Utilizing social determinants of health to identify most vulnerable neighborhoods-Latent class analysis and GIS map.

OBJECTIVES: Public Health officials are often challenged to effectively allocate limited resources. Social determinants of health (SDOH) may cluster in areas to cause unique profiles related to various adverse life events. The authors use the framework of unintended teen pregnancies to illustrate how to identify the most vulnerable neighborhoods. METHODS: This study used data from the U.S. American Community Survey, Princeton Eviction Lab, and Connecticut Office of Vital Records. Census tracts are small statistical subdivisions of a county. Latent class analysis (LCA) was employed to separate the 832 Connecticut census tracts into four distinct latent classes based on SDOH, and GIS mapping was utilized to visualize the distribution of the most vulnerable neighborhoods. GEE Poisson regression model was used to assess whether latent classes were related to the outcome. Data were analyzed in May 2021. RESULTS: LCA's results showed that class 1 (non-minority non-disadvantaged tracts) had the least diversity and lowest poverty of the four classes. Compared to class 1, class 2 (minority non-disadvantaged tracts) had more households with no health insurance and with single parents; and class 3 (non-minority disadvantaged tracts) had more households with no vehicle available, that had moved from another place in the past year, were low income, and living in renter-occupied housing. Class 4 (minority disadvantaged tracts) had the lowest socioeconomic characteristics. CONCLUSIONS: LCA can identify unique profiles for neighborhoods vulnerable to adverse events, setting up the potential for differential intervention strategies for communities with varying risk profiles. Our approach may be generalizable to other areas or other programs. KEY MESSAGES: What is already known on this topic Public health practitioners struggle to develop interventions that are universally effective. The teen birth rates vary tremendously by race and ethnicity. Unplanned teen pregnancy rates are related to multiple social determinants and behaviors. Latent class analysis has been applied successfully to address public health problems. What this study adds While it is the pregnancy that is not planned rather than the birth, access to pregnancy intention data is not available resulting in a dependency on teen birth data for developing public health strategies. Using teen birth rates to identify at-risk neighborhoods will not directly represent the teens at risk for pregnancy but rather those who delivered a live birth. Since teen birth rates often fluctuate due to small numbers, especially for small neighborhoods, LCA may avoid some of the limitations associated with direct rate comparisons. The authors illustrate how practitioners can use publicly available SDOH from the Census Bureau to identify distinct SDOH profiles for teen births at the census tract level. How this study might affect research, practice or policy These profiles of classes that are at heightened risk potentially can be used to tailor intervention plans for reducing unintended teen pregnancy. The approach may be adapted to other programs and other states to prioritize the allocation of limited resources.

A Comparison of Two Statewide Datasets to Understand Population Prevalence of Substance Use in Pregnancy: Findings and Considerations for Policy & Research.

Mental health conditions including substance use disorder are the leading cause of pregnancy-related deaths in the U.S. Unfortunately, fears of child protective services' involvement interfere with maternal self-disclosure of substance use in pregnancy. Seeking to identify more mothers with substance use disorder in pregnancy or at delivery, and responsive to changes to the federal Child Abuse Prevention and Treatment Act (CAPTA), Connecticut requires hospital personnel to submit a deidentified notification to CPS for all newborns with prenatal substance exposure. However, it is unknown whether this approach aligns with maternal self-report on substance use. For the present study, we compared population parameters derived from CAPTA notifications submitted between March-December 2019 with parameters derived from self-report data on substance use in pregnancy from mothers who gave birth during the same timeframe. Results revealed that three times as many mothers self-reported any alcohol or drug use in pregnancy compared to the rate measured with CAPTA notifications. Compared to mothers who self-reported drug use in the third trimester, CAPTA notifications were made for statistically similar rates of Black mothers but half the self-reported rate of White and Hispanic mothers. This disparity reflects that CAPTA notifications were made for twice as many Black mothers as White or Hispanic. Although CAPTA notifications are not punitive in nature, this disparity reveals that the public health aims of this policy are not yet achieved.

A 71-Year-Old Man With Diffuse Waxing and Waning Multifocal Lung Lesions, Empyema, and Episodic Fevers Reveals a Rare Diagnosis.

CASE PRESENTATION: A 71-year-old man with history of gastroesophageal reflux disease, chronic sinusitis, arthritis, hypothyroidism, and anemia of chronic disease initially sought treatment with a recurrent left pleural effusion along with other abnormal lung findings on chest CT scan. Before his referral, he was being managed for 3 years at his local hospital for waxing and waning fevers, fatigue, productive cough, chills, and night sweats. He did not report any hemoptysis or chest pain, but reported weight loss of 13 kgs in 15 months. During those 3 years, he was treated with multiple courses of antibiotics and steroids with temporary relief of symptoms. At that time, his chronic sinusitis was suspected to be the cause of his symptoms and he underwent balloon sinuplasty. He was receiving daily sublingual immunotherapy for inhaled respiratory allergens for the previous year after showing positive test results for 17 inhaled allergens. The patient had no other known immunologic workup before our evaluation.

Endogenous Estrogens, Estrogen Metabolites, and Breast Cancer Risk in Postmenopausal Chinese Women.

BACKGROUND: The role of estrogen metabolism in determining breast cancer risk and differences in breast cancer rates between high-incidence and low-incidence nations is poorly understood. METHODS: We measured urinary concentrations of estradiol and estrone (parent estrogens) and 13 estrogen metabolites formed by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring in a nested case-control study of 399 postmenopausal invasive breast cancer case participants and 399 matched control participants from the population-based Shanghai Women's Health Study cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by quartiles of metabolic pathway groups, pathway ratios, and individual estrogens/estrogen metabolites were estimated by multivariable conditional logistic regression. Urinary estrogen/estrogen metabolite measures were compared with those of postmenopausal non-hormone-using Asian Americans, a population with three-fold higher breast cancer incidence rates. All statistical tests were two-sided. RESULTS: Urinary concentrations of parent estrogens were strongly associated with breast cancer risk (ORQ4vsQ1 = 1.94, 95% CI = 1.21 to 3.12, Ptrend = .01). Of the pathway ratios, the 2-pathway:total estrogens/estrogen metabolites and 2-pathway:parent estrogens were inversely associated with risk (ORQ4vsQ1 = 0.57, 95% CI = 0.35 to 0.91, Ptrend = .03, and ORQ4vsQ1 = 0.61, 95% CI = 0.37 to 0.99, Ptrend = .04, respectively). After adjusting for parent estrogens, these associations remained clearly inverse but lost statistical significance (ORQ4vsQ1 = 0.65, 95% CI = 0.39 to 1.06, Ptrend = .12 and ORQ4vsQ1 = 0.76, 95% CI = 0.44 to 1.32, Ptrend = .28). The urinary concentration of all estrogens/estrogen metabolites combined in Asian American women was triple that in Shanghai women. CONCLUSIONS: Lower urinary parent estrogen concentrations and more extensive 2-hydroxylation were each associated with reduced postmenopausal breast cancer risk in a low-risk nation. Markedly higher total estrogen/estrogen metabolite concentrations in postmenopausal United States women (Asian Americans) than in Shanghai women may partly explain higher breast cancer rates in the United States.

Quantifying the Role of Circulating Unconjugated Estradiol in Mediating the Body Mass Index-Breast Cancer Association.

BACKGROUND: Higher body mass index (BMI) and circulating estrogen levels each increase postmenopausal breast cancer risk, particularly estrogen receptor-positive (ER(+)) tumors. Higher BMI also increases estrogen production. METHODS: We estimated the proportion of the BMI-ER(+) breast cancer association mediated through estrogen in a case-control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Participants included 143 women with invasive ER(+) breast cancer and 268 matched controls, all postmenopausal and never having used hormone therapy at baseline. We used liquid chromatography-tandem mass spectrometry to measure 15 estrogens and estrogen metabolites in baseline serum. We calculated BMI from self-reported height and weight at baseline. We estimated the mediating effect of unconjugated estradiol on the BMI-ER(+) breast cancer association using Aalen additive hazards and Cox regression models. RESULTS: All estrogens and estrogen metabolites were statistically significantly correlated with BMI, with unconjugated estradiol most strongly correlated [Pearson correlation (r) = 0.45]. Approximately 7% to 10% of the effect of overweight, 12% to 15% of the effect of obesity, and 19% to 20% of the effect of a 5 kg/m(2) BMI increase on ER(+) breast cancer risk was mediated through unconjugated estradiol. The BMI-breast cancer association, once adjusted for unconjugated estradiol, was not modified by further adjustment for two metabolic ratios statistically significantly associated with both breast cancer and BMI. CONCLUSION: Circulating unconjugated estradiol levels partially mediate the BMI-breast cancer association, but other potentially important estrogen mediators (e.g., bioavailable estradiol) were not evaluated. IMPACT: Further research is required to identify mechanisms underlying the BMI-breast cancer association.

Estrogen metabolism and risk of breast cancer in postmenopausal women.

BACKGROUND: Estrogens are recognized causal factors in breast cancer. Interindividual variation in estrogen metabolism may also influence the risk of breast cancer and could provide clues to mechanisms of breast carcinogenesis. Long-standing hypotheses about how estrogen metabolism might influence breast cancer have not been adequately evaluated in epidemiological studies because of the lack of accurate, reproducible, and high-throughput assays for estrogen metabolites. METHODS: We conducted a prospective case-control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Participants included 277 women who developed invasive breast cancer (case subjects) and 423 matched control subjects; at PLCO baseline, all subjects were aged 55-74 years, postmenopausal and not using hormone therapy, and provided a blood sample. Liquid chromatography-tandem mass spectrometry was used to measure serum concentrations of 15 estrogens and estrogen metabolites, in unconjugated and conjugated forms, including the parent estrogens, estrone and estradiol, and estrogen metabolites in pathways defined by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring. We calculated hazard ratios (HRs) approximating risk in highest vs lowest deciles of individual estrogens and estrogen metabolites, estrogens and estrogen metabolites grouped by metabolic pathways, and metabolic pathway ratios using multivariable Cox proportional hazards models. All statistical tests were two-sided. RESULTS: Nearly all estrogens, estrogen metabolites, and metabolic pathway groups were associated with an increased risk of breast cancer; the serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). No estrogen, estrogen metabolite, or metabolic pathway group remained statistically significantly associated with the risk of breast cancer after adjusting for unconjugated estradiol. The ratio of the 2-hydroxylation pathway to parent estrogens (HR = 0.66, 95% CI = 0.51 to 0.87) and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols (HR = 1.34, 95% CI = 1.04 to 1.72) were statistically significantly associated with the risk of breast cancer and remained so after adjustment for unconjugated estradiol. CONCLUSIONS: More extensive 2-hydroxylation of parent estrogens is associated with lower risk, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols is associated with higher risk of postmenopausal breast cancer.

Analysis of the temporal and concentration-dependent effects of BMP-4, VEGF, and TPO on development of embryonic stem cell-derived mesoderm and blood progenitors in a defined, serum-free media.

OBJECTIVE: To develop a robust serum-free (SF) system for generation of hemogenic mesoderm and blood progenitors from pluripotent cells. MATERIALS AND METHODS: Embryonic stem cells (ESCs) maintained in N2B27 supplemented with leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP)-4 were induced to differentiate into Brachyury/T-expressing cells (measured using a green fluorescent protein reporter) and myeloid-erythroid colony-forming cells (ME-CFCs), by removing LIF, changing the base media formulation, and via the time- and concentration-dependent addition of other factors. RESULTS: Presence of 10 ng/mL BMP-4 permitted the emergence of cells expressing T and the vascular endothelial growth factor receptor (VEGFR)-2, however, <5% of the cells were double-positive on day 4. Adjusting the SF media formulation allowed only 5 ng/mL BMP-4 to yield 24% +/- 4% Brachyury-green fluorescent protein VEGFR-2(+) cells by day 4. These cells could develop into ME-CFC, producing 4.4 +/- 0.8 CFC per 1000 cells at day 8. We also examined the timing and concentration sensitivity of BMP-4, VEGF, and thrombopoietin (TPO) during differentiation. BMP-4 with 50 ng/mL TPO generated 232 +/- 48 CFC per 5 x 10(4) cells, similar to the serum-control, and this response could be enhanced to 292 +/- 42 CFC per 5 x 10(4) cells by early (between day 0-5), but not late (after day 5) VEGF treatment. CONCLUSION: Moving to SF systems facilitates directed differentiation by eliminating confounding signals. This article describes modifications to the N2B27 media that amplify mesoderm induction and extends earlier work defining blood progenitor cell induction from ESC with BMP-4, VEGF, and TPO.

A novel calcium-sensing receptor antagonist transiently stimulates parathyroid hormone secretion in vivo.

Circulating calcium (Ca(2+)) is a primary regulator of bone homeostasis through its action on PTH secretion. Extracellular Ca(2+) modulates PTH secretion through a cell surface G protein-coupled receptor, the calcium-sensing receptor (CaR). The expression of the CaR suggests a critical role in cellular regulation by calcium in various organs, including parathyroid gland, bone, and kidney. Despite an obvious pharmacological utility for CaR antagonists in the treatment of disease, only a limited number of such classes of compounds exist. We have identified a novel class of small molecules with specific activity at the CaR. This class of compounds is represented by compound 1. It possesses potent antagonist activity at the human CaR with IC(50) values of 64 nm and 230 nm in inhibiting intracellular Ca(2+) flux and inositol phosphate generation in vitro, respectively. When administered to male rats in vivo, compound 1 robustly increased serum PTH levels. The stimulation of PTH secretion was rapid and transient when administered either iv or orally. The pharmacokinetic profile of compound 1 after oral administration revealed that maximal plasma levels of compound were reached within 1 h and the half-life of the compound to be approximately 2 h in rats. These data describe a representative compound of a novel chemical class than previously described allosteric modulators that offer a new avenue for the development of improved treatments of osteoporosis.

Platelet activating factor-induced apoptosis is inhibited by ectopic expression of the platelet activating factor G-protein coupled receptor.

The pro-inflammatory lipid mediator platelet activating factor (PAF: 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) accumulates in ischemia, epilepsy, and human immunodeficiency virus-1-associated dementia and is implicated in neuronal loss. The present study was undertaken to establish a role for its G-protein coupled receptor in regulating neurotoxicity. PC12 cells do not express PAF receptor mRNA as demonstrated by northern analysis and RT-PCR. In the absence of the G-protein coupled receptor, PAF (0.1-1 micro m) triggered chromatin condensation, DNA strand breaks, oligonucleosomal fragmentation, and nuclear disintegration characteristic of apoptosis. Lyso-PAF (0.001-1 micro m), the immediate metabolite of PAF, did not elicit apoptotic death. Concentrations of PAF or lyso-PAF that exceeded critical micelle concentration had physicochemical effects on plasma membrane resulting in necrosis. Apoptosis but not necrosis was inhibited by the PAF antagonist BN52021 (1-100 micro m) but not CV3988 (0.2-20 micro m). Ectopic PAF receptor expression protected PC12 transfectants from ligand-induced apoptosis. PAF receptor-mediated protection was inhibited by CV3988 (1 micro m). These data provide empirical evidence that: (i) PAF can initiate apoptosis independently of its G-protein coupled receptor; (ii) PAF signaling initiated by its G-protein coupled receptor is cytoprotective to PC12 cells; (iii) the pro- and anti-apoptotic effects of PAF on PC12 cells can be pharmacologically distinguished using two different PAF antagonists.