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Background: Type 2 diabetes (T2D) has been associated with increased risk of breast cancer. However, the role of metformin, the first-line anti-diabetic drug, in breast cancer carcinogenesis has not been elucidated completely. We aimed to examine further the association between the use of metformin and other anti-diabetic medication and breast cancer incidence within two large prospective cohort studies. Methods: We followed 184,437 women who participated in the Nurses’ Health Study (NHS;1994-2016) and the NHSII (1995-2017), with the baseline tied to the date metformin was introduced into the United States market. Information on T2D diagnosis, metformin, and other anti-diabetic medication, and other covariates were self-reported at baseline and repeatedly assessed by follow-up questionnaires every two to four years. Breast cancer cases were self-reported and confirmed by medical record review. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between metformin/other anti-diabetic medication use and breast cancer incidence were estimated using Cox proportional hazards regression models. Results: During 3,412,366 person-years of follow-up, we ascertained 9,442 incident invasive breast cancer cases, of which 720 were among women with T2D. Compared with women without T2D (n=168,498), similar risks of developing breast cancer were observed among those who ever used metformin (HR =0.95; 95%CI=0.79-1.13) and among those who received medications other than metformin (HR =1.11; 95%CI=0.91-1.37). Among women with T2D (n=15,939), compared with never metformin users, ever use of metformin overall was not associated with breast cancer (HR =0.90; 95%CI=0.72-1.13), but a lower risk of breast cancer was observed among past metformin users (HR =0.72; 95%CI=0.52-0.99). Longer duration of metformin use was not associated with risk of breast cancer (each 2-year interval: HR =0.98; 95%CI=0.93-1.03, p-trend=0.32). However, among women with substantial weight increase since age 18 (>25 kg), greater than 5 years of metformin use was associated with a lower risk of breast cancer (HR =0.62; 95%CI=0.43-0.89). Conclusion: Although we observed inverse associations among past metformin users, similar associations were not found among current users. Overall, metformin use was not strongly associated with the risk of developing breast cancer among the general cohort population or among women with T2D. Citation Format: Tengteng Wang, Jae H. Kang, Boyang Chai, Wendy Y. Chen, Michelle D. Holmes, Jennifer Erdrich, Edward L. Giovannucci, Frank B. Hu, Bernard A. Rosner, Rulla M. Tamimi, Walter C. Willett, A. Heather Eliassen. Metformin and other anti-diabetic medication use and breast cancer incidence in the Nurses’ Health Studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5902.

Background Branched chain amino acids (BCAAs) are essential amino acids common throughout the US diet. Although circulating BCAAs have been implicated in insulin resistance and some obesity-related cancers, the relationship between dietary intake of BCAAs and incident breast cancer is unknown. We sought to evaluate the association between long-term dietary intakes of BCAAs and invasive breast cancer risk. Methods Our analyses included 196 161 women from the Nurses’ Health Study and Nurses’ Health Study II longitudinal cohorts. Average intakes of total and individual BCAAs (isoleucine, leucine, valine) were estimated from repeated diet questionnaires and incident self-reported breast cancer cases were confirmed via medical record review. Cox proportional hazards models, adjusted for reproductive history, lifestyle, body mass index, and other breast cancer risk factors, were used to estimate hazard ratios and 95% confidence intervals. Results We observed 10 046 incident cases of breast cancer over a median of 20.8 years of follow-up. No associations between dietary intakes of total or individual BCAAs with breast cancer risk were observed. Compared with women in the bottom quintile of BCAA intake, the hazard ratio of breast cancer for those in the top quintile was 1.05 (95% confidence interval = 0.98 to 1.12; 2-sided Ptrend = .20). Findings were consistent across molecular subtypes and according to type 2 diabetes diagnosis and body mass index categories. Conclusions Dietary intakes of BCAAs are not likely a risk factor for breast cancer.

Rationale & Objective Among individuals with chronic kidney disease (CKD), poor self-reported health is associated with adverse outcomes including hospitalization and death. We sought to examine the association between health-related quality-of-life (HRQoL) and depressive symptoms in advanced CKD and subsequent access to the kidney transplant waiting list. Study Design Prospective cohort study. Setting & Population 1,676 Chronic Renal Insufficiency Cohort (CRIC) study participants with estimated glomerular filtration rates ≤ 30 mL/min/1.73 m2 at study entry or during follow-up. Exposures HRQoL ascertained by 5 scales of the Kidney Disease Quality of Life-36 Survey (Physical Component Summary [PCS], Mental Component Summary, Symptoms, Burdens, and Effects), with higher scores indicating better HRQoL, and depressive symptoms ascertained using the Beck Depression Inventory. Outcomes Time to kidney transplant wait-listing and time to pre-emptive wait-listing. Analytic Approach Time-to-event analysis using Cox proportional hazards regression. Results During a median follow-up of 5.1 years, 652 (39%) participants were wait-listed, of whom 304 were preemptively wait-listed. Adjusted for demographics, comorbid conditions, estimated glomerular filtration rate slope, and cognitive function, participants with the highest scores on the Burden and Effects scales, respectively, had lower rates of wait-listing than those with the lowest scores on the Burden (wait-listing adjusted hazard ratio [aHR], 0.70; 95% CI, 0.57-0.85; P, Visual abstract

IntroductionRetention on antiretroviral therapy (ART) is critical for the successful adoption of the test and treat policy by sub‐Saharan African countries, and for realizing the United Nations programme on HIV and AIDS target of 90‐90‐90. This qualitative study explores HIV positive clients’ reasons for discontinuing ART under the Max ART test and treat implementation study in Swaziland.MethodsClients identified as lost to follow‐up (LTFU) in the programme database, who had initiated ART under the intervention arm of the Max ART study, were purposively selected from two facilities. LTFU was defined as stopping ART refill for three months or longer from the date of last appointment, and not being classified as transferred out or deceased. Semi‐structured face‐to‐face interviews were conducted with nine clients and one treatment supporter between July and August 2017. All interviews were conducted in the local language, audio‐recorded, summarized or transcribed and translated to English for thematic analysis.ResultsRespondents described mobility as the first step in a chain of events that affected retention in care. It was entwined with precarious employment, care delivery, interactions with health workers, lack of social support, anticipated stigma and ART‐related side‐effects, including the exacerbation of hunger. The chains of events involved several intersecting reasons that occurred one after the other as a series of contiguous and linked events that led to clients’ eventual discontinuation of ART. The individual accounts of step‐by‐step decision‐making revealed the influence of multi‐layered contexts and the importance of critical life‐events.ConclusionsClients’ reasons for abandoning ART are a complex, inextricably interwoven chain of events rather than a single occurrence. Mobility is often the first step in the process and commonly results from precarious economic and social circumstances. Currently the health system poorly caters to the reality of people's mobile lives. Interventions should seek to increase healthcare workers’ understanding of the chain of events leading up to discontinuation on ART and the social dilemmas that clients face.

The roles of specific fatty acids in breast cancer etiology are unclear, particularly among premenopausal women. We examined 34 individual fatty acids, measured in blood erythrocytes collected between 1996-1999, and breast cancer risk in a nested case-control study of primarily premenopausal women in the Nurses' Health Study II. Breast cancer cases diagnosed after blood collection and before June 2010 (n=794) were matched to controls and conditional logistic regression was used to estimate OR's (95% CI's) for associations of fatty acids with breast cancer; unconditional logistic regression was used for stratified analyses. Fatty acids were not significantly associated with breast cancer risk overall; however, heterogeneity by body mass index (BMI) was observed. Among overweight/obese women (BMI≥25), several odd-chain saturated (SFA, e.g. 17:0, ORQ4vsQ1(95%CI) =1.85 (1.18-2.88), ptrend=0.006 pint

Background Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD. Study Design Cross-sectional and longitudinal observational analysis. Setting & Participants Adults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. Predictor Quartiles of plasma CX3CL1 levels at baseline. Outcomes Baseline estimated glomerular filtration rate from a creatinine and cystatin C–based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A 1c level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality. Results Among 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P =0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P P =0.02) and the composite outcome (1.09; 95% CI, 1.00-1.19; P =0.04). Limitations Study design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect. Conclusions Circulating CX3CL1 level may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX3CL1 affects the pathogenesis of atherosclerosis and diabetes.

Elevated fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease. As a potential mediating mechanism, FGF23 induces left ventricular hypertrophy; however, its role in arterial calcification is less clear. In order to study this, we quantified coronary artery and thoracic aorta calcium by computed tomography in 1501 patients from the Chronic Renal Insufficiency Cohort (CRIC) study within a median of 376 days (interquartile range 331–420 days) of baseline. Baseline plasma FGF23 was not associated with the prevalence or severity of coronary artery calcium after multivariable adjustment. In contrast, higher serum phosphate levels were associated with prevalence and severity of coronary artery calcium, even after adjustment for FGF23. Neither FGF23 nor serum phosphate were consistently associated with thoracic aorta calcium. We could not detect mRNA expression of FGF23 or its coreceptor, klotho, in human or mouse vascular smooth muscle cells, or normal or calcified mouse aorta. Whereas elevated phosphate concentrations induced calcification in vitro , FGF23 had no effect on phosphate uptake or phosphate-induced calcification regardless of phosphate concentration or even in the presence of soluble klotho. Thus, in contrast to serum phosphate, FGF23 is not associated with arterial calcification and does not promote calcification experimentally. Hence, phosphate and FGF23 promote cardiovascular disease through distinct mechanisms.

Background It is not clear whether the pattern of kidney function decline in patients with chronic kidney disease (CKD) may relate to outcomes after reaching end-stage renal disease (ESRD). We hypothesize that an abrupt decline in kidney function prior to ESRD predicts early death after initiating maintenance hemodialysis therapy. Study Design Prospective cohort study. Setting & Participants The Chronic Renal Insufficiency Cohort (CRIC) Study enrolled men and women with mild to moderate CKD. For this study, we studied 661 individuals who developed chronic kidney failure that required hemodialysis therapy initiation. Predictors The primary predictor was the presence of an abrupt decline in kidney function prior to ESRD. We incorporated annual estimated glomerular filtration rates (eGFRs) into a mixed-effects model to estimate patient-specific eGFRs at 3 months prior to initiation of hemodialysis therapy. Abrupt decline was defined as having an extrapolated eGFR≥30mL/min/1.73m 2 at that time point. Outcomes All-cause mortality within 1 year after initiating hemodialysis therapy. Measurements Multivariable Cox proportional hazards. Results Among 661 patients with CKD initiating hemodialysis therapy, 56 (8.5%) had an abrupt predialysis decline in kidney function and 69 died within 1 year after initiating hemodialysis therapy. After adjustment for demographics, cardiovascular disease, diabetes, and cancer, abrupt decline in kidney function was associated with a 3-fold higher risk for death within the first year of ESRD (adjusted HR, 3.09; 95% CI, 1.65-5.76). Limitations Relatively small number of outcomes; infrequent (yearly) eGFR determinations; lack of more granular clinical data. Conclusions Abrupt decline in kidney function prior to ESRD occurred in a significant minority of incident hemodialysis patients and predicted early death in ESRD.

Although subjects with chronic kidney disease (CKD) are at markedly increased risk for cardiovascular mortality, the relationship between CKD and aortic valve calcification has not been fully elucidated. Also, few data are available on the relationship of aortic valve calcification and earlier stages of CKD. We sought to assess the relationship of aortic valve calcium (AVC) with estimated glomerular filtration rate (eGFR), traditional and novel cardiovascular risk factors, and markers of bone metabolism in the Chronic Renal Insufficiency Cohort (CRIC) Study. All patients who underwent aortic valve scanning in the CRIC study were included. The relationship between AVC and eGFR, traditional and novel cardiovascular risk factors, and markers of calcium metabolism were analyzed using both unadjusted and adjusted regression models. A total of 1964 CRIC participants underwent computed tomography for AVC quantification. Decreased renal function was independently associated with increased levels of AVC (eGFR 47.11 ml/min/1.73m2, 44.17 ml/min/1.73m2, and 39 ml/min/1.73m2, respectively, p< 0.001). This association persisted after adjusting for traditional, but not novel, AVC risk factors. Adjusted regression models identified several traditional and novel risk factors for AVC in patients with CKD. There was a difference in AVC risk factors between black and non-black patients. In conclusion, our study shows that eGFR is associated in a dose-dependent manner with AVC in patients with CKD, and this association is independent of traditional cardiovascular risk factors.

Brachial pulse pressure (bPP) predicts kidney function in CKD. Pulse wave velocity (PWV) may provide additional prediction of CKD progression, and was evaluated longitudinally in CKD patients enrolled in the CRIC cohort. bPP was used because it shows superior CKD progression prediction in humans. There were 2821 participants in CRIC who underwent an assessment of PWV most of whom were studied at their second year follow-up visit. Of these 43 % were women, 48% diabetic, mean age 60 years and mean estimated GFR of 44.6 mL/min/1.73m2. Blacks were 40%, whites 44%, and Hispanics 12%. Mean blood pressure was 127/70 mmHg; mean bPP was 54 mmHg. The interaction of PWV with bPP on the occurrence of ESRD (dialysis or a transplant) [left panel of figure] and a combined endpoint of halving of the eGFR or ESRD [right panel], was analyzed used Cox regression. Events by tertiles of PWV (10.3m/sec) and bPP (62 mmHg) are shown in the figure. There were significant interactions between PWV and bPP for both outcomes. For ESRD the hazard ratio of the highest tertiles of PWV/bPP compared with the lowest was 3.18 (p

Table S1. Multivariate-adjusteda hazard ratios (HRs) and 95% confidence intervals for breast cancer by ER/PR status in relation to parity and lactation: Nurses’ Health Study (1976–2012) and Nurses’ Health Study II (1989–2013). Table S2. Multivariate-adjusteda hazard ratios (HRs) and 95% confidence intervals for breast cancer by ER status in relation to parity and lactation, stratified by time since last birth: Nurses’ Health Study (1976–2012) and Nurses’ Health Study II (1989–2013) (DOCX 30 kb)

Table S1. Multivariate-adjusteda hazard ratios (HRs) and 95% confidence intervals for breast cancer by ER/PR status in relation to parity and lactation: Nurses’ Health Study (1976–2012) and Nurses’ Health Study II (1989–2013). Table S2. Multivariate-adjusteda hazard ratios (HRs) and 95% confidence intervals for breast cancer by ER status in relation to parity and lactation, stratified by time since last birth: Nurses’ Health Study (1976–2012) and Nurses’ Health Study II (1989–2013) (DOCX 30 kb)