Common Variants Associated With OSMR Expression Contribute to Carotid Plaque Vulnerability, but Not to Cardiovascular Disease in Humans

Background and Aims: Oncostatin M (OSM) signaling is implicated in atherosclerosis, however the mechanism remains unclear. We investigated the impact of common genetic variants in OSM and its receptors, OSMR and LIFR, on overall plaque vulnerability, plaque phenotype, intraplaque OSMR and LIFR expression, coronary artery calcification burden and cardiovascular disease susceptibility. Methods and Results: We queried Genotype-Tissue Expression data and found that rs13168867 (C allele) was associated with decreased OSMR expression and that rs10491509 (A allele) was associated with increased LIFR expression in arterial tissues. No variant was significantly associated with OSM expression. We associated these two variants with plaque characteristics from 1,443 genotyped carotid endarterectomy patients in the Athero-Express Biobank Study. After correction for multiple testing, rs13168867 was significantly associated with an increased overall plaque vulnerability (β = 0.118 ± s.e. = 0.040, p = 3.00 × 10−3, C allele). Looking at individual plaque characteristics, rs13168867 showed strongest associations with intraplaque fat (β = 0.248 ± s.e. = 0.088, p = 4.66 × 10−3, C allele) and collagen content (β = −0.259 ± s.e. = 0.095, p = 6.22 × 10−3, C allele), but these associations were not significant after correction for multiple testing. rs13168867 was not associated with intraplaque OSMR expression. Neither was intraplaque OSMR expression associated with plaque vulnerability and no known OSMR eQTLs were associated with coronary artery calcification burden, or cardiovascular disease susceptibility. No associations were found for rs10491509 in the LIFR locus. Conclusions: Our study suggests that rs1316887 in the OSMR locus is associated with increased plaque vulnerability, but not with coronary calcification or cardiovascular disease risk. It remains unclear through which precise biological mechanisms OSM signaling exerts its effects on plaque morphology. However, the OSM-OSMR/LIFR pathway is unlikely to be causally involved in lifetime cardiovascular disease susceptibility

International comparison of spending and utilization at the end of life for hip fracture patients.

ObjectiveTo identify and explore differences in spending and utilization of key health services at the end of life among hip fracture patients across seven developed countries.Data sourcesIndividual-level claims data from the inpatient and outpatient health care sectors compiled by the International Collaborative on Costs, Outcomes, and Needs in Care (ICCONIC).Study designWe retrospectively analyzed utilization and spending from acute hospital care, emergency department, outpatient primary care and specialty physician visits, and outpatient drugs. Patterns of spending and utilization were compared in the last 30, 90, and 180 days across Australia, Canada, England, Germany, New Zealand, Spain, and the United States. We employed linear regression models to measure age- and sex-specific effects within and across countries. In addition, we analyzed hospital-centricity, that is, the days spent in hospital and site of death.Data collection/extraction methodsWe identified patients who sustained a hip fracture in 2016 and died within 12 months from date of admission.Principal findingsResource use, costs, and the proportion of deaths in hospital showed large variability being high in England and Spain, while low in New Zealand. Days in hospital significantly decreased with increasing age in Canada, Germany, Spain, and the United States. Hospital spending near date of death was significantly lower for women in Canada, Germany, and the United States. The age gradient and the sex effect were less pronounced in utilization and spending of emergency care, outpatient care, and drugs.ConclusionsAcross seven countries, we find important variations in end-of-life care for patients who sustained a hip fracture, with some differences explained by sex and age. Our work sheds important insights that may help ongoing health policy discussions on equity, efficiency, and reimbursement in health care systems

Differences in health outcomes for high-need high-cost patients across high-income countries.

ObjectiveThis study explores variations in outcomes of care for two types of patient personas-an older frail person recovering from a hip fracture and a multimorbid older patient with congestive heart failure (CHF) and diabetes.Data sourcesWe used individual-level patient data from 11 health systems.Study designWe compared inpatient mortality, mortality, and readmission rates at 30, 90, and 365 days. For the hip fracture persona, we also calculated time to surgery. Outcomes were standardized by age and sex.Data collection/extraction methodsData was compiled by the International Collaborative on Costs, Outcomes and Needs in Care across 11 countries for the years 2016-2017 (or nearest): Australia, Canada, England, France, Germany, the Netherlands, New Zealand, Spain, Sweden, Switzerland, and the United States.Principal findingsThe hip sample across ranged from 1859 patients in Aragon, Spain, to 42,849 in France. Mean age ranged from 81.2 in Switzerland to 84.7 in Australia, and the majority of hip patients across countries were female. The congestive heart failure (CHF) sample ranged from 742 patients in England to 21,803 in the United States. Mean age ranged from 77.2 in the United States to 80.3 in Sweden, and the majority of CHF patients were males. Average in-hospital mortality across countries was 4.1%. for the hip persona and 6.3% for the CHF persona. At the year mark, the mean mortality across all countries was 25.3% for the hip persona and 32.7% for CHF persona. Across both patient types, England reported the highest mortality at 1 year followed by the United States. Readmission rates for all periods were higher for the CHF persona than the hip persona. At 30 days, the average readmission rate for the hip persona was 13.8% and 27.6% for the CHF persona.ConclusionAcross 11 countries, there are meaningful differences in health system outcomes for two types of patients

Differences in health care spending and utilization among older frail adults in high-income countries: ICCONIC hip fracture persona.

ObjectiveThis study explores differences in spending and utilization of health care services for an older person with frailty before and after a hip fracture.Data sourcesWe used individual-level patient data from five care settings.Study designWe compared utilization and spending of an older person aged older than 65 years for 365 days before and after a hip fracture across 11 countries and five domains of care as follows: acute hospital care, primary care, outpatient specialty care, post-acute rehabilitative care, and outpatient drugs. Utilization and spending were age and sex standardized..Data collection/extraction methodsThe data were compiled by the International Collaborative on Costs, Outcomes, and Needs in Care (ICCONIC) across 11 countries as follows: Australia, Canada, England, France, Germany, the Netherlands, New Zealand, Spain, Sweden, Switzerland, and the United States.Principal findingsThe sample ranged from 1859 patients in Spain to 42,849 in France. Mean age ranged from 81.2 in Switzerland to 84.7 in Australia. The majority of patients across countries were female. Relative to other countries, the United States had the lowest inpatient length of stay (11.3), but the highest number of days were spent in post-acute care rehab (100.7) and, on average, had more visits to specialist providers (6.8 per year) than primary care providers (4.0 per year). Across almost all sectors, the United States spent more per person than other countries per unit ($13,622 per hospitalization,$233 per primary care visit, $386 per MD specialist visit). Patients also had high expenditures in the year prior to the hip fracture, mostly concentrated in the inpatient setting.ConclusionAcross 11 high-income countries, there is substantial variation in health care spending and utilization for an older person with frailty, both before and after a hip fracture. The United States is the most expensive country due to high prices and above average utilization of post-acute rehab care

Nitric oxide production and monoamine oxidase activity in cancer patients during interferon-α therapy

Both increased and decreased nitric oxide (NO) synthesis have been reported in patients treated with interferon-α (IFN-α). Animal studies showed that IFN-α administration results in increased levels of biogenic amines, subsequent activation of monoamine oxidases (MAOs), and finally in a change in NO production due to the H2O2 generated by MAOs. We examined the potential relationship between NO production in plasma and MAO-B activity in platelets of 43 cancer patients during 8 weeks of treatment with IFN-α. NO synthesis was quantitated by measuring both the ratio of citrulline and arginine (CIT/ARG-ratio) and total nitrite/nitrate (NOx) levels. Compared to baseline, MAO activity and NOx increased, while the CIT/ARG-ratio decreased. No associations were found between NOx, MAO and CIT/ARG-ratio. Only few associations were observed between changes in the biochemical parameters and changes in psychopathology induced by IFN-α, of which the association between changes in CIT and lassitude was the most consistent. The results suggest that peripheral NO production and MAO activity are unrelated to each other, and that peripheral changes in these biochemical parameters induced by IFN-α are unlikely to contribute to definite psychiatric disturbance

A methodology for identifying high-need, high-cost patient personas for international comparisons.

ObjectiveTo establish a methodological approach to compare two high-need, high-cost (HNHC) patient personas internationally.Data sourcesLinked individual-level administrative data from the inpatient and outpatient sectors compiled by the International Collaborative on Costs, Outcomes, and Needs in Care (ICCONIC) across 11 countries: Australia, Canada, England, France, Germany, the Netherlands, New Zealand, Spain, Sweden, Switzerland, and the United States.Study designWe outline a methodological approach to identify HNHC patient types for international comparisons that reflect complex, priority populations defined by the National Academy of Medicine. We define two patient profiles using accessible patient-level datasets linked across different domains of care-hospital care, primary care, outpatient specialty care, post-acute rehabilitative care, long-term care, home-health care, and outpatient drugs. The personas include a frail older adult with a hip fracture with subsequent hip replacement and an older person with complex multimorbidity, including heart failure and diabetes. We demonstrate their comparability by examining the characteristics and clinical diagnoses captured across countries.Data collection/extraction methodsData collected by ICCONIC partners.Principal findingsAcross 11 countries, the identification of HNHC patient personas was feasible to examine variations in healthcare utilization, spending, and patient outcomes. The ability of countries to examine linked, individual-level data varied, with the Netherlands, Canada, and Germany able to comprehensively examine care across all seven domains, whereas other countries such as England, Switzerland, and New Zealand were more limited. All countries were able to identify a hip fracture persona and a heart failure persona. Patient characteristics were reassuringly similar across countries.ConclusionAlthough there are cross-country differences in the availability and structure of data sources, countries had the ability to effectively identify comparable HNHC personas for international study. This work serves as the methodological paper for six accompanying papers examining differences in spending, utilization, and outcomes for these personas across countries

Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability

Correct transcription is crucial for life. However, DNA damage severely impedes elongating RNA polymerase II, causing transcription inhibition and transcription-replication conflicts. Cells are equipped with intricate mechanisms to counteract the severe consequence of these transcription-blocking lesions. However, the exact mechanism and factors involved remain largely unknown. Here, using a genome-wide CRISPR-Cas9 screen, we identified the elongation factor ELOF1 as an important factor in the transcription stress response following DNA damage. We show that ELOF1 has an evolutionarily conserved role in transcription-coupled nucleotide excision repair (TC-NER), where it promotes recruitment of the TC-NER factors UVSSA and TFIIH to efficiently repair transcription-blocking lesions and resume transcription. Additionally, ELOF1 modulates transcription to protect cells against transcription-mediated replication stress, thereby preserving genome stability. Thus, ELOF1 protects the transcription machinery from DNA damage via two distinct mechanisms