Exposure to per- and polyfluoroalkyl substances and breast cancer risk: a systematic review and meta-analysis of epidemiologic studies.

We synthesized the epidemiologic evidence on the associations between per- and polyfluoroalkyl substances (PFAS) exposure and breast cancer risk. Our systematic review and meta-analysis included 18 and 11 articles, respectively, covering studies up to February 2023. The summary relative risks (RRs) estimated by random-effects meta-analyses did not support an association between PFAS and overall breast cancer risk (eg, a natural log (ln)-unit increase in serum/plasma concentrations [ng/mL] for perfluorooctanoate [PFOA] RR = 0.95; 95% CI, 0.77-1.18; perfluorooctane sulfonate [PFOS] RR = 0.98; 95% CI, 0.87-1.11). However, when limiting to studies that assessed exposures prior to a breast cancer diagnosis, we observed a positive association with PFOA (a ln-unit increase, RR = 1.16; 95% CI, 0.96-1.40). We also observed some possible heterogeneous associations by tumor estrogen and progesterone receptor status among postmenopausal breast cancer cases. No meaningful changes were observed after excluding the studies with high risk of bias (Tier 3). Based on the evaluation tool developed by the National Toxicology Program, given the heterogeneity across studies and the variability in timing of exposure measurements, the epidemiologic evidence needed to determine the association between PFAS exposure and breast cancer remains inadequate. Our findings support the need for future studies with improved study designs to determine this association.

A pilot study on the effectiveness of a language-specific (Chinese) pulmonary rehabilitation programme for individuals with chronic pulmonary disease: a 2-year prospective cohort study in Sydney, Australia.

BACKGROUND AND AIMS: Pulmonary rehabilitation (PR) improves dyspnoea, fatigue and healthcare-related quality of life (QoL) in patients with chronic lung disease (CLD). Non-English-speaking background (NESB) patients face language and cultural barriers that hinder their access to PR programmes, contributing to health disparities. Our trial aimed to demonstrate the effectiveness and feasibility of a Chinese language-specific PR programme on lung function, functional exercise capacity and QoL measures. METHODS: A prospective cohort study was conducted over a 2-year period. Participants were enrolled in an 8-week PR programme with biweekly sessions conducted by Chinese-speaking physiotherapists. Baseline and post-rehabilitation testing included pulmonary function testing, 6-min walk test (6MWT), St. George Respiratory Questionnaire (SGQR) and Short Form Health Survey (SF-36). RESULTS: We enrolled 76 patients (58% male) with a median age of 77 years (interquartile range (IQR) 68-81) and achieved a completion rate of 86.8% (n = 66). CLD included chronic obstructive pulmonary disease (42%), asthma (15%) and interstitial lung disease (3%). Baseline median forced expiratory volume in 1 s (FEV1) was 1.63 L (IQR 1.17-2.05), and the median 6MWT was 282 m (IQR 232-332). Post-intervention median 6MWT increased to 332 m (IQR 290-390), and the median FEV1 was 1.99 L (IQR 1.3-2.1). Both QoL measures (SGQR and SF-36) showed significant improvement after intervention (P < 0.05). CONCLUSION: Our study demonstrates that a language-specific PR programme is feasible, improving outcomes in NESB patients with CLD. The improvement in 6MWT and QoL measures was comparable to English-based programmes. Ensuring equal access to healthcare programmes, regardless of cultural background or language barriers, is crucial in promoting health equity.

Serum perfluorooctane sulfonate and perfluorooctanoate and risk of postmenopausal breast cancer according to hormone receptor status: An analysis in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

Per- and polyfluoroalkyl substances (PFAS) are highly persistent endocrine-disrupting chemicals that may contribute to breast cancer development; however, epidemiologic evidence is limited. We investigated associations between prediagnostic serum levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and postmenopausal breast cancer risk, overall and by hormone receptor status, in a nested case-control study of 621 cases and 621 matched controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. PFOS and PFOA levels were determined based on serum metabolomic profiling performed using ultraperformance liquid chromatography-tandem mass spectrometry. We used multivariable conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each PFAS and breast cancer risk, overall, by estrogen receptor (ER) or progesterone receptor (PR) status, and by joint ER/PR status. We found little evidence of association between PFOS or PFOA and breast cancer risk overall. However, in subtype-specific analyses, we observed statistically significant increased risks of ER+, PR+, and ER+/PR+ tumors for the third vs lowest quartile of serum PFOS (ORs [95% CIs] = 1.59 [1.01-2.50], 2.34 [1.29-4.23], and 2.19 [1.21-3.98], respectively) and elevated but nonstatistically significant ORs for the fourth quartile. Conversely, for PFOA, modest positive associations with ER-, PR-, ER+/PR-, and ER-/PR- tumors were generally seen in the upper quartiles. Our findings contribute evidence supporting positive associations between serum PFOS and hormone receptor-positive tumors, and possibly between PFOA and receptor-negative tumors. Future prospective studies incorporating tumor hormone receptor status are needed to better understand the role of PFAS in breast cancer etiology.

Iron Status and Associated Factors among Canadian Women: Results from the Canadian Health Measures Survey.

BACKGROUND: Iron deficiency and overload may negatively impact women's health. There has been limited assessment of iron status and its associated factors among Canadian women. OBJECTIVES: This study investigated associations of various sociodemographic, lifestyle, medication, and dietary factors with body iron stores among pre- and postmenopausal women in Canada. METHODS: Analyses were conducted using cross-sectional, nationally representative survey and biomarker data from women aged 20-79 y (n = 6362) in the Canadian Health Measures Survey (2009-2017). Body iron stores were assessed by measuring serum concentrations of ferritin (SF). Information on potential correlates was collected during an in-home interview. Multivariable linear regression analyses were performed to evaluate associations with SF concentration, and logistic regression was used to estimate associations with iron deficiency (SF <15 µg/L) or elevated iron stores (SF >150 µg/L). RESULTS: Geometric mean SF concentrations were significantly higher in postmenopausal than in premenopausal women (73.2 versus 33.8 µg/L; P < 0.001). The prevalence of iron deficiency among pre- and postmenopausal women was 16.0% and 4.0%, respectively, whereas that of elevated iron stores was 2.7% and 21.0%, respectively. After simultaneous adjustment for multiple factors, including high-sensitivity CRP (inflammation marker), we found that age, East/Southeast Asian (versus White) race/ethnicity, alcohol, and red meat consumption were positively associated with SF concentration among pre- and postmenopausal women. In addition, aspirin use and dairy consumption were inversely associated with SF concentration among postmenopausal women only. Similar patterns were observed for associations with elevated iron stores among postmenopausal women, whereas higher grain consumption was associated with an increased prevalence of iron deficiency among premenopausal women. CONCLUSIONS: Sociodemographic, lifestyle, medication, and dietary factors are correlated with iron status determined by SF concentration among Canadian women. The findings may have implications for intervention strategies aimed at optimizing body iron stores in pre- and postmenopausal women.

The Effectiveness of Individual and Environmental Infection Control Measures in Reducing the Transmission of Mycobacterium tuberculosis: A Systematic Review.

BACKGROUND: Transmission of Mycobacterium tuberculosis in healthcare settings is a preventable driver of the global tuberculosis epidemic. We aimed to assess the evidence for infection control interventions, including cough etiquette, engineering and personal respiratory protection measures, to prevent transmission of M. tuberculosis in healthcare settings. METHODS: Three independent systematic reviews were performed using 6 databases and clinical trials websites. Randomized trials, cohort studies, before-after studies, and case-control studies were included. Searches were performed for controlled studies evaluating respiratory hygiene, engineering, and personal respiratory protection measures. Outcome measures included the incidence of tuberculosis infection and disease. Studies involving transmission to either humans or animals were included. RESULTS: Evaluation of respiratory hygiene and cough etiquette interventions identified 4 human studies, with 22 855 participants, and 1 guinea pig study. Studies in humans evaluated the effects of multiple concurrent interventions. Patient use of surgical masks reduced infection by 14.8%, and tuberculosis disease was reduced by between 0.5% and 28.9%. Engineering and environmental interventions were evaluated in 10 studies of humans, including 31 776 human participants, and 2 guinea pig studies. Mechanical ventilation was associated with between 2.9% and 14% less infection. Nine studies of personal respiratory protection were included, including 33 913 participants. Infection was reduced by between 0% and 14.8% in studies where particulate respirators were used. The quality of included studies was assessed as low. CONCLUSIONS: Respiratory hygiene, engineering, and environmental infection controls and personal respiratory protection interventions were associated with reduced transmission of M. tuberculosis and reduced tuberculosis disease in healthcare settings.

Risk factors for early-onset colorectal cancer: a population-based case-control study in Ontario, Canada.

PURPOSE: There has been an alarming increase in colorectal cancer (CRC) incidence among young adults aged < 50 years, and factors driving this upward trend are unknown. This study investigated associations between various medical, lifestyle, and dietary factors and risk of early-onset CRC (EO-CRC). METHODS: A population-based case-control study was conducted in Ontario, Canada during 2018-2019. EO-CRC cases aged 20-49 years (n = 175) were identified from the Ontario Cancer Registry; sex- and age group-matched controls (n = 253) were recruited through random digit dialing. Data on potential a priori risk factors were collected using a web-based self-reported questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression. RESULTS: Family history of CRC in a first- or second-degree relative (OR 2.37; 95% CI 1.47-3.84), longer sedentary time (≥ 10 vs. < 5 h/day, OR 1.93; 95% CI 1.02-3.65), greater consumption of sugary drinks (≥ 7 vs. < 1 drinks/week, OR 2.99; 95% CI 1.57-5.68), and a more Westernized dietary pattern (quartile 4 vs. 1, OR 1.92; 95% CI 1.01-3.66) were each associated with an increased risk of EO-CRC. Conversely, calcium supplement use (OR 0.53; 95% CI 0.31-0.92), history of allergy or asthma (OR 0.62; 95% CI 0.39-0.98), and greater parity in females (≥ 3 vs. nulliparity, OR 0.29; 95% CI 0.11-0.76) were each associated with a reduced risk. CONCLUSION: Modifiable factors, particularly sedentary behavior and unhealthy diet including sugary drink consumption, may be associated with EO-CRC risk. Our findings, if replicated, may help inform prevention strategies targeted at younger persons.

Iron intake, oxidative stress-related genes and breast cancer risk.

Iron has been suggested to contribute to breast cancer development through oxidative stress generation. Our study investigated associations between iron intake and breast cancer risk, overall and by menopausal and estrogen receptor/progesterone receptor (ER/PR) status, and modification by oxidative stress-related genetic polymorphisms (MnSOD, GSTM1 and GSTT1). A population-based case-control study (3,030 cases and 3,402 controls) was conducted in Ontario, Canada. Iron intake (total, dietary, supplemental, heme, nonheme) was assessed using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression models. Interactions between iron intake and genotypes were assessed among 1,696 cases and 1,761 controls providing DNA. Overall, no associations were observed between iron intake and breast cancer risk. Among premenopausal women, total, dietary and dietary nonheme iron were positively associated with ER-/PR- breast cancer risk (all ptrend < 0.05). Among postmenopausal women, supplemental iron was associated with reduced breast cancer risk (OR>18 vs. 0 mg/day = 0.68, 95% CI: 0.51-0.91), and dietary heme iron was associated with an increased risk, particularly the ER-/PR- subtype (ORhighest vs. lowest quintile = 1.69, 95% CI: 1.16-2.47; ptrend = 0.02). Furthermore, GSTT1 and combined GSTM1/GSTT1 polymorphisms modified some of the associations. For example, higher dietary iron was most strongly associated with increased breast cancer risk among women with GSTT1 deletion or GSTM1/GSTT1 double deletions (pinteraction < 0.05). Findings suggest that iron intake may have different effects on breast cancer risk according to menopausal and hormone receptor status, as well as genotypes affecting antioxidant capacity.

Iron intake, body iron status, and risk of breast cancer: a systematic review and meta-analysis.

BACKGROUND: Iron has been shown to promote breast carcinogenesis in animal models through generation of oxidative stress and interaction with estrogen. Heme iron, which is found exclusively in animal-sourced foods, is suggested to have a more detrimental effect. Epidemiological evidence of the association between iron and breast cancer risk remains inconclusive and has not been comprehensively summarized. This systematic review and meta-analysis evaluated associations between both iron intake and body iron status and breast cancer risk. METHODS: Four electronic databases (MEDLINE, EMBASE, CINAHL, and Scopus) were searched up to December 2018 for studies assessing iron intake and/or biomarkers of iron status in relation to breast cancer risk. Using random-effects meta-analyses, pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated comparing the highest vs. lowest category of each iron measure. Dose-response meta-analyses were also performed to investigate linear and nonlinear associations. RESULTS: A total of 27 studies were included in the review, of which 23 were eligible for meta-analysis of one or more iron intake/status measures. Comparing the highest vs. lowest category, heme iron intake was significantly associated with increased breast cancer risk, with a pooled RR of 1.12 (95% CI: 1.04-1.22), whereas no associations were found for dietary (1.01, 95% CI: 0.89-1.15), supplemental (1.02, 95% CI: 0.91-1.13), or total (0.97, 95% CI: 0.82-1.14) iron intake. Associations of iron status indicators with breast cancer risk were generally in the positive direction; however, a significant pooled RR was found only for serum/plasma levels (highest vs. lowest) of iron (1.22, 95% CI: 1.01-1.47), but not for ferritin (1.13, 95% CI: 0.78-1.62), transferrin saturation (1.16, 95% CI: 0.91-1.47), or total iron-binding capacity (1.10, 95% CI: 0.97-1.25). In addition, a nonlinear dose-response was observed for heme iron intake and serum iron (both Pnonlinearity < 0.05). CONCLUSIONS: Heme iron intake and serum iron levels may be positively associated with breast cancer risk. Although associations were modest, these findings may have public health implications given the widespread consumption of (heme) iron-rich foods. In light of methodological and research gaps identified, further research is warranted to better elucidate the relationship between iron and breast cancer risk.

Effect of Dietary Flaxseed Intake on Circulating Sex Hormone Levels among Postmenopausal Women: A Randomized Controlled Intervention Trial.

Lignan intake, and its richest food source, flaxseed, have been associated with reduced breast cancer risk. Endogenous sex hormones, such as estrogens, play a role in breast cancer development, and lignans may alter these sex hormone levels. To assess the effect of flaxseed on circulating sex hormones, a randomized controlled trial was conducted among 99 postmenopausal women in Toronto, Canada. The intervention arm consumed 2 tablespoons (15 g) of ground flaxseed daily for 7 weeks; the control arm maintained usual diet. Baseline and week 7 concentrations of 14 serum sex hormones were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoassay, and serum enterolignans (lignan biomarker) using LC-MS/MS. Intervention effects on sex hormone levels were assessed using analysis of covariance. Serum enterolignans increased among the flaxseed arm (+516%). Women consuming flaxseed (vs. controls) had increased serum 2-hydroxyestrone [treatment effect ratio (TER) = 1.54; 95% CI: 1.18-2.00] and 2:16α-hydroxyestrone ratio (TER =1.54; 95% CI: 1.15-2.06); effects on other hormones were not statistically significant. Within the flaxseed arm, change in enterolignan level was positively correlated with changes in 2-hydroxyestrone and 2:16α-hydroxyestrone ratio, and negatively with prolactin. Findings suggest flaxseed affects certain circulating sex hormone levels with possible implications for future breast cancer prevention research.

CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion.

CDK12 (cyclin-dependent kinase 12) is a regulatory kinase with evolutionarily conserved roles in modulating transcription elongation. Recent tumor genome studies of breast and ovarian cancers highlighted recurrent CDK12 mutations, which have been shown to disrupt DNA repair in cell-based assays. In breast cancers, CDK12 is also frequently co-amplified with the HER2 (ERBB2) oncogene. The mechanisms underlying functions of CDK12 in general and in cancer remain poorly defined. Based on global analysis of mRNA transcripts in normal and breast cancer cell lines with and without CDK12 amplification, we demonstrate that CDK12 primarily regulates alternative last exon (ALE) splicing, a specialized subtype of alternative mRNA splicing, that is both gene- and cell type-specific. These are unusual properties for spliceosome regulatory factors, which typically regulate multiple forms of alternative splicing in a global manner. In breast cancer cells, regulation by CDK12 modulates ALE splicing of the DNA damage response activator ATM and a DNAJB6 isoform that influences cell invasion and tumorigenesis in xenografts. We found that there is a direct correlation between CDK12 levels, DNAJB6 isoform levels and the migration capacity and invasiveness of breast tumor cells. This suggests that CDK12 gene amplification can contribute to the pathogenesis of the cancer.

Risk factors for falls among seniors: implications of gender.

Despite extensive literature on falls among seniors, little is known about gender-specific risk factors. To determine the prevalence of falls by gender and sociodemographic, lifestyle/behavioral, and medical factors, we conducted a cross-sectional study in a nationally representative sample of Canadian adults who were 65 years of age or older (n = 14,881) from the Canadian Community Health Survey-Healthy Aging (2008-2009). Logistic regression models were applied to investigate gender-specific associations between potential risk factors and falls. In men, stroke (odds ratio (OR) = 1.91), nutritional risk (OR = 1.86), post-secondary school degree (OR = 1.68), eye disorder (OR = 1.35), widowed/separated/divorced marital status (OR = 1.28), and arthritis (OR = 1.27) were independently associated with significantly higher odds of falls. In women, significant independent correlates of falls included stroke (OR = 1.53), age of 85 years or older (OR = 1.51), nutritional risk (OR = 1.39), consumption of at least 1 alcoholic drink per week (OR = 1.39), use of 5 or more medications (OR = 1.36), arthritis (OR = 1.36), diabetes (OR = 1.31), and osteoporosis (OR = 1.22). Higher physical activity levels were protective in both genders, and higher household income was protective in women. Gender should be considered when planning fall prevention strategies.

Epidemiology of work-related traumatic brain injury: a systematic review.

OBJECTIVE: This systematic review aimed to describe the burden and risk factors of work-related traumatic brain injury (wrTBI) and evaluate methodological quality of existing literature on wrTBI. METHODS: A search of electronic databases (MEDLINE, EMBASE, PsycINFO, and CINAHL) was conducted to identify articles published between 1980 and 2013 using a combination of terms for work, TBI, and epidemiology, without geographical limitations. RESULTS: Ninety-eight studies were included in this review, of which 24 specifically focused on wrTBI. In general, male workers, those in the youngest and oldest age groups, and those working in the primary (e.g., agriculture, forestry, mining) or construction industries were more likely to sustain wrTBI, with falls being the most common mechanism of injury. CONCLUSIONS: This review identified workers at highest risk of wrTBI, with implications for prevention efforts. Future research of better methodological quality is needed to provide a more complete picture of the epidemiology of wrTBI.

Examining the epidemiology of work-related traumatic brain injury through a sex/gender lens: analysis of workers' compensation claims in Victoria, Australia.

OBJECTIVES: To provide an overview of the epidemiology of work-related traumatic brain injury (wrTBI) in the state of Victoria, Australia. Specifically, we investigated sex differences in incidence, demographics, injury characteristics, in addition to outcomes associated with wrTBI. METHODS: This study involved secondary analysis of administrative workers' compensation claims data obtained from the Victorian WorkCover Authority for the period 2004-2011. Sex-specific and industry-specific rates of wrTBI were calculated using denominators derived from the Australian Bureau of Statistics. A descriptive analysis of all variables was conducted for the total wrTBI population and stratified by sex. RESULTS: Among 4186 wrTBI cases identified, 36.4% were females. The annual incidence of wrTBI was estimated at 19.8/100 000 workers. The rate for males was 1.43 (95% CI 1.35 to 1.53) times that for females, but the gap between the two sexes appeared to have narrowed over time. Compared to males, females were older at time of injury and had lower preinjury income. Males had higher rates than females across most industry sectors, with the exception of education/training (RR 0.77, 95% CI 0.64 to 0.93) and professional/scientific/technical services (RR 0.64, 95% CI 0.44 to 0.93). For both sexes, the most common injury mechanism was struck by/against, followed by falls. WrTBI among males was associated with longer duration of work disability and higher claim costs compared to females. CONCLUSIONS: This study found significant sex differences in various risk factors and outcomes of wrTBI. Sex/gender should be taken into consideration in future research and prevention strategies.

Urinary biomonitoring of glyphosate exposure among male farmers and nonfarmers in the Biomarkers of Exposure and Effect in Agriculture (BEEA) study.

Glyphosate is the most widely applied herbicide worldwide. Glyphosate biomonitoring data are limited for agricultural settings. We measured urinary glyphosate concentrations and assessed exposure determinants in the Biomarkers of Exposure and Effect in Agriculture (BEEA) study. We selected four groups of BEEA participants based on self-reported pesticide exposure: recently exposed farmers with occupational glyphosate use in the last 7 days (n = 98), farmers with high lifetime glyphosate use (>80th percentile) but no use in the last 7 days (n = 70), farming controls with minimal lifetime use (n = 100), and nonfarming controls with no occupational pesticide exposures and no recent home/garden glyphosate use (n = 100). Glyphosate was quantified in first morning void urine using ion chromatography isotope-dilution tandem mass spectrometry. We estimated associations between urinary glyphosate concentrations and potential determinants using multivariable linear regression. Glyphosate was detected (≥0.2 µg/L) in urine of most farmers with recent (91 %) and high lifetime (93 %) use, as well as farming (88 %) and nonfarming (81 %) controls; geometric mean concentrations were 0.89, 0.59, 0.46, and 0.39 µg/L (0.79, 0.51, 0.42, and 0.37 µg/g creatinine), respectively. Compared with both control groups, urinary glyphosate concentrations were significantly elevated among recently exposed farmers (P < 0.0001), particularly those who used glyphosate in the previous day [vs. nonfarming controls; geometric mean ratio (GMR) = 5.46; 95 % confidence interval (CI): 3.75, 7.93]. Concentrations among high lifetime exposed farmers were also elevated (P < 0.01 vs. nonfarming controls). Among recently exposed farmers, glyphosate concentrations were higher among those not wearing gloves when applying glyphosate (GMR = 1.91; 95 % CI: 1.17, 3.11), not wearing long-sleeved shirts when mixing/loading glyphosate (GMR = 2.00; 95 % CI: 1.04, 3.86), applying glyphosate exclusively using broadcast/boom sprayers (vs. hand sprayer only; GMR = 1.70; 95 % CI: 1.00, 2.92), and applying glyphosate to crops (vs. non-crop; GMR = 1.72; 95 % CI: 1.04, 2.84). Both farmers and nonfarmers are exposed to glyphosate, with recency of occupational glyphosate use being the strongest determinant of urinary glyphosate concentrations. Continued biomonitoring of glyphosate in various settings is warranted.

Assessment of genetic and nongenetic interactions for the prediction of depressive symptomatology: an analysis of the Wisconsin Longitudinal Study using machine learning algorithms.

OBJECTIVES: We examined depression within a multidimensional framework consisting of genetic, environmental, and sociobehavioral factors and, using machine learning algorithms, explored interactions among these factors that might better explain the etiology of depressive symptoms. METHODS: We measured current depressive symptoms using the Center for Epidemiologic Studies Depression Scale (n = 6378 participants in the Wisconsin Longitudinal Study). Genetic factors were 78 single nucleotide polymorphisms (SNPs); environmental factors-13 stressful life events (SLEs), plus a composite proportion of SLEs index; and sociobehavioral factors-18 personality, intelligence, and other health or behavioral measures. We performed traditional SNP associations via logistic regression likelihood ratio testing and explored interactions with support vector machines and Bayesian networks. RESULTS: After correction for multiple testing, we found no significant single genotypic associations with depressive symptoms. Machine learning algorithms showed no evidence of interactions. Naïve Bayes produced the best models in both subsets and included only environmental and sociobehavioral factors. CONCLUSIONS: We found no single or interactive associations with genetic factors and depressive symptoms. Various environmental and sociobehavioral factors were more predictive of depressive symptoms, yet their impacts were independent of one another. A genome-wide analysis of genetic alterations using machine learning methodologies will provide a framework for identifying genetic-environmental-sociobehavioral interactions in depressive symptoms.

Serum concentrations of per- and polyfluoroalkyl substances and risk of renal cell carcinoma in the Multiethnic Cohort Study.

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent organic pollutants detectable in the serum of most U.S. adults. We previously reported a positive association between serum perfluorooctanoate (PFOA) concentrations and risk of renal cell carcinoma (RCC) within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, comprising predominantly White individuals enrolled in 1993-2001. To extend our investigations to a larger and more racially and ethnically diverse population, we conducted a nested case-control study of serum PFAS concentrations and RCC within the Multiethnic Cohort Study. We measured pre-diagnostic serum concentrations of nine PFAS among 428 RCC cases and 428 individually matched controls. We estimated odds ratios (ORs) and 95 % confidence intervals (CIs) for risk of RCC in relation to each PFAS using conditional logistic regression, adjusting for RCC risk factors and other PFAS. PFOA was not associated with RCC risk overall [doubling in serum concentration, ORcontinuous = 0.89 (95 %CI = 0.67, 1.18)]. However, we observed suggestive positive associations among White participants [2.12 (0.87, 5.18)] and among participants who had blood drawn before 2002 [1.49 (0.77, 2.87)]. Furthermore, higher perfluorononanoate (PFNA) concentration was associated with increased risk of RCC overall [fourth vs. first quartile, OR = 1.84 (0.97, 3.50), Ptrend = 0.04; ORcontinuous = 1.29 (0.97, 1.71)], with the strongest association observed among African American participants [ORcontinuous = 3.69 (1.33, 10.25)], followed by Native Hawaiian [2.24 (0.70, 7.19)] and White [1.98 (0.92, 4.25)] participants. Most other PFAS were not associated with RCC. While PFOA was not associated with RCC risk overall in this racially and ethnically diverse population, the positive associations observed among White participants and those with sera collected before 2002 are consistent with previous PLCO findings. Our study also provided new evidence of a positive association between PFNA and RCC risk that was strongest in African American participants. These findings highlight the need for additional epidemiologic research investigating PFAS exposures and RCC in large racially and ethnically diverse populations.

Glyphosate exposure and urinary oxidative stress biomarkers in the Agricultural Health Study.

BACKGROUND: Glyphosate is the most widely applied herbicide worldwide, and its use has been associated with increased risks of certain hematopoietic cancers in epidemiologic studies. Animal and in vitro experiments suggest that glyphosate may induce oxidative stress, a key characteristic of carcinogens; however, evidence in human populations remains scarce. We investigated associations between glyphosate exposure and urinary oxidative stress biomarkers in the Biomarkers of Exposure and Effect in Agriculture study, a molecular epidemiologic subcohort in the Agricultural Health Study. METHODS: This analysis included 268 male farmers selected based on self-reported recent and lifetime occupational glyphosate use and 100 age- and geography-matched male nonfarmers. Concentrations of glyphosate and oxidative stress biomarkers (8-hydroxy-2'-deoxyguanosine [8-OHdG], 8-iso-prostaglandin-F2α, and malondialdehyde [MDA]) were quantified in first-morning-void urine. We performed multivariable linear regression to evaluate associations of urinary glyphosate and self-reported glyphosate use with each oxidative stress biomarker. RESULTS: Urinary glyphosate concentrations were positively associated with levels of 8-OHdG (highest vs lowest glyphosate quartile; geometric mean ratio = 1.15, 95% confidence interval = 1.03 to 1.28; Ptrend = .02) and MDA (geometric mean ratio = 1.20, 95% confidence interval = 1.03 to 1.40; Ptrend = .06) overall. Among farmers reporting recent glyphosate use (last 7 days), use in the previous day was also associated with statistically significantly increased 8-OHdG and MDA levels. Compared with nonfarmers, we observed elevated 8-iso-prostaglandin-F2α levels among farmers with recent, high past 12-month, or high lifetime glyphosate use. CONCLUSIONS: Our findings contribute to the weight of evidence supporting an association between glyphosate exposure and oxidative stress in humans and may inform evaluations of the carcinogenic potential of this herbicide.

Glyphosate Use and Mosaic Loss of Chromosome Y among Male Farmers in the Agricultural Health Study.

BACKGROUND: Glyphosate is the most commonly used herbicide worldwide and has been implicated in the development of certain hematologic cancers. Although mechanistic studies in human cells and animals support the genotoxic effects of glyphosate, evidence in human populations is scarce. OBJECTIVES: We evaluated the association between lifetime occupational glyphosate use and mosaic loss of chromosome Y (mLOY) as a marker of genotoxicity among male farmers. METHODS: We analyzed blood-derived DNA from 1,606 farmers ≥50 years of age in the Biomarkers of Exposure and Effect in Agriculture study, a subcohort of the Agricultural Health Study. mLOY was detected using genotyping array intensity data in the pseudoautosomal region of the sex chromosomes. Cumulative lifetime glyphosate use was assessed using self-reported pesticide exposure histories. Using multivariable logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between glyphosate use and any detectable mLOY (overall mLOY) or mLOY affecting ≥10% of cells (expanded mLOY). RESULTS: Overall, mLOY was detected in 21.4% of farmers, and 9.8% of all farmers had expanded mLOY. Increasing total lifetime days of glyphosate use was associated with expanded mLOY [highest vs. lowest quartile; OR=1.75 (95% CI: 1.00, 3.07), ptrend=0.03] but not with overall mLOY; the associations with expanded mLOY were most apparent among older (≥70 years of age) men [OR=2.30 (95% CI: 1.13, 4.67), ptrend=0.01], never smokers [OR=2.32 (95% CI: 1.04, 5.21), ptrend=0.04], and nonobese men [OR=2.04 (95% CI: 0.99, 4.19), ptrend=0.03]. Similar patterns of associations were observed for intensity-weighted lifetime days of glyphosate use. DISCUSSION: High lifetime glyphosate use could be associated with mLOY affecting a larger fraction of cells, suggesting glyphosate could confer genotoxic or selective effects relevant for clonal expansion. As the first study to investigate this association, our findings contribute novel evidence regarding the carcinogenic potential of glyphosate and require replication in future studies. https://doi.org/10.1289/EHP12834.

Individualised treatment for multidrug-resistant tuberculosis in New South Wales, Australia.

OBJECTIVE: Multidrug-resistant tuberculosis (MDR-TB) presents a major global health challenge. In high-income countries, treatment is individualised to optimise efficacy and reduce toxicity. We aimed to evaluate the outcomes of patients with MDR-TB receiving individualised antibiotic therapy in Australia. METHODS: This retrospective cohort study was performed in the city of Sydney in Australia and included patients diagnosed with bacteriologically confirmed MDR-TB diagnosed between 2000 and 2016. The clinical characteristics of patients and treatment details were extracted from medical records. The incidence of adverse events and end-of-treatment outcomes were also evaluated. RESULTS: Fifty-five patients with MDR-TB were identified at TB clinics in seven hospitals. The median age was 32 years (interquartile range [IQR]: 27-36 years). The median duration of the intensive phase treatment was six months (IQR 6-7 months). All patients' treatment administration was directly observed. The commonest reported adverse event was ototoxicity (44%; 23/52) and successful treatment outcomes were achieved by 95% (52/55) of patients. CONCLUSION: This study demonstrated the high treatment success rate that can be achieved using individualised treatment for MDR-TB in a well-resourced setting. Implications for public health: The expansion of individualised therapy promises to contribute to MDR-TB control and advance the ambitious goal of TB elimination by 2035.

Latent tuberculosis infection among contacts of patients with multidrug-resistant tuberculosis in New South Wales, Australia.

BACKGROUND: Contacts of an individual with active tuberculosis (TB) disease have a higher risk of developing latent TB infection (LTBI) or active TB disease. Contact tracing is a public health measure that seeks to identify exposed contacts, screen them for co-prevalent TB and consider prophylactic treatment to prevent progression from LTBI to active TB disease. The investigators sought to determine the prevalence of LTBI and active TB disease among contacts of patients with multidrug-resistant (MDR)-TB in New South Wales, Australia. METHODOLOGY: A retrospective cohort study was performed among the contacts of patients diagnosed with MDR-TB between 2000 and 2016, inclusive, at seven chest clinics. Medical records were used to identify eligible contacts. Outcomes of screening and prophylactic treatment regimens offered to MDR-TB contacts with LTBI were characterised. Collected data included demographic information, screening tests results and initial management. RESULTS: In total, 247 contacts of 55 MDR-TB patients were identified. LTBI was identified in 105 contacts (42.5%). Preventive treatment was received by 20 contacts with LTBI (32.3%) in the form of various regimens, ranging from one to three antimicrobials, with various doses and durations. One contact with LTBI who was untreated progressed to active TB disease during the study period, according to clinic notes. CONCLUSION: Contacts of MDR-TB patients have a high prevalence of LTBI. Management of these contacts varies substantially in New South Wales, reflecting a lack of definitive evidence for preventive therapy. Further research is required to determine the optimal management of this population.