Lewy body dementia is the second most common neurodegenerative dementia after Alzheimer's disease. Disease-modifying therapies for this disabling neuropsychiatric condition are critically needed. To ...identify drugs associated with the risk of developing Lewy body dementia, we performed a population-based case-control study of 148 170 US Medicare participants diagnosed with Lewy body dementia between 1 January 2008 and 31 December 2014 and of 1 253 043 frequency-matched controls. We estimated odds ratios and 95% confidence intervals for the association of Lewy body dementia risk with 1017 prescription drugs overall and separately for the three major racial groups (Black, Hispanic and White Americans). We identified significantly reduced Lewy body dementia risk associated with drugs used to treat cardiovascular diseases (anti-hypertensives: odds ratio = 0.72, 95% confidence interval = 0.70-0.74,
-value = 0; cholesterol-lowering agents: odds ratio = 0.85, 95% confidence interval = 0.83-0.87,
-value = 0; anti-diabetics: odds ratio = 0.83, 95% confidence interval = 0.62-0.72,
-value = 0). Notably, anti-diabetic medications were associated with a larger risk reduction among Black Lewy body dementia patients compared with other racial groups (Black: odds ratio = 0.67, 95% confidence interval = 0.62-0.72,
-value = 0; Hispanic: odds ratio = 0.86, 95% = 0.80-0.92,
-value = 5.16 × 10
; White: odds ratio = 0.85, 95% confidence interval = 0.82-0.88,
-value = 0). To independently confirm the epidemiological findings, we looked for evidence of genetic overlap between Lewy body dementia and cardiovascular traits using whole-genome sequence data generated for 2591 Lewy body dementia patients and 4027 controls. Bivariate mixed modelling identified shared genetic risk between Lewy body dementia and low-density lipoprotein cholesterol levels, Type 2 diabetes and hypertension. By combining epidemiological and genomic data, we demonstrated that drugs treating cardiovascular diseases are associated with reduced Lewy body dementia risk, and these associations varied across racial groups. Future randomized clinical trials need to confirm our findings, but our data suggest that assiduous management of cardiovascular diseases may be beneficial in this understudied form of dementia.
Background
In April 2007, the National Quality Forum (NQF) endorsed the first nationally recognized hospital-based performance measures for stage I, II, and III breast cancer. The purpose of this ...study was to document compliance with the 3 NQF breast quality indicators during 2 time intervals in a metropolitan public hospital.
Materials and Methods
Tumor registry and medical records were used to identify patient demographics and treatments before (2005–2006) and after (2008) implementations in 2007 as a result of the NQF audit. Program changes included: hiring a dedicated medical oncology nurse practitioner, requiring the radiation oncology case manager to attend weekly multidisciplinary conferences, educating Patient Navigators of the importance of multimodal care, and providing support groups for patients addressing importance of completion of all treatment options.
Results
A total of 213 female patients were diagnosed with and treated for stage I, II, or III breast cancer in 2005–2006 and 2008. Of these, 189 (89%) were African American (AA) women. Also, 70 patients of 86 (81.3%) received radiation therapy, 60 of 77 (77.9%) received or were considered for adjuvant chemotherapy, and 124 of 144 (86.1%) for hormonal therapy according to NQF indicators. After 2007, patients receiving radiation therapy increased from 75.8 to 95.8%. Patients receiving or considered for adjuvant chemotherapy or hormonal therapy increased from 73.7 to 93.7% and from 84.1 to 90.0%, respectively.
Conclusions
NQF breast cancer indicators provided a mechanism to improve compliance of multimodal treatment in our center. Raising awareness of these indicators in the multidisciplinary conference, hiring dedicated personnel, and educating patients has led to major improvements in breast cancer care.
We have investigated the expression and regulatory properties of the two alternative oxidase (Aox) proteins that are expressed in tomato (
Lycopersicon esculentum L. Mill cv. Sweetie) after storage ...of green fruit at 4 °C. Four
Aox genes were identified in the tomato genome, of which two (
LeAox1a and
LeAox1b) were demonstrated to be expressed in cold-treated fruit. The activity and regulatory properties of LeAox1a and LeAox1b were assayed after expression of each protein in yeast cells (
Saccharomyces cerevisiae), proving that each is an active Aox protein. The LeAox1b protein was shown to have altered regulatory properties due to the substitution of a Ser for the highly conserved Cys
I residue. LeAox1b could not form inactive disulfide-linked dimers and was activated by succinate instead of pyruvate. This is the first example of a dicot species expressing a natural Cys
I/Ser isoform. The implications of the existence and expression of such Aox isoforms is discussed in the light of the hypothesised role for Aox in plant metabolism.
Abstract
Polygenic risk scores aggregate an individual’s burden of risk alleles to estimate the overall genetic risk for a specific trait or disease. Polygenic risk scores derived from genome-wide ...association studies of European populations perform poorly for other ancestral groups. Given the potential for future clinical utility, underperformance of polygenic risk scores in South Asian populations has the potential to reinforce health inequalities. To determine whether European-derived polygenic risk scores underperform at multiple sclerosis prediction in a South Asian-ancestry population compared with a European-ancestry cohort, we used data from two longitudinal genetic cohort studies: Genes & Health (2015–present), a study of ∼50 000 British–Bangladeshi and British–Pakistani individuals, and UK Biobank (2006–present), which is comprised of ∼500 000 predominantly White British individuals. We compared individuals with and without multiple sclerosis in both studies (Genes & Health: NCases = 42, NControl = 40 490; UK Biobank: NCases = 2091, NControl = 374 866). Polygenic risk scores were calculated using clumping and thresholding with risk allele effect sizes obtained from the largest multiple sclerosis genome-wide association study to date. Scores were calculated with and without the major histocompatibility complex region, the most influential locus in determining multiple sclerosis risk. Polygenic risk score prediction was evaluated using Nagelkerke’s pseudo-R2 metric adjusted for case ascertainment, age, sex and the first four genetic principal components. We found that, as expected, European-derived polygenic risk scores perform poorly in the Genes & Health cohort, explaining 1.1% (including the major histocompatibility complex) and 1.5% (excluding the major histocompatibility complex) of disease risk. In contrast, multiple sclerosis polygenic risk scores explained 4.8% (including the major histocompatibility complex) and 2.8% (excluding the major histocompatibility complex) of disease risk in European-ancestry UK Biobank participants. These findings suggest that polygenic risk score prediction of multiple sclerosis based on European genome-wide association study results is less accurate in a South Asian population. Genetic studies of ancestrally diverse populations are required to ensure that polygenic risk scores can be useful across ancestries.
Breedon et al. report that polygenic risk scores for multiple sclerosis derived from the European-ancestry genetic studies underperform in a South Asian-ancestry population. Their results stress the need for ancestrally diverse genetic studies of multiple sclerosis risk to ensure the generalizability of polygenic risk scores.
Graphical Abstract
Graphical abstract
Video Abstract
10.1093/braincomms/fcad041_video1
Video Abstract
fcad041media1
6322542771112
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