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Obesity is known to be a major risk factor for diabetes, but the magnitude of risk and variation between blacks and whites are less well documented in populations heavily affected by obesity. Herein we assess rates and risks of incident diabetes in a diverse southern population where obesity is common. A total of 24,000 black and 14,064 white adults aged 40-79 in the Southern Community Cohort Study with no self-reported diabetes at study enrollment during 2002-2009 was followed for up to 10 (median 4.5) years. Incidence rates, odds ratios (OR) and accompanying 95% confidence intervals (CI) for medication-treated incident diabetes were determined according to body mass index (BMI) and other characteristics, including tobacco and alcohol consumption, healthy eating and physical activity indices, and socioeconomic status (SES). Risk of incident diabetes rose monotonically with increasing BMI, but the trends differed between blacks and whites (pinteraction < .0001). Adjusted ORs (CIs) for diabetes among those with BMI≥40 vs 20-25 kg/m2 were 11.9 (8.4-16.8) for whites and 4.0 (3.3-4.8) for blacks. Diabetes incidence was more than twice as high among blacks than whites of normal BMI, but the racial difference became attenuated as BMI rose, with estimated 5-year probabilities of developing diabetes approaching 20% for both blacks and whites with BMI≥40 kg/m2. Diabetes risk was also associated with low SES, significantly (pinteraction≤.02) more so for whites, current cigarette smoking, and lower healthy eating and physical activity indices, although high BMI remained the predominant risk factor among both blacks and whites. From baseline prevalence and 20-year projections of the incidence trends, we estimate that the large majority of surviving cohort participants with BMI≥40 kg/m2 will be diagnosed with diabetes. Even using conservative criteria to ascertain diabetes incidence (i.e., requiring diabetes medication use and ignoring undiagnosed cases), rates of obesity-associated diabetes were exceptionally high in this low-income adult population. The findings indicate that effective strategies to halt the rising prevalence of obesity are needed to avoid substantial increases in diabetes in coming years.

Biallelic inactivation of cancer susceptibility gene BRCA1 leads to breast and ovarian carcinogenesis. Paradoxically, BRCA1 deficiency in mice results in early embryonic lethality, and similarly, lack of BRCA1 in human cells is thought to result in cellular lethality in view of BRCA1's essential function. To survive homozygous BRCA1 inactivation during tumorigenesis, precancerous cells must accumulate additional genetic alterations, such as p53 mutations, but this requirement for an extra genetic \"hit\" contradicts the two-hit theory for the accelerated carcinogenesis associated with familial cancer syndromes. Here, we show that heterozygous BRCA1 inactivation results in genomic instability in nontumorigenic human breast epithelial cells in vitro and in vivo. Using somatic cell gene targeting, we demonstrated that a heterozygous BRCA1 185delAG mutation confers impaired homology-mediated DNA repair and hypersensitivity to genotoxic stress. Heterozygous mutant BRCA1 cell clones also showed a higher degree of gene copy number loss and loss of heterozygosity in SNP array analyses. In BRCA1 heterozygous clones and nontumorigenic breast epithelial tissues from BRCA mutation carriers, FISH revealed elevated genomic instability when compared with their respective controls. Thus, BRCA1 haploinsufficiency may accelerate hereditary breast carcinogenesis by facilitating additional genetic alterations.

ObjectiveTo report on longitudinal tobacco product cessation rates, by product type, among adults (ages 18+ years) in the USA between 2013 and 2019.MethodsThe Population Assessment of Tobacco and Health Study, a nationally representative, longitudinal cohort study was used to report on annual and biennial rates of the following three cessation behaviours across 2013–2019: (1) discontinuing tobacco product use (ie, transition from past 30-day use to no past 30-day use), (2) attempting to quit tobacco product use and (3) quitting tobacco product use among those who attempted to quit. Each cessation behaviour was evaluated separately for cigarettes, electronic nicotine delivery systems (ENDS), cigars, hookah and smokeless tobacco. Generalised estimating equations were used to evaluate linear and nonlinear trends in cessation rates across the study period.ResultsBetween 2013 and 2019, rates of discontinuing cigarette smoking among adults in the USA statistically increased from 16% to 18%, though these were consistently lower than rates of discontinuing use of other tobacco products. Similarly, quit attempt rates and rates of quitting among attempters increased for cigarette smokers. However, rates of discontinuing ENDS use sharply declined across the study period, from 62% to 44%.ConclusionsFindings show that tobacco product cessation rates have been changing in recent years in the USA alongside the changing tobacco product marketplace and regulatory environment, though rates of discontinuing cigarette smoking remain relatively low. Findings can serve as a benchmark against which future cessation rates can be compared to evaluate the impacts of future tobacco regulatory policies.

Cigar smoking remains a public health issue in the United States (U.S.), with a heterogeneous prevalence based on sociodemographic characteristics. Nationally representative data suggest changes in cigar smoking over time, with some evidence for sociodemographic differences. Using data from the 2002–2019 National Survey on Drug Use and Health (NSDUH), the prevalence of past-30-day cigar smoking was examined overall and stratified by sociodemographic characteristics; joinpoint regression examined the trends. Logistic regression analyses identified the correlates of cigar smoking using 2020 NSDUH data. From 2002 to 2004, the prevalence of cigar smoking remained stable (5.33–5.73%), but declined from 2004 to 2019 (5.73–4.29%). Cigar smoking declined in some periods between 2002–2019 among the non-Hispanic White, Hispanic, ages 12–17, ages 18–20, ages 21–25, age ≥ 35, and male subgroups, but remained unchanged among the non-Hispanic Other, ages 26–34, and female subgroups. Cigar smoking increased among non-Hispanic Black persons overall from 2002 to 2019 (6.67–8.02%). Past-30-day cigarette smoking and drug or alcohol use disorder was associated with an increased likelihood of cigar use, while female sex was associated with a decreased likelihood of cigar use, across all age groups. Though a decline in the prevalence of past-30-day cigar smoking is seen in the general population, the same is not evident among all sociodemographic subgroups. Our findings have the potential to inform tobacco cessation efforts within clinical practice, as well as regulatory efforts to reduce cigar use.

Ovarian carcinoma is composed of a heterogeneous group of tumors with distinct clinico-pathological and molecular features. Alteration of telomerase activity has been reported in ovarian tumors but the pattern of telomere length in their specific histological subtypes has not been reported. In this study, we performed quantitative telomere fluorescence in situ hybridization on a total of 219 ovarian carcinomas including 106 high-grade serous carcinomas, 26 low-grade serous carcinomas, 56 clear cell carcinomas and 31 low-grade endometrioid carcinomas. The mean relative telomere length of carcinoma to stromal cells was calculated as a telomere index. This index was significantly higher in clear cell carcinoma compared with the other histologic types ( P =0.007). Overall there was no association between the telomere index and mortality, but when stratified by histologic types, the hazard ratio for death among women with clear cell carcinoma with a telomere index >1 was significantly increased at 4.93 (95% CI 1.64–14.86, P =0.005) when compared with those with a telomere index ≤1. In conclusion, our results provide new evidence that telomere length significantly differs by histologic type in ovarian carcinoma. Specifically, clear cell carcinomas have longer mean relative telomere lengths compared with the other histologic types and longer telomeres in clear cell carcinoma are associated with increased mortality suggesting that aberrations in telomere length may have an important role in the development and progression of this neoplasm.

Telomeres are nucleoprotein structures that protect chromosome ends from degradation and recombination. Cancers often have critically shortened telomeres, contributing to genomic instability. Many of these tumors activate telomerase to stabilize telomeric ends and achieve a capacity for unlimited replication. Telomere shortening has been reported in in situ and invasive carcinomas, including breast, and has been associated with disease recurrence after surgical resection. However, previous studies have not evaluated breast cancer subtypes. The objective of this study was to evaluate telomere lengths in different subtypes of breast cancer. Breast carcinomas ( n =103) identified between 2001 and 2010 from patients seen at the Johns Hopkins Hospital were categorized into luminal A ( n =18), luminal B ( n =28), HER-2-positive ( n =20) and triple-negative carcinomas ( n =37) based on tumor characteristics. Telomere lengths were assessed directly at the single cell level by fluorescence in situ hybridization, and patient groups were compared using Fisher's exact tests. ER-negative status ( P =0.022), PR-negative status ( P =0.008), HER-2-positive status ( P =0.023) and p53-positive status ( P =0.022) were associated with shorter telomere length. A larger proportion of luminal A cancers had normal or long telomere lengths as compared with luminal B cases ( P =0.002), HER-2-positive cases ( P =0.011) or triple-negative cases ( P =0.0003). Luminal B, HER-2-positive and triple-negative cases did not differ significantly. Telomere length was shorter in more aggressive subtypes, such as luminal B, HER-2-positive and triple-negative tumors, suggesting that tumor telomere length may have utility as a prognostic and/or risk marker for breast cancer.

Reports demonstrate the role of M-CSF (CSF1) in tumor progression in mouse models as well as the prognostic value of macrophage numbers in breast cancer patients. Recently, a subset of CD14+ monocytes expressing the Tie2 receptor, once thought to be predominantly expressed on endothelial cells, has been characterized. We hypothesized that increased levels of CSF1 in breast tumors can regulate differentiation of Tie2- monocytes to a Tie2+ phenotype. We treated CD14+ human monocytes with CSF1 and found a significant increase in CD14+/Tie2+ positivity. To understand if CSF1-induced Tie2 expression on these cells improved their migratory ability, we pre-treated CD14+ monocytes with CSF1 and used Boyden chemotaxis chambers to observe enhanced response to angiopoietin-2 (ANG2), the chemotactic ligand for the Tie2 receptor. We found that CSF1 pre-treatment significantly augmented chemotaxis and that Tie2 receptor upregulation was responsible as siRNA targeting Tie2 receptor abrogated this effect. To understand any augmented angiogenic effect produced by treating these cells with CSF1, we cultured human umbilical vein endothelial cells (HUVECs) with conditioned supernatants from CSF1-pre-treated CD14+ monocytes for a tube formation assay. While supernatants from CSF1-pre-treated TEMs increased HUVEC branching, a neutralizing antibody against the CSF1R abrogated this activity, as did siRNA against the Tie2 receptor. To test our hypothesis in vivo, we treated PyMT tumor-bearing mice with CSF1 and observed an expansion in the TEM population relative to total F4/80+ cells, which resulted in increased angiogenesis. Investigation into the mechanism of Tie2 receptor upregulation on CD14+ monocytes by CSF1 revealed a synergistic contribution from the PI3 kinase and HIF pathways as the PI3 kinase inhibitor LY294002, as well as HIF-1α-deficient macrophages differentiated from the bone marrow of HIF-1αfl/fl/LysMcre mice, diminished CSF1-stimulated Tie2 receptor expression.

Background teen Mental Health First Aid (tMHFA) is a universal mental health literacy, stigma reduction, help-seeking, and suicide prevention program designed for adolescents in Years 10–12 of secondary school (16–18 years). tMHFA is delivered by trained instructors, in a regular classroom setting, to increase the knowledge, attitudes and behaviours that adolescents’ require to better support peers with mental health problems or mental health crises. Methods To explore the efficacy of tMHFA, a cluster crossover randomised controlled trial was conducted with Year 10 students in four schools in Victoria, Australia, using physical first aid training as the control intervention. Of the 1942 eligible students, 1,624 completed baseline and 894 completed follow-up surveys. Online surveys, administered one week before training and again 12-months later, included vignettes depicting peers John (depression and suicide risk) and Jeanie (social anxiety/phobia), measures of mental health first aid (quality of first aid intentions, confidence, first aid behaviours provided, and first aid behaviours received), mental health literacy (beliefs about adult help, help-seeking intentions), and stigma (social distance, weak-not-sick, dangerous/unpredictable, and would not tell anyone). Results The primary outcome—quality of first aid intentions towards the John vignette—showed statistically significant group x time interactions, with tMHFA students reporting more helpful and less unhelpful first aid intentions, than PFA students did over time. Confidence in providing first aid also showed significant interactions. First aid behaviours—both those provided to a peer with a mental health problem and those received from a peer—showed null results. Ratings of both beliefs about adult help and help-seeking intentions were found to be significantly improved among tMHFA students at follow-up. A group x time interaction was found on one stigma scale (would not tell anyone). Conclusions This trial showed that, one year after training, tMHFA improves first aid intentions towards peers with depression and suicide risk, confidence in helping peers with mental health problems, willingness to tell someone and seek help from an adult or health professional if experiencing a mental health problem. Trial registration This research was registered with Australia New Zealand Clinical Trials Registry: ACTRN12614000061639 .

In adolescents (12–17 years), it is unknown whether COVID-19 vaccination reduces progression from COVID-19 to Long COVID (LC) beyond preventing SARS-CoV-2 infection. We assessed the effect of vaccination among SARS-CoV-2 infected adolescents. Participants were recruited from over 60 US healthcare and community settings. The exposure was any COVID-19 vaccination 6 months prior to infection. The outcome was LC defined using the LC research index. Vaccinated (n = 724) and unvaccinated (n = 507) adolescents were matched on sex, infection date, and enrollment date. The risk of LC was 36 % lower (95 % CI, 17 %, 50 %) in vaccinated compared to unvaccinated participants. Vaccination reduces the risk of LC. Given the profound impact LC can have on the health and well-being of adolescents and the limited availability of treatments during this developmental stage, this supports vaccination as a strategy for preventing LC by demonstrating an important secondary prevention effect.