Metformin and other anti-diabetic medication use and breast cancer incidence in the Nurses' Health Studies.

We aimed to examine the association between the use of metformin and other anti-diabetic medications and breast cancer incidence within two large prospective cohort studies. We followed 185,181 women who participated in the Nurses' Health Study (NHS; 1994-2016) and the NHSII (1995-2017), with baseline corresponding to the date metformin was approved for type 2 diabetes (T2D) treatment in the US Information on T2D diagnosis, anti-diabetes medications, and other covariates was self-reported at baseline and repeatedly assessed by follow-up questionnaires every 2 years. Breast cancer cases were self-reported and confirmed by medical record review. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between medication use and breast cancer were estimated using Cox proportional hazards regression models, adjusting for breast cancer risk factors. During 3,324,881 person-years of follow-up, we ascertained 9,192 incident invasive breast cancer cases, of which 451 were among women with T2D. Compared with women without T2D (n = 169,263), neither metformin use (HR = 0.97; 95% CI = 0.81-1.15) nor other anti-diabetic medications use (HR = 1.11; 95% CI = 0.90-1.36) associated with significantly lower breast cancer incidence. Among women with T2D (n = 15,918), compared with metformin never users, metformin ever use was not significantly inversely associated with breast cancer (HR = 0.92; 95% CI = 0.74-1.15). Although we observed that past use of metformin was inversely associated with breast cancer in the T2D population (HR = 0.67; 95% CI = 0.48-0.94), current use (HR = 1.01; 95% CI = 0.80-1.27) and longer duration of metformin use were not associated with breast cancer (each 2-year interval: HR = 1.01; 95% CI = 0.95-1.07). Overall, metformin use was not associated with the risk of developing breast cancer among the overall cohort population or among women with T2D.

Parity, breastfeeding, and breast cancer risk by hormone receptor status and molecular phenotype: results from the Nurses' Health Studies.

BACKGROUND: Epidemiologic data suggest that parity increases risk of hormone receptor-negative breast cancer and that breastfeeding attenuates this association. Prospective data, particularly on the joint effects of higher parity and breastfeeding, are limited. METHODS: We investigated parity, breastfeeding, and breast cancer risk by hormone-receptor (estrogen (ER) and progesterone receptor (PR)) and molecular subtypes (luminal A, luminal B, HER2-enriched, and basal-like) in the Nurses' Health Study (NHS; 1976-2012) and NHSII (1989-2013). A total of 12,452 (ER+ n = 8235; ER- n = 1978) breast cancers were diagnosed among 199,514 women. We used Cox proportional hazards models, adjusted for breast cancer risk factors, to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Parous women had lower risk of ER+ breast cancer (vs. nulliparous, HR = 0.82 [0.77-0.88]); no association was observed for ER- disease (0.98 [0.84-1.13]; Phet = 0.03). Among parous women, breastfeeding was associated with lower risk of ER- (vs. never 0.82 [0.74-0.91]), but not ER+, disease (0.99 [0.94-1.05]; Phet < 0.001). Compared to nulliparous women, higher parity was inversely associated with luminal B breast cancer regardless of breastfeeding (≥ 3 children: ever breastfed, 0.78 [0.62-0.98]; never breastfed, 0.76 [0.58-1.00]) and luminal A disease only among women who had breastfed (≥ 3 children, 0.84 [0.71-0.99]). Basal-like breast cancer risk was suggestively higher among women with higher parity who never breastfed; associations were null among those who ever breastfed. CONCLUSIONS: This study provides evidence that breastfeeding is inversely associated with hormone receptor-negative breast cancers, representing an accessible and cost-effective risk-reduction strategy for aggressive disease subtypes.

Erythrocyte membrane fatty acids and breast cancer risk: a prospective analysis in the nurses' health study II.

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 and 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 <0.001), trans (TFA, e.g. 18:1, ORQ4vsQ1 (95% CI) =2.33 (1.45-3.77), ptrend <0.001, pint =0.007) and dairy-derived fatty acids (SFA 15:0 + 17:0 + TFA 16:1n-7t; ORQ4vsQ1 (95% CI) =1.83(1.16-2.89), ptrend =0.005, pint <0.001) were positively associated, and n-3 polyunsaturated fatty acids (n-3 PUFA, e.g. alpha-linolenic acid; ORQ4vsQ1 (95% CI) =0.57 (0.36-0.89), ptrend =0.017, pint =0.03) were inversely associated with breast cancer. Total SFA were inversely associated with breast cancer among women with BMI < 25 (ORQ4vsQ1 (95% CI) =0.68 (0.46-0.98), ptrend =0.05, pint =0.01). Thus, while specific fatty acids were not associated with breast cancer overall, our findings suggest positive associations of several SFA, TFA and dairy-derived fatty acids and inverse associations of n-3 PUFA with breast cancer among overweight/obese women. Given these fatty acids are influenced by diet, and therefore are potentially modifiable, further investigation of these associations among overweight/obese women is warranted.

Abrupt Decline in Kidney Function Before Initiating Hemodialysis and All-Cause Mortality: The Chronic Renal Insufficiency Cohort (CRIC) Study.

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.

Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

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 A1c 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<0.001) in adjusted models. During a mean follow-up of 6 years, there were 352 deaths, 176 myocardial infarctions, and 484 composite outcomes. In fully adjusted models, 1-SD higher CX3CL1 level increased the hazard for all-cause mortality (1.11; 95% CI, 1.00-1.22; 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.

Planetary Health Diet Index and risk of total and cause-specific mortality in three prospective cohorts.

BACKGROUND: In 2019, the EAT-Lancet Commission proposed a healthy dietary pattern that, along with reductions in food waste and improved agricultural practices, could feed the increasing global population sustainably. We developed a Planetary Health Diet Index (PHDI) to quantify adherence to the EAT-Lancet reference diet. OBJECTIVES: We aimed to assess associations between PHDI and total and cause-specific mortality in 3 prospective cohorts of males and females in the United States. METHODS: We followed 66,692 females from the Nurses' Health Study (1986-2019), 92,438 females from the Nurses' Health Study II (1989-2019), and 47,274 males from the Health Professionals Follow-up Study (1986-2018) who were free of cancer, diabetes, and major cardiovascular diseases at baseline. The PHDI was calculated every 4 y using a semiquantitative food frequency questionnaire. Hazard ratios (HRs) were calculated using multivariable proportional-hazards models. RESULTS: During follow-up, we documented 31,330 deaths among females and 23,206 among males. When comparing the highest with the lowest quintile of PHDI, the pooled multivariable-adjusted HRs were 0.77 [95% confidence interval (CI): 0.75, 0.80] for all-cause mortality (P-trend < 0.0001). The PHDI was associated with lower risk of deaths from cardiovascular diseases (HR: 0.86; 95% CI: 0.81, 0.91), cancer (HR: 0.90; 95% CI: 0.85, 0.95), respiratory diseases (HR: 0.53; 95% CI: 0.48, 0.59), and neurodegenerative diseases (HR: 0.72; 95% CI: 0.67, 0.78). In females, but not males, the PHDI was also significantly associated with a lower risk of deaths from infectious diseases (HR: 0.62; 95% CI: 0.51, 0.76). PHDI scores were also associated inversely with greenhouse gas emissions and other environmental impacts. CONCLUSIONS: In 3 large United States-based prospective cohorts of males and females with up to 34 y of follow-up, a higher PHDI was associated with lower risk of total and cause-specific mortality and environment impacts.

Fibroblast growth factor 23 is not associated with and does not induce arterial calcification.

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.

Neighborhood socioeconomic status and mortality in the nurses' health study (NHS) and the nurses' health study II (NHSII).

Few studies have prospectively examined long-term associations between neighborhood socioeconomic status (nSES) and mortality risk, independent of demographic and lifestyle risk factors. Methods: We assessed associations between nSES and all-cause, nonaccidental mortality among women in the Nurses' Health Study (NHS) 1986-2014 (N = 101,701) and Nurses' Health Study II (NHSII) 1989-2015 (N = 101,230). Mortality was ascertained from the National Death Index (NHS: 19,228 deaths; NHSII: 1556 deaths). Time-varying nSES was determined for the Census tract of each residential address. We used principal component analysis (PCA) to identify nSES variable groups. Multivariable Cox proportional hazards models were conditioned on age and calendar period and included time-varying demographic, lifestyle, and individual SES factors. Results: For NHS, hazard ratios (HRs) comparing the fifth to first nSES quintiles ranged from 0.89 (95% confidence interval [CI] = 0.84, 0.94) for percent of households receiving interest/dividends, to 1.11 (95% CI = 1.06, 1.17) for percent of households receiving public assistance income. In NHSII, HRs ranged from 0.72 (95% CI: 0.58, 0.88) for the percent of households receiving interest/dividends, to 1.27 (95% CI: 1.07, 1.49) for the proportion of households headed by a single female. PCA revealed three constructs: education/income, poverty/wealth, and racial composition. The racial composition construct was associated with mortality (HRNHS: 1.03; 95% CI = 1.01, 1.04). Conclusion: In two cohorts with extensive follow-up, individual nSES variables and PCA component scores were associated with mortality. nSES is an important population-level predictor of mortality, even among a cohort of women with little individual-level variability in SES.

Dietary Intake of Branched Chain Amino Acids and Breast Cancer Risk in the NHS and NHS II Prospective Cohorts.

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 P trend = .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.

Early access to antiretroviral therapy versus standard of care among HIV-positive participants in Eswatini in the public health sector: the MaxART stepped-wedge randomized controlled trial.

INTRODUCTION: The WHO recommends antiretroviral treatment (ART) for all HIV-positive patients regardless of CD4 count or disease stage, referred to as "Early Access to ART for All" (EAAA). The health systems effects of EAAA implementation are unknown. This trial was implemented in a government-managed public health system with the aim to examine the "real world" impact of EAAA on care retention and viral suppression. METHODS: In this stepped-wedge randomized controlled trial, 14 public sector health facilities in Eswatini were paired and randomly assigned to stepwise transition from standard of care (SoC) to EAAA. ART-naïve participants ≥18 years who were not pregnant or breastfeeding were eligible for enrolment. We used Cox proportional hazard models with censoring at clinic transition to estimate the effects of EAAA on retention in care and retention and viral suppression combined. RESULTS: Between September 2014 and August 2017, 3405 participants were enrolled. In SoC and EAAA respectively, 12-month HIV care retention rates were 80% (95% CI: 77 to 83) and 86% (95% CI: 83 to 88). The 12-month combined retention and viral suppression endpoint rates were 44% (95% CI: 40 to 48) under SoC compared to 80% (95% CI: 77 to 83) under EAAA. EAAA increased both retention (HR: 1·60, 95% CI: 1·15 to 2·21, p = 0.005) and retention and viral suppression combined (HR: 4.88, 95% CI: 2.96 to 8.05, p < 0.001). We also identified significant gaps in current health systems ability to provide viral load (VL) monitoring with 80% participants in SoC and 66% in EAAA having a missing VL at last contact. CONCLUSIONS: The observed improvement in retention in care and on the combined retention and viral suppression provides an important co-benefit of EAAA to HIV-positive adults themselves, at least in the short term. Our results from this "real world" health systems trial strongly support EAAA for Eswatini and countries with similar HIV epidemics and health systems. VL monitoring needs to be scaled up for appropriate care management.

Health-Related Quality of Life, Depressive Symptoms, and Kidney Transplant Access in Advanced CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

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 < 0.001) and Effects scales (wait-listing aHR, 0.74; 95% CI, 0.59-0.92; P = 0.007). Participants with fewer depressive symptoms (ie, Beck Depression Inventory score < 14) had lower wait-listing rates than those with more depressive symptoms (aHR, 0.81; 95% CI, 0.66-0.99; P = 0.04). Participants with lower Burden and Effects scale scores and those with higher Symptoms and PCS scores had higher pre-emptive wait-listing rates (aHR in highest tertile of PCS relative to lowest tertile, 1.58; 95% CI, 1.12-2.23; P = 0.01). LIMITATIONS: Unmeasured confounders. CONCLUSIONS: Self-reported health in late-stage CKD may influence the timing of kidney transplantation.

Understanding reasons for discontinued antiretroviral treatment among clients in test and treat: a qualitative study in Swaziland.

INTRODUCTION: Retention 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 MaxART test and treat implementation study in Swaziland. METHODS: Clients identified as lost to follow-up (LTFU) in the programme database, who had initiated ART under the intervention arm of the MaxART 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. RESULTS: Respondents 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. CONCLUSIONS: Clients' 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.

Relation of aortic valve calcium to chronic kidney disease (from the Chronic Renal Insufficiency Cohort Study).

Although subjects with chronic kidney disease (CKD) are at markedly increased risk for cardiovascular mortality, the relation between CKD and aortic valve calcification has not been fully elucidated. Also, few data are available on the relation of aortic valve calcification and earlier stages of CKD. We sought to assess the relation 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 relation 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 1,964 CRIC participants underwent computed tomography for AVC quantification. Decreased renal function was independently associated with increased levels of AVC (eGFR 47.11, 44.17, and 39 ml/min/1.73 m2, 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 nonblack 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.