Branched chain amino acids harbor distinct and often opposing effects on health and disease.

BACKGROUND: The branched chain amino acids (BCAA) leucine, isoleucine, and valine are essential nutrients that have been associated with diabetes, cancers, and cardiovascular diseases. Observational studies suggest that BCAAs exert homogeneous phenotypic effects, but these findings are inconsistent with results from experimental human and animal studies. METHODS: Hypothesizing that inconsistencies between observational and experimental BCAA studies reflect bias from shared lifestyle and genetic factors in observational studies, we used data from the UK Biobank and applied multivariable Mendelian randomization causal inference methods designed to address these biases. RESULTS: In n = 97,469 participants of European ancestry (mean age = 56.7 years; 54.1% female), we estimate distinct and often opposing total causal effects for each BCAA. For example, of the 117 phenotypes with evidence of a statistically significant total causal effect for at least one BCAA, almost half (44%, n = 52) are associated with only one BCAA. These 52 associations include total causal effects of valine on diabetic eye disease [odds ratio = 1.51, 95% confidence interval (CI) = 1.31, 1.76], valine on albuminuria (odds ratio = 1.14, 95% CI = 1.08, 1.20), and isoleucine on angina (odds ratio = 1.17, 95% CI = 1.31, 1.76). CONCLUSIONS: Our results suggest that the observational literature provides a flawed picture of BCAA phenotypic effects that is inconsistent with experimental studies and could mislead efforts developing novel therapeutics. More broadly, these findings motivate the development and application of causal inference approaches that enable 'omics studies conducted in observational settings to account for the biasing effects of shared genetic and lifestyle factors.

The three branched chain amino acids (BCAAs) leucine, isoleucine, and valine are important building blocks of muscle proteins that are obtained from the diet. Many studies in human populations have examined whether BCAAs affect health and disease. These human studies report results that are inconsistent with results from highly controlled animal studies. Because interest in the therapeutic targeting of BCAAs is growing, we wanted to better understand these discrepancies. Briefly, we used data from a large database that captured many diseases (e.g., cardiovascular disease, cancers, and respiratory disease) and new statistical methods. Our results showed that discrepancies between human studies and animal studies may reflect errors in the ways human studies were designed and conducted. As a result, these human studies may provide a flawed picture of BCAA effects that could mislead efforts developing novel therapeutics.

Sleep disturbances among cancer survivors.

PURPOSE: We investigated sleep disturbances among cancer survivors compared to similarly aged women without cancer history. METHODS: We identified 2067 women with a history of cancer other than breast or non-melanoma skin cancer at enrollment in the Sister Study, a US-wide cohort of women with a family history of breast cancer. Cancer survivors were matched with up to 5 cancer-free women (N = 9717) on age at enrollment. An index age (for covariate classification) was defined as the age at cancer diagnosis for survivors and the same age for their matched comparators. Sleep disturbances included duration, sleep medication usage, insomnia symptoms, long sleep-latency onset (≥30 min to fall asleep), frequent night awakenings (waking ≥3/night, ≥ 3 times/week), frequent napping (≥ 3 times/week), and a composite outcome of ≥ 1sleep disturbance. Multivariable linear regression (effect estimate, 95% confidence interval (CI)) and logistic regression (odds ratio, OR, 95% CI) were used for continuous and dichotomous outcomes, respectively. RESULTS: At enrollment, cancer survivors were on average 13.8 years (range=0, 62) from diagnosis. After adjustment for age at enrollment and depression, diabetes, hypertension, and menopausal status prior to the index age, sleep disturbances were generally not more common among cancer survivors compared to those without cancer. However, among cancer survivors, those > 2 years from diagnosis were more likely to report ≥ 1 sleep disturbance (OR=1.44; 1.07, 1.93) compared to survivors 0-2 years from diagnosis. CONCLUSION: Addressing sleep disturbances may improve well-being for cancer survivors.

Ancestral diversity in lipoprotein(a) studies helps address evidence gaps.

INTRODUCTION: The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations. METHODS: Here, we examined how ancestrally diverse studies could clarify Lp(a)'s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations. RESULTS: Fourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R2=15% in East Asians) to high (R2=50% in Europeans) accuracy. For all populations, PRS showed promise as a 'rule out' for elevated Lp(a) because certainty of assignment to the low-risk threshold was high (88.0%-99.9%) across PRS thresholds (80th-99th percentile). Causal effects of increased Lp(a) with increased glycated haemoglobin were estimated for Europeans (p value =1.4×10-6), although inverse effects in Africans and East Asians suggested the potential for heterogeneous causal effects. Finally, Hispanic/Latinos were the only population in which known associations with coronary atherosclerosis and ischaemic heart disease were identified in external testing of Lp(a) PRS phenotypic effects. CONCLUSIONS: Our results emphasise the merits of prioritising ancestral diversity when addressing Lp(a) evidence gaps.

Hypertensive conditions of pregnancy, preterm birth, and premenopausal breast cancer risk: a premenopausal breast cancer collaborative group analysis.

PURPOSE: Women with preeclampsia are more likely to deliver preterm. Reports of inverse associations between preeclampsia and breast cancer risk, and positive associations between preterm birth and breast cancer risk are difficult to reconcile. We investigated the co-occurrence of preeclampsia/gestational hypertension with preterm birth and breast cancer risk using data from the Premenopausal Breast Cancer Collaborative Group. METHODS: Across 6 cohorts, 3096 premenopausal breast cancers were diagnosed among 184,866 parous women. We estimated multivariable hazard ratios (HR) and 95% confidence intervals (CI) for premenopausal breast cancer risk using Cox proportional hazards regression. RESULTS: Overall, preterm birth was not associated (HR 1.02, 95% CI 0.92, 1.14), and preeclampsia was inversely associated (HR 0.86, 95% CI 0.76, 0.99), with premenopausal breast cancer risk. In stratified analyses using data from 3 cohorts, preterm birth associations with breast cancer risk were modified by hypertensive conditions in first pregnancies (P-interaction = 0.09). Preterm birth was positively associated with premenopausal breast cancer in strata of women with preeclampsia or gestational hypertension (HR 1.52, 95% CI: 1.06, 2.18), but not among women with normotensive pregnancy (HR = 1.09, 95% CI: 0.93, 1.28). When stratified by preterm birth, the inverse association with preeclampsia was more apparent, but not statistically different (P-interaction = 0.2), among women who did not deliver preterm (HR = 0.82, 95% CI 0.68, 1.00) than those who did (HR = 1.07, 95% CI 0.73, 1.56). CONCLUSION: Findings support an overall inverse association of preeclampsia history with premenopausal breast cancer risk. Estimates for preterm birth and breast cancer may vary according to other conditions of pregnancy.

Residential ultraviolet radiation and breast cancer risk in a large prospective cohort.

BACKGROUND: Ambient ultraviolet (UV) radiation has been increasing due to climate change. While this may result in adverse health consequences such as an increased incidence of skin cancer, UV radiation is also a source of vitamin D, which has been hypothesized to be protective for breast cancer risk. METHODS: Using a spatiotemporal kriging model, we estimated residential UV exposure levels for the enrollment addresses (2003-2009) of breast cancer-free women aged 35-74 years participating in the Sister Study and living in the contiguous United States (N = 48,450). Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the risk associated with UV exposure levels (mW/m2) categorized in quintiles. We examined the association for breast cancer overall (invasive and ductal carcinoma in situ) and by estrogen receptor (ER) status of the tumor. We considered effect modification by regular (≥4 times/week) vitamin D supplement use. RESULTS: Over a median of 10.5 years of follow up, 3,510 incident breast cancer diagnoses were reported. We found no evidence of an association between living in areas with higher levels of UV radiation and overall breast cancer risk (HRQ5 vs. Q1 = 1.00, 95% CI: 0.90, 1.11). Higher UV levels were inversely associated with the risk of ER- breast cancer (HRQ5 vs. Q1 = 0.73, 95% CI: 0.55-0.99), but not ER+ (HR Q5 vs. Q1 = 1.04, 95% CI: 0.92-1.18). For ER- breast cancer, the inverse association was only evident in women who did not regularly take vitamin D supplements (HRQ5 vs. Q1 = 0.52, 95% CI: 0.33-0.81) compared with those who did regularly take vitamin D supplements (HRQ5 vs. Q1 = 1.02, 95% CI: 0.68-1.54; p-for-heterogeneity = 0.12). CONCLUSIONS: The findings from this study support a role for UV exposure and vitamin D in the etiology of ER- breast cancer.

HER2 Testing Characteristics Can Predict Residual Cancer Burden following Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer.

OBJECTIVES: The response to HER2-targeted neoadjuvant chemotherapy (NAC) in HER2-positive (+) breast cancer can be quantified using residual cancer burden (RCB) pathologic evaluation to predict relapse free/overall survival. However, more information is needed to characterize the relationship between patterns of HER2 testing results and response to NAC. We evaluated clinicopathologic characteristics associated with RCB categories in HER2+ patients who underwent HER2-directed NAC. METHODS: A retrospective chart review was conducted with Stage I-III HER2+ breast cancer cases following NAC and surgical resection. HER2 immunohistochemistry (IHC) staining and fluorescence in situ hybridization (FISH), histologic/clinical characteristics, hormone receptor status, and RCB scores (RCB-0, RCB-I, RCB-II, and RCB-III) were evaluated. RESULTS: 64/151 (42.4%) patients with HER2+ disease had pathologic complete response (pCR). Tumors with suboptimal response (RCB-II and RCB-III) were more likely to demonstrate less than 100% HER2 IHC 3+ staining (p < 0.0001), lower HER2 FISH copies (p < 0.0001), and lower HER2/CEP17 ratios (p = 0.0015) compared to RCB-I and RCB-II responses. Estrogen receptor classification using ≥10% versus ≥1% staining showed greater association with higher RCB categories. CONCLUSIONS: HER2+ characteristics show differing response to therapy despite all being categorized as positive; tumors with less than 100% IHC 3+ staining, lower HER2 FISH copies, and lower HER2/CEP17 ratios resulted in higher RCB scores.

Disparities in Awareness of Hepatitis C Virus Among US Adults: An Analysis of the 2019 Health Information National Trends Survey.

BACKGROUND: The U.S. Preventive Services Task Force updated hepatitis C virus (HCV) screening 2020 guidelines to target adults aged 18 to 79 years: a major shift from the prior focus on high-risk populations ("baby boomers" aged ≥55 years as of 2019). To inform efforts to maximize HCV screening coverage, our objective was to identify demographic groups reporting a lack of HCV awareness, particularly by race/ethnicity and age, and sources of health information. METHODS: We used nationally representative data of adults (≥18 years) included in the 2019 Health Information National Trends Survey (n = 5438). Awareness of HCV was defined using the following question: "Have you ever heard of the hepatitis C virus (also known as Hep C or HCV)?" We estimated frequencies by demographic groups and computed risk differences (RDs) with 95% confidence intervals (CIs) to compare lack of HCV awareness by age (<55 and ≥55 years) and race/ethnicity. RESULTS: Overall, 17% of adults never heard of HCV. Younger adults (<55 years; 21%) were more likely to have never heard of HCV compared with older adults (≥55 years; 12%; χ2P < 0.001). This observation was consistent across most demographic characteristics including, racial/ethnic categories, and residing in the Southern United States. More than one-third of adults with low English fluency had a lack of HCV awareness in both age groups (χ2P = 0.537). Non-Hispanic (NH) Asian (RD, 25%; 95% CI, 6.9%-43.3%) and Hispanic (RD, 10%; 95% CI, 0.01%-19.6%) adults younger than 55 years were significantly more likely to have never heard of HCV compared with their NH White counterparts after adjustment for sex, educational level, household income, English fluency, and having a regular provider. Adults younger than 55 years with a lack of HCV awareness commonly obtained their health information from the Internet across most sociodemographic characteristics. CONCLUSIONS: Hispanic and NH Asian young adults should be targeted for public health messaging regarding HCV screening, potentially through social media campaigns.

Risk factors for de novo and therapy-related myelodysplastic syndromes (MDS).

PURPOSE: Myelodysplastic syndromes (MDS) are classified as de novo and therapy-related (tMDS). We evaluated associations between MDS risk factors separately for de novo and tMDS. METHODS: The study population included 346 de novo MDS cases, 37 tMDS cases and 682 population controls frequency matched by age and sex. Polytomous logistic regression was performed to calculate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: After adjustment, former smoking status (OR = 1.45, 95% CI: 1.10-1.93), personal history of autoimmune disease (OR = 1.34, 95% CI: 0.99-1.82) and exposure to benzene (OR = 1.48, 95% CI: 1.00-2.19) were associated with de novo MDS. Risk estimates for the associations between smoking, autoimmune disease, and benzene exposure were similar in magnitude but non-significant in tMDS cases. Among individuals with a previous diagnosis of cancer, de novo MDS cases and controls were more likely to have had a previous solid tumor, while tMDS cases more commonly had a previous hematologic malignancy. CONCLUSIONS: We observed similar associations between smoking, history of autoimmune disease and benzene exposure in de novo and tMDS although estimates for tMDS were imprecise due to small sample sizes. Future analyses with larger sample sizes will be required to confirm whether environmental factors influence risk of tMDS.