Dynamics of cognitive variability with age and its genetic underpinning in NIHR BioResource Genes and Cognition cohort participants.

A leading explanation for translational failure in neurodegenerative disease is that new drugs are evaluated late in the disease course when clinical features have become irreversible. Here, to address this gap, we cognitively profiled 21,051 people aged 17-85 years as part of the Genes and Cognition cohort within the National Institute for Health and Care Research BioResource across England. We describe the cohort, present cognitive trajectories and show the potential utility. Surprisingly, when studied at scale, the APOE genotype had negligible impact on cognitive performance. Different cognitive domains had distinct genetic architectures, with one indicating brain region-specific activation of microglia and another with glycogen metabolism. Thus, the molecular and cellular mechanisms underpinning cognition are distinct from dementia risk loci, presenting different targets to slow down age-related cognitive decline. Participants can now be recalled stratified by genotype and cognitive phenotype for natural history and interventional studies of neurodegenerative and other disorders.

A cfDNA methylation-based tissue-of-origin classifier for cancers of unknown primary.

Cancers of Unknown Primary (CUP) remains a diagnostic and therapeutic challenge due to biological heterogeneity and poor responses to standard chemotherapy. Predicting tissue-of-origin (TOO) molecularly could help refine this diagnosis, with tissue acquisition barriers mitigated via liquid biopsies. However, TOO liquid biopsies are unexplored in CUP cohorts. Here we describe CUPiD, a machine learning classifier for accurate TOO predictions across 29 tumour classes using circulating cell-free DNA (cfDNA) methylation patterns. We tested CUPiD on 143 cfDNA samples from patients with 13 cancer types alongside 27 non-cancer controls, with overall sensitivity of 84.6% and TOO accuracy of 96.8%. In an additional cohort of 41 patients with CUP CUPiD predictions were made in 32/41 (78.0%) cases, with 88.5% of the predictions clinically consistent with a subsequent or suspected primary tumour diagnosis, when available (23/26 patients). Combining CUPiD with cfDNA mutation data demonstrated potential diagnosis re-classification and/or treatment change in this hard-to-treat cancer group.

Crystal structures of sulfonamide protected bicyclic guanidines: (S)-8-{[(tert-butyl-dimethyl-sil-yl)-oxy]meth-yl}-1-[(2,2,4,6,7-penta-methyl-2,3-di-hydro-benzo-furan-5-yl)sulfon-yl]-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium tri-fluoro-methane-sulfonate and (S)-8-(iodo-meth-yl)-1-tosyl-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium iodide.

Two compounds, (S)-8-{[(tert-butyl-dimethyl-sil-yl)-oxy]meth-yl}-1-[(2,2,4,6,7-penta-methyl-2,3-di-hydro-benzo-furan-5-yl)sulfon-yl]-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium tri-fluoro-methane-sulfonate, C27H46N3O4SSi+·CF3O3S-, (1) and (S)-8-(iodo-meth-yl)-1-tosyl-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium iodide, C15H21IN3O2S+·I-, (2), have been synthesized and characterized. They are bicyclic guanidinium salts and were synthesized from N-(tert-but-oxy-carbon-yl)-l-me-thio-nine (Boc-l-Met-OH). The guanidine is protected by a 2,2,4,6,7-penta-methyl-dihydro-benzo-furan-5-sulfonyl (Pbf, 1) or a tosyl (2) group. In the crystals of both compounds, the guanidinium group is almost planar and the N-H forms an intra-molecular hydrogen bond in a six-membered ring to the oxygen atom of the sulfonamide protecting group.

Availability of off-marketplace plans with lower premiums for higher-income families.

OBJECTIVES: Families with incomes above 400% of the federal poverty level were ineligible for marketplace premium tax credits before 2021 and may again be after 2025. Current laws temporarily removed this income cap, but because credits cap out-of-pocket premiums for a reference plan as a share of income, some higher-income families still receive zero tax credits. We quantified (1) premium differences between on- and off-marketplace plans and (2) the association between these premium differences and state decisions to finance cost-sharing reductions (CSRs) for lower-income families. STUDY DESIGN: We created a comprehensive database of on- and off-marketplace plans in each county (including both federal and state-based marketplaces). METHODS: By county and metal level, we compared on- and off-marketplace (1) plan premiums in 2020 and (2) growth rates in the numbers of plans. We contrasted outcomes for states by how insurers were instructed to finance CSRs. RESULTS: In 2020, 89% of the US population lived in counties where some plans were offered exclusively off-marketplace. In these counties, for a 45-year-old choosing among silver plans in 2020 and who did not qualify for premium subsidies, premiums for the lowest-cost off-marketplace plans averaged 11.3% less than premiums for the lowest-cost on-marketplace plans. In contrast, for bronze and gold plans, the lowest-cost off-marketplace plans were, on average, more expensive. Silver plan premiums were 6.1% higher off-marketplace than on-marketplace in states that loaded CSRs on all silver plans, and 13.5% lower in states that loaded CSRs only on on-marketplace silver plans. CONCLUSIONS: Higher-income individuals and families may consider purchasing Affordable Care Act-compliant silver plans off-marketplace and thereby reduce their premiums. State and federal policy makers should consider the impact of their decisions on the choice between on- and off-marketplace plans.

A Method for Perfusion of Tissue-Isolated Human Tumor Xenografts in Nude Rats to Investigate the Oncostatic Role of the Physiological Nocturnal Melatonin Signal.

The tissue-isolated human tumor perfusion methodology enables the elucidation of physiological melatonin's oncostatic impact on cancer metabolism and physiology. Here we describe an apparatus and surgical technique for perfusing tissue-isolated human tumor xenografts in nude rats in situ that ensures continuous blood flow to and from the tissue. This system and methodology have proven quite successful in examining the receptor-mediated oncostatic effects of the physiological nocturnal melatonin signal on metabolism and physiology in a variety of epithelial and mesenchymal human tumors.

A Method for Growing Tissue-Isolated Human Tumor Xenografts in Nude Rats for Melatonin/Cancer Studies.

The tissue-isolated tumor model permits the investigation of melatonin's influence on human tumor growth and metabolism in laboratory rats in vivo. Here we describe a unique surgical technique for implanting and growing human tumor xenografts on a vascular stalk composed of the nude rat epigastric artery and vein that provides a continuous blood supply from a single source to the tissue-isolated tumor while insuring the absence of extraneous vascular connections. A variety of human tumor types may be implanted and grown utilizing this unique model that may provide a plethora of scientific data from a single tumor examined.

cfDNA methylome profiling for detection and subtyping of small cell lung cancers.

Small cell lung cancer (SCLC) is characterized by morphologic, epigenetic and transcriptomic heterogeneity. Subtypes based upon predominant transcription factor expression have been defined that, in mouse models and cell lines, exhibit potential differential therapeutic vulnerabilities, with epigenetically distinct SCLC subtypes also described. The clinical relevance of these subtypes is unclear, due in part to challenges in obtaining tumor biopsies for reliable profiling. Here we describe a robust workflow for genome-wide DNA methylation profiling applied to both patient-derived models and to patients' circulating cell-free DNA (cfDNA). Tumor-specific methylation patterns were readily detected in cfDNA samples from patients with SCLC and were correlated with survival outcomes. cfDNA methylation also discriminated between the transcription factor SCLC subtypes, a precedent for a liquid biopsy cfDNA-methylation approach to molecularly subtype SCLC. Our data reveal the potential clinical utility of cfDNA methylation profiling as a universally applicable liquid biopsy approach for the sensitive detection, monitoring and molecular subtyping of patients with SCLC.

Effects of Medicaid expansion on insurance coverage and health services use among adults with disabilities newly eligible for Medicaid.

OBJECTIVE: To estimate the effects of Affordable Care Act (ACA) Medicaid expansion on insurance and health services use for adults with disabilities who were newly eligible for Medicaid. DATA SOURCES: 2008-2018 Medical Expenditure Panel Survey data. STUDY DESIGN: We used the Agency for Healthcare Research and Quality (AHRQ) PUBSIM model to identify adults aged 26-64 years with disabilities who were newly Medicaid-eligible in expansion states or would have been eligible in non-expansion states had those states opted to expand. Outcomes included insurance coverage; access to care; receipt of primary care, outpatient specialty physician services, and preventive services; and out-of-pocket health care spending. To estimate the effects of Medicaid expansion, we used two-way fixed effects models and a triple differences framework to compare pre-post changes in each outcome in expansion and non-expansion states for adults with and without disabilities. EXTRACTION METHODS: We simulated Medicaid eligibility with the AHRQ PUBSIM model, which uses state-specific Medicaid rules and MEPS data on family relationships, state of residence, and income. PRINCIPAL FINDINGS: Among adults with disabilities who were newly eligible for Medicaid, Medicaid expansion was associated with significant increases in full-year Medicaid coverage (35.9 percentage points [pp], p < 0.001), receipt of primary care (15.5 pp, p < 0.01), and receipt of flu shots (19.2 pp, p < 0.01), and a significant decrease in out-of-pocket spending (-$457, p < 0.01). There were larger improvements for adults with disabilities compared to those without disabilities in full-year Medicaid coverage (11.0 pp, p < 0.01) and receipt of flu shots (18.0 pp, p < 0.05). CONCLUSIONS: Medicaid expansion was associated with improvements in full-year insurance coverage, receipt of primary and preventive care, and out-of-pocket spending for adults with disabilities who were newly eligible for Medicaid. For insurance coverage, preventive care, and some primary care measures, there were differentially larger improvements for adults with disabilities than for those without disabilities.

Tobacco Surcharges Associated With Reduced ACA Marketplace Enrollment.

The Affordable Care Act (ACA) allows insurers to charge tobacco users who have nongroup coverage up to 50 percent more than nonusers of tobacco. In this study we used 2014-19 administrative data on enrollees in the federally facilitated ACA Marketplace, HealthCare.gov, to examine the relationships among surcharge rates, total Marketplace enrollment, and enrollment by tobacco users. We found that the tobacco surcharge rate averaged approximately 14 percent and that it was associated with lower total enrollment as well as a reduced share of total enrollees who reported any tobacco use. Our analysis also found that tobacco surcharges have a significantly larger effect on tobacco users' share of enrollment in rural areas than in urban areas, which may in turn contribute to urban-rural health disparities. Given that tobacco surcharges may decrease Marketplace enrollment overall and shift the composition of enrollment away from tobacco users, our findings suggest that reducing tobacco surcharges may increase total Marketplace enrollment.

ACA Marketplaces Became Less Affordable Over Time For Many Middle-Class Families, Especially The Near-Elderly.

The Affordable Care Act provides tax credits for Marketplace insurance, but before 2021, families with incomes above four times the federal poverty level did not qualify for tax credits and could face substantial financial burdens when purchasing coverage. As a measure of affordability, we calculated potential Marketplace premiums as a percentage of family income among families with incomes of 401-600 percent of poverty. In 2015 half of this middle-class population would have paid at least 7.7 percent of their income for the lowest-cost bronze plan; in 2019 they would have paid at least 11.3 percent of their income. By 2019 half of the near-elderly ages 55-64 would have paid at least 18.9 percent of their income for the lowest-cost bronze plan in their area. The American Rescue Plan Act temporarily expanded tax credit eligibility for 2021 and 2022, but our results suggest that families with incomes of 401-600 percent of poverty will again face substantial financial burdens after the temporary subsidies expire.

Disease Modelling of Cognitive Outcomes and Biomarkers in the European Prevention of Alzheimer's Dementia Longitudinal Cohort.

A key challenge for the secondary prevention of Alzheimer's dementia is the need to identify individuals early on in the disease process through sensitive cognitive tests and biomarkers. The European Prevention of Alzheimer's Dementia (EPAD) consortium recruited participants into a longitudinal cohort study with the aim of building a readiness cohort for a proof-of-concept clinical trial and also to generate a rich longitudinal data-set for disease modelling. Data have been collected on a wide range of measurements including cognitive outcomes, neuroimaging, cerebrospinal fluid biomarkers, genetics and other clinical and environmental risk factors, and are available for 1,828 eligible participants at baseline, 1,567 at 6 months, 1,188 at one-year follow-up, 383 at 2 years, and 89 participants at three-year follow-up visit. We novelly apply state-of-the-art longitudinal modelling and risk stratification approaches to these data in order to characterise disease progression and biological heterogeneity within the cohort. Specifically, we use longitudinal class-specific mixed effects models to characterise the different clinical disease trajectories and a semi-supervised Bayesian clustering approach to explore whether participants can be stratified into homogeneous subgroups that have different patterns of cognitive functioning evolution, while also having subgroup-specific profiles in terms of baseline biomarkers and longitudinal rate of change in biomarkers.

Dietary Melatonin and Omega-3 Fatty Acids Induce Human Cancer Xenograft Regression In Vivo in Rats by Suppressing Linoleic Acid Uptake and Metabolism.

Melatonin, the circadian nighttime neurohormone, and eicosapentaenoic acid (EPA) and docosahexaenoic acids (DHA), which are omega-3 fatty acids (FA) found in high concentrations in fish oil (FO) and plants, abrogate the oncogenic effects of linoleic acid (LA), an omega-6 FA, on the growth of rodent tumors and human breast, prostate, and head and neck squamous cell carcinoma (HNSCC) xenografts in vivo. Here we determined and compared the long-term effects of these inhibitory agents on tumor regression and LA uptake and metabolism to the mitogenic agent 13-[S]-hydroxyoctadecadienoic acid (13-[S]-HODE) in human prostate cancer 3 (PC3) and FaDu HNSCC xenografts in tumor-bearing male nude rats. Rats in this study were split into 3 groups and fed one of 2 diets: one diet containing 5% corn oil (CO, high LA), 5% CO oil and melatonin (2 µg/mL) or an alternative diet 5% FO (low LA). Rats whose diet contained melatonin had a faster rate of regression of PC3 prostate cancer xenografts than those receiving the FO diet, while both in the melatonin and FO groups induced the same rate of regression of HNSCC xenografts. The results also demonstrated that dietary intake of melatonin or FO significantly inhibited tumor LA uptake, cAMP content, 13-[S]-HODE formation, [³H]-thymidine incorporation into tumor DNA, and tumor DNA content. Therefore, long-term ingestion of either melatonin or FO can induce regression of PC3 prostate and HNSCC xenografts via a mechanism involving the suppression of LA uptake and metabolism by the tumor cells.

Shielding of viruses such as SARS-Cov-2 from ultraviolet radiation in particles generated by sneezing or coughing: Numerical simulations of survival fractions.

SARS-CoV-2 and other microbes within aerosol particles can be partially shielded from UV radiation. The particles refract and absorb light, and thereby reduce the UV intensity at various locations within the particle. Previously, we demonstrated shielding in calculations of UV intensities within spherical approximations of SARS-CoV-2 virions within spherical particles approximating dried-to-equilibrium respiratory fluids. The purpose of this paper is to extend that work to survival fractions of virions (i.e., fractions of virions that can infect cells) within spherical particles approximating dried respiratory fluids, and to investigate the implications of these calculations for using UV light for disinfection. The particles may be on a surface or in air. Here, the survival fraction (S) of a set of individual virions illuminated with a UV fluence (F, in J/m2) is assumed described by S(kF) = exp(-kF), where k is the UV inactivation rate constant (m2/J). The average survival fraction (Sp) of the simulated virions in a group of particles is calculated using the energy absorbed by each virion in the particles. The results show that virions within particles of dried respiratory fluids can have larger Sp than do individual virions. For individual virions, and virions within 1-, 5-, and 9-µm particles illuminated (normal incidence) on a surface with 260-nm UV light, the Sp = 0.00005, 0.0155, 0.22, and 0.28, respectively, when kF = 10. The Sp decrease to <10-7, <10-7, 0.077, and 0.15, respectively, for kF = 100. Results also show that illuminating particles with UV beams from widely separated directions can strongly reduce the Sp. These results suggest that the size distributions and optical properties of the dried particles of virion-containing respiratory fluids are likely important to effectively designing and using UV germicidal irradiation systems for microbes in particles. The results suggest the use of reflective surfaces to increase the angles of illumination and decrease the Sp. The results suggest the need for measurements of the Sp of SARS-CoV-2 in particles having compositions and sizes relevant to the modes of disease transmission.

Effects of Daytime Blue-Enriched LED Light on Physiologic Parameters of Three Common Mouse Strains Maintained on an IVC System.

Light has been a crucial part of everyday life since the beginning of time. Most recently, light-emitting diode (LED) light enriched in the blue-appearing portion of the visible spectrum (465 to 485 nm), which is more efficient in energy use, is becoming the normal lighting technology in facilities around the world. Previous reports revealed that blue-enriched LED light at day (bLAD) enhances animal health and wellbeing as compared with cool white fluorescent (CWF) lighting. We hypothesized that bLAD, compared with CWF light, has a positive influence on basic physiologic indices such as food consumption, water consumption, weight gain, nesting behavior, complete blood count, and blood chemistry profile. To test this, we allocated 360 mice into equal-sized groups by sex, strain (C3H/HeNCrl, C57BL/6NCrl, BALB/cAnNCrl), lighting conditions, and 6 blood collection time points (n = 5 mice/sex/strain/lighting condition/time point). Food consumption, water consumption, body weight, nest location, and nest type were recorded every 3 d. At the end of the study, all mice were anesthetized over a period of 1 wk and blood was collected via cardiocentesis at 6 different time points. Overall, male C3H/HeNCrl consumed more food under bLAD conditions as compared with CWF conditions; male C3H/HeNCrl had lower cholesterol levels under bLAD conditions than under CWF conditions; female BALB/cAnNCrl mice had higher serum total protein under bLAD conditions than under CWF conditions; female C57BL/6NCrl mice had higher phosphorus levels under bLAD conditions than under CWF conditions, and female C3H/HeNCrl mice had a higher neutrophil count under bLAD conditions as compared with CWF conditions. Although sex and strain differences were found in various physiologic parameters under bLAD as compared with CWF lighting conditions, the differences were minimal. Thus, this study suggests that for these strains of mice, bLAD and CWF are largely equivalent with regard to indices of health and wellbeing, although some differences could affect research outcomes.

The effects of Medicaid on access to care and adherence to recommended preventive services.

OBJECTIVE: To quantify the impact of Medicaid enrollment on access to care and adherence to recommended preventive services. DATA SOURCE: 2005-2015 Medical Expenditure Panel Survey Household Component. STUDY DESIGN: We examined several access measures and utilization of several preventive services within the past year and within the time frame recommended by the United States Preventive Services Task Force, if more than a year. We estimated local average treatment effects of Medicaid enrollment using a new, two-stage regression model developed by Nguimkeu, Denteh, and Tchernis. This model accounts for both endogenous and underreported Medicaid enrollment by using a partial observability bivariate probit regression as the first stage. We identify the model with an exogenous measure of Medicaid eligibility, the simulated Medicaid eligibility rate by state, year, and parents vs childless adults. A wide range of changes in Medicaid eligibility occurred during the time period studied. DATA COLLECTION/EXTRACTION METHODS: Sample of low-income, nonelderly adults not receiving disability benefits. PRINCIPAL FINDINGS: Medicaid enrollment decreased the probability of having unmet needs for medical care by 7.5 percentage points and the probability of experiencing delays getting prescription drugs by 7.7 percentage points. Medicaid enrollment increased the probability of having a usual source of care by 16.5 percentage points, the probability of having a routine checkup by 17.1 percentage points, and the probability of having a flu shot in past year by 12.6 percentage points. CONCLUSION: Medicaid enrollment increased access to care and use of some preventive services. Additional research is needed on impacts for subgroups, such as parents, childless adults, and the smaller and generally older populations for whom screening tests are recommended.

Viruses such as SARS-CoV-2 can be partially shielded from UV radiation when in particles generated by sneezing or coughing: Numerical simulations.

UV radiation can inactivate viruses such as SARS-CoV-2. However, designing effective UV germicidal irradiation (UVGI) systems can be difficult because the effects of dried respiratory droplets and other fomites on UV light intensities are poorly understood. Numerical modeling of UV intensities inside virus-containing particles on surfaces can increase understanding of these possible reductions in UV intensity. We model UV intensities within spherical approximations of virions randomly positioned within spherical particles. The model virions and dried particles have sizes and optical properties to approximate SARS-CoV-2 and dried particles formed from respiratory droplets, respectively. In 1-, 5- and 9-µm diameter particles on a surface, illuminated by 260-nm UV light from a direction perpendicular to the surface, 0%, 10% and 18% (respectively) of simulated virions are exposed to intensities less than 1/100th of intensities in individually exposed virions (i.e., they are partially shielded). Even for 302-nm light (simulating sunlight), where absorption is small, 0% and 11% of virions in 1- and 9-µm particles have exposures 1/100th those of individually exposed virions. Shielding is small to negligible in sub-micron particles. Results show that shielding of virions in a particle can be reduced by illuminating a particle either from multiple widely separated incident directions, or by illuminating a particle rotating in air for a time sufficient to rotate through enough orientations. Because highly UV-reflective paints and surfaces can increase the angular ranges of illumination and the intensities within particles, they appear likely to be useful for reducing shielding of virions embedded within particles.

Sonic hedgehog signaling in astrocytes.

Astrocytes are complex cells that perform a broad array of essential functions in the healthy and injured nervous system. The recognition that these cells are integral components of various processes, including synapse formation, modulation of synaptic activity, and response to injury, underscores the need to identify the molecular signaling programs orchestrating these diverse functional properties. Emerging studies have identified the Sonic hedgehog (Shh) signaling pathway as an essential regulator of the molecular identity and functional properties of astrocytes. Well established as a powerful regulator of diverse neurodevelopmental processes in the embryonic nervous system, its functional significance in astrocytes is only beginning to be revealed. Notably, Shh signaling is active only in discrete subpopulations of astrocytes distributed throughout the brain, a feature that has potential to yield novel insights into functional specialization of astrocytes. Here, we discuss Shh signaling and emerging data that point to essential roles for this pleiotropic signaling pathway in regulating various functional properties of astrocytes in the healthy and injured brain.

Patient-Centered Medical Homes and Pediatric Preventive Counseling.

OBJECTIVE: To measure pediatric preventive counseling at patient-centered medical homes (PCMHs) compared with practices that reported undertaking some or no quality-related activities. METHODS: We analyzed 4814 children and adolescents ages 0 to 17 who visited their usual sources of care in the nationally representative Medical Expenditure Panel Survey Medical Organizations Survey (MEPS-MOS), a household survey combined with a survey of household members' usual sources of care. We identified PCMHs using lists from certifying or accrediting organizations. For other practices in the MEPS-MOS, 2 quality-related activities were 1) reports to physicians about their clinical quality of care, and 2) electronic health record system reminders to physicians. Regressions controlled for practice, child, and family characteristics. RESULTS: Compared with other practices, PCMHs were generally associated with greater likelihood of receiving preventive counseling. Estimates varied with the quality-related activities of the comparison practices. Counseling against smoking in the home was 10.4 to 18.7 percentage points (both P < .01) more likely for PCMHs. More associations were statistically significant for PCMHs compared with practices that undertook 1 of 2 quality-related activities examined. Among children ages 2 to 5, compared with practices undertaking both quality-related activities, those with PCMHs were more likely to receive counseling on 3 of 5 topics. Among adolescents, compared with practices undertaking both quality-related activities, those with PCMHs were more likely to receive counseling on smoking, exercise, and eating healthy. CONCLUSIONS: PCMHs were associated with substantially greater receipt of pediatric preventive counseling. Evaluations of PCMHs need to account for the quality-related activities of comparison practices.

Net Spending On Retail Specialty Drugs Grew Rapidly, Especially For Private Insurance And Medicare Part D.

Specialty drugs are expensive, but spending on specialty drugs is difficult to measure because of proprietary rebate payments by manufacturers to insurers, pharmacy benefit managers, and state Medicaid agencies. Our study extends recent research that documented growing use of and spending on specialty drugs by incorporating manufacturer rebates for both public and private payers. Although specialty drugs make up a small portion of retail prescriptions filled, we found that they accounted for 37.7 percent of retail and mail-order prescription spending net of rebates in 2016-17. From 2010-11 to 2016-17, spending net of rebates tripled for Medicare Part D beneficiaries and more than doubled for people with private insurance. Medicaid spending net of rebates rose more slowly. These results can help inform decision makers as they strive to balance the costs and benefits of innovative drugs.