to Part D plans in 2008. Some plans placed selected generic OADs and statins on zero co-pay tiers whereas others did not. Randomization eliminated selection effects which could bias the study findings. METHODS: We analyzed a 5% random sample of Medicare beneficiaries with diabetes from the Chronic Condition Data Warehouse using Part D claims, formulary provisions, and co-pay tiers together with a special file prepared by CMS that identified all randomly assigned LIS recipients in 2008. We calculated proportions using generic drugs in the 2 classes and annual days' supply among users in plans with and without zero co-pay tiers for the country as a whole and California (where zero co-pay plans were particularly popular). RESULTS: We found that the demand for generic OADs was not significantly different in plans with and without zero co-pay tiers. By contrast, a large difference was observed in the percent of LIS recipients using generic statins in plans with zero co-pay tiers (61.4% vs 54.6%; P <.01). However, the difference disappeared once we controlled for formulary restrictions on the most popular brand statin at the time (Lipitor). CONCLUSIONS: This cautionary tale suggests that policy makers should give greater consideration to formulary provisions when evaluating the effects of free generics in value-based insurance designs.

How Low-Income Subsidy Recipients Respond to Medicare Part D Cost Sharing.

OBJECTIVES: To determine the magnitude and mechanisms of response to Medicare Part D cost sharing by low-income subsidy (LIS) recipients using oral hypoglycemic agents (OHAs) and statins. DATA SOURCES: Medicare data for a 5 percent random sample of beneficiaries with diabetes enrolled in fee-for-service Part D drug plans in 2008. STUDY DESIGN: We evaluated the impact of differences between generic and brand cost sharing rates among cohorts of LIS and non-LIS recipients to determine if wider price spreads increased the generic dispensing rate (GDR) and reduced total drug use and cost. PRINCIPAL FINDINGS: We found little association between cost sharing and aggregate OHA and statin use. In adjusted analyses, non-LIS beneficiaries who paid 46 percent of total OHA costs had 2.5 percent fewer OHA days supply than full benefit dual eligibles who paid just 5 percent of their therapy costs. For statins, the difference in days supply between those facing the lowest and highest cost sharing was 4.6 percent. Higher cost sharing was associated with filling fewer but larger prescriptions for both generics and brands. CONCLUSIONS: Higher generic and brand copays had little association with OHA and statin use among LIS recipients. This implies that modest changes in required cost sharing for these medicines would have very little substantive impact on generic dispensing or utilization patterns among LIS recipients and thus would have little effect on total program spending. At the same time, any increases in out-of-pocket costs would be expected to shift costs and place greater financial burden on low-income beneficiaries, particularly those in poor health.