Mammographic density mediates the protective effect of early-life body size on breast cancer risk.

The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%-79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.

Differences in Smoking Behavior by Nativity, Race/Ethnicity, and Education among Women Diagnosed with Breast Cancer.

BACKGROUND: We evaluated smoking differences across nativity and race/ethnicity among women diagnosed with breast cancer. METHODS: In our Northern Californian pooled population of 5,653 [670 Asian, 690 Hispanic, and 4,300 non-Hispanic White (White)] women diagnosed with breast cancer, we evaluated smoking differences across nativity, race/ethnicity, and acculturation and effect modification of nativity by race/ethnicity and education. RESULTS: Foreign-born women currently smoked less than US-born women [odds ratio (OR) = 0.46, 95% confidence limit (CL): 0.29-0.72]. Hispanic (OR = 0.50; 95% CL: 0.32-0.78) women currently smoked less than White women. Among those who ever smoked (n = 2,557), foreign-born women smoked 5.23 fewer pack-years (PY) than US-born women (95% CL: -2.75 to -7.70). Furthermore, Asian (-4.60, 95% CL: -0.81 to -8.39) and Hispanic (-6.79, 95% CL: -4.14 to -9.43) women smoked fewer PY than White women. Associations were generally suggestive of greater smoking with greater acculturation (immigration age, US years, survey language). Finally, associations for nativity differed by education but not race/ethnicity, with a higher likelihood of smoking in US-born women only among those with less than a bachelor's degree (OR = 2.84, 95% CL: 2.15-3.77; current smoking: P = 0.01, PY: P = 0.05). CONCLUSIONS: Asian and Hispanic (vs. White) and foreign-born (vs. US-born) breast cancer survivors reported fewer smoking behaviors. Smoking differences across nativity and education were driven by higher rates of smoking in US-born women with lower educational attainment. IMPACT: Smoking behavioral patterns were similar among breast cancer survivors and the general population, informing potential smoking interventions.

Cardiovascular Disease Risk Factor Control in People With and Without HIV.

BACKGROUND: Management of hypertension, dyslipidemia, diabetes and other modifiable factors may mitigate the cardiovascular disease (CVD) risk in people with human immunodeficiency virus (HIV, PWH) compared with people without HIV (PWoH). METHODS: This was a retrospective cohort study of 8285 PWH and 170 517 PWoH from an integrated health system. Risk factor control was measured using a novel disease management index (DMI) accounting for amount/duration above treatment goals (0% to 100% [perfect control]), including 2 DMIs for hypertension (diastolic and systolic blood pressure), 3 for dyslipidemia (low-density lipoprotein, total cholesterol, triglycerides), and 1 for diabetes (HbA1c). CVD risk by HIV status was evaluated overall and in subgroups defined by DMIs, smoking, alcohol use, and overweight/obesity in adjusted Cox proportional hazards models. RESULTS: PWH and PWoH had similar DMIs (80%-100%) except for triglycerides (worse for PWH) and HbA1c (better for PWH). In adjusted models, PWH had an elevated risk of CVD compared with PWoH (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.07-1.31). This association was attenuated in subgroups with controlled dyslipidemia and diabetes but remained elevated for PWH with controlled hypertension or higher total cholesterol. The strongest HIV status association with CVD was seen in the subgroup with frequent unhealthy alcohol use (HR, 2.13; 95% CI, 1.04-4.34). CONCLUSIONS: Control of dyslipidemia and diabetes, but not hypertension, attenuated the HIV status association with CVD. The strong association of HIV and CVD with frequent unhealthy alcohol use suggests enhanced screening and treatment of alcohol problems in PWH is warranted.

The mediating role of mammographic density in the protective effect of early-life adiposity on breast cancer risk: a multivariable Mendelian randomization study.

Observational studies suggest that mammographic density (MD) may have a role in the unexplained protective effect of childhood adiposity on breast cancer risk. Here, we investigated a complex and interlinked relationship between puberty onset, adiposity, MD, and their effects on breast cancer using Mendelian randomization (MR). We estimated the effects of childhood and adulthood adiposity, and age at menarche on MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)) using MR and multivariable MR (MVMR), allowing us to disentangle their total and direct effects. Next, we examined the effect of MD on breast cancer risk, including risk of molecular subtypes, and accounting for genetic pleiotropy. Finally, we used MVMR to evaluate whether the protective effect of childhood adiposity on breast cancer was mediated by MD. Childhood adiposity had a strong inverse effect on mammographic DA, while adulthood adiposity increased NDA. Later menarche had an effect of increasing DA and PD, but when accounting for childhood adiposity, this effect attenuated to the null. DA and PD had a risk-increasing effect on breast cancer across all subtypes. The MD single-nucleotide polymorphism (SNP) estimates were extremely heterogeneous, and examination of the SNPs suggested different mechanisms may be linking MD and breast cancer. Finally, MR mediation analysis estimated that 56% (95% CIs [32% - 79%]) of the childhood adiposity effect on breast cancer risk was mediated via DA. In this work, we sought to disentangle the relationship between factors affecting MD and breast cancer. We showed that higher childhood adiposity decreases mammographic DA, which subsequently leads to reduced breast cancer risk. Understanding this mechanism is of great importance for identifying potential targets of intervention, since advocating weight gain in childhood would not be recommended.

Examination of fully automated mammographic density measures using LIBRA and breast cancer risk in a cohort of 21,000 non-Hispanic white women.

BACKGROUND: Breast density is strongly associated with breast cancer risk. Fully automated quantitative density assessment methods have recently been developed that could facilitate large-scale studies, although data on associations with long-term breast cancer risk are limited. We examined LIBRA assessments and breast cancer risk and compared results to prior assessments using Cumulus, an established computer-assisted method requiring manual thresholding. METHODS: We conducted a cohort study among 21,150 non-Hispanic white female participants of the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California who were 40-74 years at enrollment, followed for up to 10 years, and had archived processed screening mammograms acquired on Hologic or General Electric full-field digital mammography (FFDM) machines and prior Cumulus density assessments available for analysis. Dense area (DA), non-dense area (NDA), and percent density (PD) were assessed using LIBRA software. Cox regression was used to estimate hazard ratios (HRs) for breast cancer associated with DA, NDA and PD modeled continuously in standard deviation (SD) increments, adjusting for age, mammogram year, body mass index, parity, first-degree family history of breast cancer, and menopausal hormone use. We also examined differences by machine type and breast view. RESULTS: The adjusted HRs for breast cancer associated with each SD increment of DA, NDA and PD were 1.36 (95% confidence interval, 1.18-1.57), 0.85 (0.77-0.93) and 1.44 (1.26-1.66) for LIBRA and 1.44 (1.33-1.55), 0.81 (0.74-0.89) and 1.54 (1.34-1.77) for Cumulus, respectively. LIBRA results were generally similar by machine type and breast view, although associations were strongest for Hologic machines and mediolateral oblique views. Results were also similar during the first 2 years, 2-5 years and 5-10 years after the baseline mammogram. CONCLUSION: Associations with breast cancer risk were generally similar for LIBRA and Cumulus density measures and were sustained for up to 10 years. These findings support the suitability of fully automated LIBRA assessments on processed FFDM images for large-scale research on breast density and cancer risk.

Patterns of Substance Use During Early Pregnancy and Associations With Behavioral Health Characteristics.

OBJECTIVES: The aims of the study are to identify patterns of early pregnancy substance use and to examine how these patterns relate to behavioral health conditions measured in early pregnancy. METHODS: We conducted a retrospective observational study (N= 265,274 pregnancies) screened for alcohol, cannabis, nicotine, pharmaceutical opioids, and stimulants during the first trimester via self-report and urine toxicology tests in Kaiser Permanente Northern California from January 1, 2012, to December 31, 2019. To identify patterns of prenatal substance use, we conducted latent class analysis. We then calculated the prevalence of depression, anxiety, intimate partner violence, and family drug use history for each prenatal substance use group and compared the prevalences by estimating prevalence ratios using modified Poisson regression, adjusting for sociodemographic characteristics. RESULTS: We identified the following 4 latent groups with different patterns of substance use: ( a ) predominantly alcohol and no other substances (9.30%), ( b ) predominantly cannabis and no other substances (4.88%), ( c ) predominantly nicotine and some pharmaceutical opioids (1.09%), and ( d ) high-polysubstance (alcohol, cannabis, nicotine, and stimulants; 0.36%); these pregnancies were compared with ( e ) no prenatal substance use (84.37%). The prevalence of all behavioral health conditions was elevated in all prenatal substance use groups compared with the no substance use group. Furthermore, the prevalence of depressive and anxiety disorders, intimate partner violence and family drug use history were greater in the high-polysubstance cluster than the alcohol and cannabis clusters. CONCLUSIONS: Results highlight the importance of screening and interventions for all types of substance use during early pregnancy and suggest a particularly high need to prioritize targeting early interventions to pregnant and reproductive age individuals with polysubstance use.

Current tobacco smoking and risk of SARS-CoV-2 infection and hospitalization: Evaluating the role of socio-demographic factors and comorbidities.

Our recently published study of >2.4 million adults in Northern California indicated that current versus never-tobacco smoking was associated with lower risk of SARS-CoV-2 infection and less severe coronavirus disease 2019 (COVID-19). We extended this research by evaluating whether these associations were moderated by socio-demographic factors and medical comorbidities. This retrospective cohort study of 1,885,826 adults with current or never-smoking status in Kaiser Permanente Northern California from 3/5/2020 (baseline) to 12/31/2020 (pre-vaccine) included electronic health record-based socio-demographics (sex, age, race/ethnicity, neighborhood deprivation index (NDI)) and medical comorbidities (obesity, cardiovascular conditions, diabetes, renal disease, respiratory conditions). We estimated the adjusted risk of SARS-CoV-2 infection and hospitalization (≤30 days of infection) associated with smoking status using Cox proportional hazard regression models. We estimated associations within subgroups of socio-demographics and comorbidities, and tested for effect modification using interaction terms. During the study, 35,627 patients had SARS-CoV-2 infection. Current versus never-smoking status was associated with lower adjusted rates of SARS-CoV-2 infection (aHR ranging from 0.51 to 0.89) and hospitalization (aHR ranging from 0.32 to 0.70) within nearly every socio-demographic and comorbidity subgroup. Statistically significant interactions showed that the magnitude of protection for SARS-CoV-2 infection varied by sex, age, race/ethnicity, NDI, cardiovascular conditions and diabetes, and for SARS-CoV-2 hospitalization by age and renal disease. Taken together, results indicated that while some socio-demographics and comorbidities moderated the associations, the lower risk of SARS-CoV-2 infection and hospitalization associated with current versus never-smoking status persisted among patients regardless of socio-demographics or comorbidities.

Association of Long-term Exposure to Particulate Air Pollution With Cardiovascular Events in California.

Importance: Long-term exposure to fine particulate air pollution (PM2.5) is a known risk factor for cardiovascular events, but controversy remains as to whether the current National Ambient Air Quality Standard (12 µg/m3 for 1-year mean PM2.5) is sufficiently protective. Objective: To evaluate the associations between long-term fine particulate air pollution and cardiovascular events using electronic health record and geocoded address data. Design, Setting, and Participants: This retrospective cohort study included adults in the Kaiser Permanente Northern California integrated health care system during 2007 to 2016 and followed for up to 10 years. Study participants had no prior stroke or acute myocardial infarction (AMI), and lived in Northern California for at least 1 year. Analyses were conducted January 2020 to December 2022. Exposure: Long-term exposure to PM2.5. Individual-level time-varying 1-year mean PM2.5 exposures for every study participant were updated monthly from baseline through the end of follow-up, accounting for address changes. Main Outcomes and Measures: Incident AMI, ischemic heart disease (IHD) mortality, and cardiovascular disease (CVD) mortality. Cox proportional hazards models were fit with age as time scale, adjusted for sex, race and ethnicity, socioeconomic status, smoking, body mass index, baseline comorbidities, and baseline medication use. Associations below the current regulation limit were also examined. Results: The study cohort included 3.7 million adults (mean [SD] age: 41.1 [17.2] years; 1 992 058 [52.5%] female, 20 205 [0.5%] American Indian or Alaskan Native, 714 043 [18.8%] Asian, 287 980 [7.6%] Black, 696 796 [18.4%] Hispanic, 174 261 [4.6%] multiracial, 1 904 793 [50.2%] White). There was a 12% (95% CI, 7%-18%) increased risk of incident AMI, a 21% (95% CI, 13%-30%) increased risk of IHD mortality, and an 8% (95% CI, 3%-13%) increased risk of CVD mortality associated with a 10 µg/m3 increase in 1-year mean PM2.5. PM2.5 exposure at moderate concentrations (10.0 to 11.9 µg/m3) was associated with increased risks of incident AMI (6% [95% CI, 3%-10%]) and IHD mortality (7% [95% CI, 2%-12%]) compared with low concentrations (less than 8 µg/m3). Conclusions and Relevance: In this study, long-term PM2.5 exposure at moderate concentrations was associated with increased risks of incident AMI, IHD mortality, and CVD mortality. This study's findings add to the evidence that the current regulatory standard is not sufficiently protective.

MiXcan: a framework for cell-type-aware transcriptome-wide association studies with an application to breast cancer.

Human bulk tissue samples comprise multiple cell types with diverse roles in disease etiology. Conventional transcriptome-wide association study approaches predict genetically regulated gene expression at the tissue level, without considering cell-type heterogeneity, and test associations of predicted tissue-level expression with disease. Here we develop MiXcan, a cell-type-aware transcriptome-wide association study approach that predicts cell-type-level expression, identifies disease-associated genes via combination of cell-type-level association signals for multiple cell types, and provides insight into the disease-critical cell type. As a proof of concept, we conducted cell-type-aware analyses of breast cancer in 58,648 women and identified 12 transcriptome-wide significant genes using MiXcan compared with only eight genes using conventional approaches. Importantly, MiXcan identified genes with distinct associations in mammary epithelial versus stromal cells, including three new breast cancer susceptibility genes. These findings demonstrate that cell-type-aware transcriptome-wide analyses can reveal new insights into the genetic and cellular etiology of breast cancer and other diseases.

Tobacco Smoking and Risk of SARS-CoV-2 Infection and Disease Severity Among Adults in an Integrated Healthcare System in California.

INTRODUCTION: The relationship between tobacco smoking status and SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) severity is highly debated. We conducted a retrospective cohort study of >2.4 million adults in a large healthcare system to evaluate whether smoking is associated with SARS-CoV-2 infection and disease severity. AIMS AND METHODS: This retrospective cohort study of 2,427,293 adults in KPNC from March 5, 2020 (baseline) to December 31, 2020 (pre-vaccine) included smoking status (current, former, never), socio-demographics, and comorbidities from the electronic health record. SARS-CoV-2 infection (identified by a positive PCR test) and COVID-19 severity (hospitalization, ICU admission or death ≤ 30 days of COVID-19 diagnosis) were estimated in time-to-event analyses using Cox proportional hazard regression models adjusting for covariates. Secondary analyses examined COVID-19 severity among patients with COVID-19 using logistic regression. RESULTS: During the study, 44,270 patients had SARS-CoV-2 infection. Current smoking was associated with lower adjusted rates of SARS-CoV-2 infection (aHR = 0.64 95% CI: 0.61-0.67), COVID-19-related hospitalization (aHR = 0.48 95% CI: 0.40-0.58), ICU admission (aHR = 0.62 95% CI: 0.42-0.87), and death (aHR = 0.52 95% CI: 0.27-0.89) than never-smoking. Former smoking was associated with a lower adjusted rate of SARS-CoV-2 infection (aHR = 0.96 95% CI: 0.94-0.99) and higher adjusted rates of hospitalization (aHR = 1.10 95% CI: 1.03-1.08) and death (aHR = 1.32 95% CI: 1.11-1.56) than never-smoking. Logistic regression analyses among patients with COVID-19 found lower odds of hospitalization for current versus never-smoking and higher odds of hospitalization and death for former versus never-smoking. CONCLUSIONS: In the largest US study to date on smoking and COVID-19, current and former smoking showed lower risk of SARS-CoV-2 infection than never-smoking, while a history of smoking was associated with higher risk of severe COVID-19. IMPLICATIONS: In this cohort study of 2.4 million adults, adjusting for socio-demographics and medical comorbidities, current tobacco smoking was associated with a lower risk of both SARS-CoV-2 infection and severe COVID-19 illness compared to never-smoking. A history of smoking was associated with a slightly lower risk of SARS-CoV-2 infection and a modestly higher risk of severe COVID-19 illness compared to never-smoking. The lower observed COVID-19 risk for current versus never-smoking deserves further investigation. Results support prioritizing individuals with smoking-related comorbidities for vaccine outreach and treatments as they become available.

Electronic cigarette use and risk of COVID-19 among young adults without a history of cigarette smoking.

It is unknown whether use of e-cigarettes increases susceptibility to COVID-19. In a large clinical sample of young adults, we evaluated whether current or ever e-cigarette use was associated with polymerase chain reaction (PCR)-confirmed COVID-19. To address the confounding of combustible smoking, the sample was restricted to never smokers. This retrospective cohort study analyzed data from the electronic health records of 74,853 young adults (aged 18-35 years), without a history of cigarette smoking, who were screened for e-cigarette use (current, former, never) in the Kaiser Permanente Northern California (KPNC) healthcare system from 3/5/2020 (baseline) to 11/30/2020 (pre-vaccine). COVID-19 risk was estimated in time-to-event analyses using multivariable Cox proportional hazard regression models, adjusted for socio-demographics and medical comorbidities. E-cigarette status in the cohort was: 1.6% current, 1.2% former, and 97.2% never. During follow-up, 1965 (2.6%) patients acquired COVID-19. We did not find evidence that current (vs never) e-cigarette use was associated with risk of COVID-19 (aHR = 1.12 95%CI:0.77-1.62). However, we did find suggestive evidence that former (versus never) e-cigarette use may be associated with greater risk of COVID-19 (aHR = 1.39 95%CI:0.98-1.96). While e-cigarette use is associated with health risks for young adults, results from this study suggest that current use of e-cigarettes may not increase susceptibility for COVID-19 among young adults who have never smoked cigarettes.

Trends in Cannabis Polysubstance Use During Early Pregnancy Among Patients in a Large Health Care System in Northern California.

Importance: Rates of prenatal cannabis use are increasing alongside perceptions that cannabis is a harmless therapeutic for pregnancy-related ailments, while rates of prenatal use of alcohol and tobacco are decreasing. It is important to examine whether cannabis use during pregnancy is increasing similarly among patients with and patients without co-occurring substance use. Objectives: To examine trends in cannabis polysubstance use during pregnancy and to test differences in cannabis use over time among pregnant individuals who use only cannabis vs those who use cannabis and other substances. Design, Setting, and Participants: This cross-sectional time-series study used data from 367 138 pregnancies among 281 590 unique pregnant patients universally screened for prenatal substance use as part of standard care in Kaiser Permanente Northern California from January 1, 2009, to December 31, 2018. Statistical analysis was performed from October 5, 2021, to April 18, 2022. Exposures: Time (calendar year). Main Outcomes and Measures: Use of substances during early pregnancy was assessed via universal screening with a self-administered questionnaire (for cannabis, alcohol, stimulants, and nicotine) and/or positive results of a urine toxicology test (for cannabis, alcohol, stimulants, and pharmaceutical opioids), and data were extracted from the electronic health record. Results: The study sample of 367 138 pregnancies from 281 590 unique pregnant patients (median gestation at time of screening, 8.6 weeks [IQR, 7.3-10.6 weeks]) was 25.9% Asian or Pacific Islander, 6.6% Black, 25.8% Hispanic, 38.0% non-Hispanic White, and 3.6% other race or ethnicity; 1.1% were aged 11 to 17 years, 14.9% were aged 18 to 24 years, 61.9% were aged 25 to 34 years, and 22.1% were aged 35 years or older; and the median neighborhood household income was $70 455 (IQR, $51 563-$92 625). From 2009 to 2018, adjusted rates of use of only cannabis during pregnancy (no other substances) increased substantially from 2.39% (95% CI, 2.20%-2.58%) in 2009 to 6.30% (95% CI, 6.00%-6.60%) in 2018, increasing at an annual relative rate of 1.11 (95% CI, 1.10-1.12). The rate of use of cannabis and 1 other substance also increased (annual relative rate, 1.04 [95% CI, 1.03-1.05]), but not as rapidly (P < .001 for difference), while the rate of use of cannabis and 2 or more other substances decreased slightly (annual relative rate, 0.97 [95% CI, 0.96-0.99]). Adjusted rates of prenatal use of cannabis and alcohol (1.04 [95% CI, 1.03-1.06]) and cannabis and stimulants (1.03 [95% CI, 1.01-1.06]) increased over time, while rates of prenatal use of cannabis and nicotine (0.97 [95% CI, 0.96-0.98]) decreased. Conclusions and Relevance: In this cross-sectional time-series study, rates of prenatal cannabis use during early pregnancy increased significantly more rapidly among patients without co-occurring substance use, which could reflect increased acceptability of cannabis and decreased perceptions of cannabis-related harms. Furthermore, increased rates of use of cannabis with alcohol and stimulants warrant continued monitoring.

Joint associations between neighborhood walkability, greenness, and particulate air pollution on cardiovascular mortality among adults with a history of stroke or acute myocardial infarction.

Fine particulate matter (PM2.5) is a known risk factor for cardiovascular disease (CVD). Neighborhood walkability and greenness may also be associated with CVD, but there is limited evidence on their joint or interacting effects with PM2.5. Methods: Cox proportional hazard models were used to estimate the risk of CVD mortality among adults with a history of acute myocardial infarction and/or stroke living in Northern California. We assessed the independent and joint effects of walkability, greenness (Normalized Differentiated Vegetation Index [NDVI]), and PM2.5 at residential addresses, controlling for age, sex, race/ethnicity, comorbidities, BMI, smoking, revascularization, medications, and socioeconomic status. Results: Greenness had a nonlinear association with CVD mortality (P = 0.038), with notably protective effects (HR = 0.87 [95% confidence interval {CI} = 0.78, 0.97]) at higher greenness levels (NDVI ≥ 0.3) and moderate attenuation after adjusting for PM2.5 (HR = 0.92 [95% CI = 0.82, 1.03]) per 0.1 increase in NDVI. Walkability had no independent effect on CVD mortality. PM2.5 had a strong independent effect in models adjusted for greenness and walkability (HR = 1.20 [95% CI = 1.08, 1.33)) per 10 µg/m3 increase in PM2.5. There was an interaction between walkability and PM2.5 (P = 0.037), where PM2.5 had slightly stronger associations in more walkable than less walkable neighborhoods (HR = 1.23 [95% CI = 1.06, 1.42] vs. 1.17 [95% CI = 1.04, 1.32]) per 10 µg/m3 increase in PM2.5. Greenness had no interaction with PM2.5 (P = 0.768) nor walkability (P = 0.385). Conclusions: High greenness may be protective of CVD mortality among adults with CVD history. PM2.5 associated CVD mortality risk varies slightly by level of neighborhood walkability, though these small differences may not be clinically meaningful.

Cohort and nested case-control study of cutaneous squamous cell carcinoma in solid organ transplant recipients, by medication.

BACKGROUND: Knowledge is needed about the risk of cutaneous squamous cell carcinoma (cSCC) in solid organ transplant recipients (SOTRs) using contemporary immunosuppressive regimens. OBJECTIVE: Evaluate the risk of cSCC in relation to medications used by SOTRs. METHODS: The cohort and nest case-control study included 3308 SOTRs and 65,883 persons without transplantation during 2009-2019. Incident cSCC was identified from pathology data, and medications were identified from pharmacy data. Adjusted hazard ratios and 95% confidence intervals (CIs) were estimated using Cox proportional hazards analysis, with voriconazole examined as a time-dependent variable. RESULTS: The annual incidence of cSCC was 1.69% in SOTRs and 0.30% in persons without transplantation. The adjusted hazard ratio of cSCC associated with lung transplant was 14.83 (95% CI, 9.85-22.33) for lung and 6.53-10.69 for other organs. Risk in Latinx persons was higher than in other non-White groups. Among lung recipients, the hazard ratio was 1.14 for each month of voriconazole use (95% CI, 1.04-1.26). Azathioprine use for ≥7 months, relating to mycophenolate mofetil intolerance, was associated with a 4.22-fold increased risk of cSCC (95% CI, 1.90-9.40). Belatacept and other immunsuppressive medications were not associated with risk. LIMITATION: The number of events was somewhat small. CONCLUSIONS: The knowledge of risks and benefits in diverse patients can translate to improvements in care.

Individual- and neighborhood-level socioeconomic status and risk of aggressive breast cancer subtypes in a pooled cohort of women from Kaiser Permanente Northern California.

BACKGROUND: Low socioeconomic status (SES) has been associated with a higher risk of aggressive breast cancer (BC) subtypes, but few studies have examined the independent effects of both neighborhood-level socioeconomic status (nSES) and individual-level SES measures. METHODS: This study included 5547 women from the Pathways and Life After Cancer Epidemiology cohorts who were diagnosed with invasive BC. Generalized estimating equation models were used to examine associations of nSES (a composite score based on income, poverty, education, occupation, employment, rent, and house value) and individual-level SES (income and education) with BC subtypes: luminal B (LumB), Her2-enriched (Her2-e), and triple-negative breast cancer (TNBC) relative to luminal A (LumA). Models controlled for age, race, nativity, stage, days from diagnosis to survey, and study cohort and simultaneously for nSES and individual-level SES. RESULTS: In fully adjusted models, low nSES was significantly associated with the LumB (odds ratio for quartile 1 vs quartile 4 [ORQ1vQ4 ], 1.31; 95% confidence interval [CI], 1.11-1.54; P for trend = .005) and TNBC subtypes (ORQ1vQ4 , 1.32; 95% CI, 1.02-1.71; P for trend = .037) relative to LumA. Conversely, individual education was significantly associated with only the Her2-e subtype (odds ratio for high school degree or less vs postgraduate, 1.68; 95% CI, 1.03-2.75; P for trend = .030) relative to LumA. Individual income was not significantly associated with any BC subtype. CONCLUSIONS: nSES and individual-level SES are independently associated with different BC subtypes; specifically, low nSES and individual-level education are independent predictors of more aggressive BC subtypes relative to LumA.

Particulate Matter and Cardiovascular Risk in Adults with Chronic Obstructive Pulmonary Disease.

Rationale: People with chronic obstructive pulmonary disease (COPD) have an increased risk of cardiovascular disease and may be more susceptible to air pollution exposure. However, no study has examined the association between long-term fine particulate matter exposure (≤2.5 µm in aerodynamic diameter) and risk of cardiovascular events in this potentially vulnerable population. Objectives: To estimate the association between long-term fine particulate matter and risk of cardiovascular events among adults with COPD. Methods: This retrospective cohort study included 169,714 adults with COPD who were members of the Kaiser Permanente Northern California health plan during 2007-2016. Electronic health record data were linked to 1 km modeled particulate matter ≤2.5 µm in aerodynamic diameter exposure estimates. We fit Cox proportional hazard models, adjusting for age, sex, race/ethnicity, calendar year, smoking, body mass index, comorbidities, medications, and socioeconomic status. In low exposure analyses, we examined effects below the current regulation limit (12 µg/m3). Measurements and Main Results: Among adults with COPD, a 10-µg/m3 increase in 1-year mean fine particulate matter exposure was associated with an elevated risk of cardiovascular mortality (hazard ratio, 1.10; 95% confidence interval [CI], 1.01-1.20). Effects were stronger in low exposure analyses (hazard ratio, 1.88; 95% CI, 1.56-2.27). Fine particulate matter exposure was not associated with acute myocardial infarction or stroke in overall analyses. Conclusions: Long-term fine particulate matter exposure was associated with an increased risk of cardiovascular mortality among adults with COPD. Current regulations may not sufficiently protect those with COPD.

Cross-cancer evaluation of polygenic risk scores for 16 cancer types in two large cohorts.

Even distinct cancer types share biological hallmarks. Here, we investigate polygenic risk score (PRS)-specific pleiotropy across 16 cancers in European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and UK Biobank (48,969 cases, 359,802 controls). Within cohorts, each PRS is evaluated in multivariable logistic regression models against all other cancer types. Results are then meta-analyzed across cohorts. Ten positive and one inverse cross-cancer associations are found after multiple testing correction. Two pairs show bidirectional associations; the melanoma PRS is positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS is positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS is inversely associated with lung cancer. Overall, we validate known, and uncover previously unreported, patterns of pleiotropy that have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies.

Comparison of dementia risk after age 50 between individuals with and without HIV infection.

OBJECTIVE: To compare risk of dementia after age 50 by HIV status among individuals in a primary care setting. DESIGN: Observational cohort study; participants were identified from 2013 to 2017 and followed through 2019. METHODS: Participants were people with HIV (PWH) on antiretroviral therapy (ART) and demographically similar people without HIV (PWOH), all at least 50 years old and with no prior diagnosis of dementia. The study setting was Kaiser Permanente Northern California, an integrated healthcare delivery system in the United States. Incident dementia diagnoses and baseline data on sociodemographics, smoking, alcohol use, other substance use, and clinical factors were gathered from the electronic health record. Cumulative proportion of incident dementia by HIV status was assessed using Kaplan--Meier curves. Unadjusted and adjusted hazard ratios for incident dementia by HIV status were generated using Cox proportional hazards models with age as the time scale. RESULTS: The study included 5381 PWH and 119 022 PWOH (average age at baseline: 57 and 58 years, respectively). Incident dementia was diagnosed in 117 PWH and 2427 PWOH. By age 80, 25.8% of PWH and 13.8% of PWOH had been diagnosed with dementia, corresponding with an unadjusted hazard ratio of 1.98 (95% CI 1.64-2.39). After adjustment for sociodemographic, substance use, and clinical factors, including frequency of outpatient visits, the risk of dementia among PWH remained elevated (vs. PWOH, adjusted hazard ratio = 1.58, 95% CI 1.31-1.92). CONCLUSION: Compared with PWOH, PWH were at 58% higher risk for dementia despite HIV treatment with ART. Research is needed to investigate the potential benefits of targeted risk factor management or earlier cognitive screening in this population.

Intraocular Pressure Reduction after Phacoemulsification: A Matched Cohort Study.

PURPOSE: Phacoemulsification has been linked to lowered intraocular pressure (IOP) in patients with glaucoma, ocular hypertension, anatomic narrow angles, and in glaucoma suspects, but the magnitude of change has varied. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with glaucoma treated from June 2010 through May 2015 who underwent phacoemulsification (surgical group) were matched to patients who did not (nonsurgical group) for age, gender, type of glaucoma, baseline IOP, and number and type of glaucoma medications. METHODS: Electronic medical record information was used to compare the matched surgical and nonsurgical groups. MAIN OUTCOME MEASURES: Change in IOP, change in number of glaucoma medications, and likelihood of a glaucoma procedure within 36 months after phacoemulsification. Intraocular pressure measures were obtained from Goldmann applanation tonometry when available (45%), and otherwise with the iCare tonometer (iCare USA, Raleigh, NC), the Tono-Pen (Reichert Technologies, Depew, NY), noncontact tonometry, and pneumotonometry. RESULTS: Among 16 169 matched pairs, average IOP after the index date was lower in the surgical than nonsurgical group throughout follow-up to 36 months. The difference was greatest during months 1 through 18, during which IOP increased by 0.22 mmHg from 16.49 mmHg in the average nonsurgical patient and decreased by 0.99 mmHg from 16.50 mmHg in the average surgical patient (difference in difference, 1.21 mmHg; 95% confidence interval [CI], 1.12-1.30 mmHg). The difference in difference was greatest for patients with ocular hypertension (2.00 mmHg) and for patients with preoperative IOP of 20 mmHg or more (2.46 mmHg). By 30 to 36 months, 5% (95% CI, 4%-6%) fewer surgical patients used an ophthalmic medication. In the surgical group, the odds of selective laser trabeculoplasty were reduced in patients with ocular hypertension (odds ratio [OR], 0.27; 95% CI, 0.10-0.74) or glaucoma suspects (OR, 0.31; 95% CI, 0.20-0.47), whereas the odds of glaucoma surgery were elevated in surgical patients with primary open-angle glaucoma (OR, 1.48; 95% CI, 1.08-2.01). CONCLUSIONS: The association of phacoemulsification for cataract with IOP reduction was lower than in past referral-based studies. Surgeons should expect to reduce IOP approximately 1 to 2 mmHg with phacoemulsification in patients with preoperative IOP of less than 20 mmHg.

Visual outcomes after cataract surgery: topical nonsteroidal anti-inflammatory drug prophylaxis compared with prednisolone.

PURPOSE: To compare visual outcomes in patients without a history of macular edema after phacoemulsification using combination topical nonsteroidal anti-inflammatory drug plus prednisolone with prednisolone alone. SETTING: Kaiser Permanente Northern California, USA. DESIGN: Retrospective cohort study. METHODS: Information was obtained from the electronic health record. The first measure of corrected distance visual acuity (CDVA) recorded during the period 3 weeks to 1 year after phacoemulsification was obtained. Confounding factors and clustering of eyes within patients were adjusted using linear mixed effects regression models for the continuous outcome of CDVA improvement and general estimating equations for the dichotomous outcome of 20/20 or better vs 20/25 or worse. RESULTS: The study included 62 700 health plan members of whom 26,309 (42%) used topical prednisolone alone, whereas 36,391 (58%) used combination treatment. The mean within-person change in CDVA from the preoperative measurement to the postoperative measurement was the same (-0.43 logMAR) for patients in the 2 groups. However, the group that received combination treatment was somewhat more likely to achieve CDVA of 20/20 or better (odds ratio 1.24 with 95% CI, 1.20-1.28). CONCLUSIONS: In this large study of cataract surgery patients, a small statistically significant association of combination treatment compared with prednisolone alone was observed.