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Background Xylazine has emerged as a major component of the unregulated opioid supply in several jurisdictions across the United States. However, the extent of xylazine in local drug supplies is unknown. Drug checking is a harm reduction strategy that provides information to people who use drugs and allows for insight into the composition of local drug supplies. Methods The New York City Department of Health and Mental Hygiene (DOHMH) worked with syringe service program (SSP) partners to operate a drug checking pilot study that continued as a public health program. Drug samples were submitted by SSP participants for drug checking by trained DOHMH staff and further testing by secondary laboratory partners. The secondary laboratory used both GC/MS and LC-QTOF-MS to identify compounds present in a drug sample. Results Drug samples collected from November 2021 through December 2024 were analyzed. There were N = 1027 secondary laboratory testing results that contained opioids. Of these, n = 449 (43.7%) also contained xylazine. The prevalence of opioids containing xylazine increased from 10.7% in 2021 to 53.7% through 2024. Visualization of the monthly xylazine prevalence, as well as an accompanying chi-square test for trend in proportions (χ 2  = 45.229, degrees of freedom = 1, p-value = < 0.001), provided further evidence that the prevalence of xylazine increased over time. Conclusion The prevalence of xylazine in samples containing opioids has increased in New York City from November 2021 through December 2024. Drug checking can monitor changes in the local drug supply and inform existing harm reduction efforts.

Introduction We evaluated racial/ethnic differences in the receipt of naloxone distributed by opioid overdose prevention programs (OOPPs) in New York City (NYC). Methods We used naloxone recipient racial/ethnic data collected by OOPPs from April 2018 to March 2019. We aggregated quarterly neighborhood-specific rates of naloxone receipt and other covariates to 42 NYC neighborhoods. We used a multilevel negative binomial regression model to assess the relationship between neighborhood-specific naloxone receipt rates and race/ethnicity. Race/ethnicity was stratified into four mutually exclusive groups: Latino, non-Latino Black, non-Latino White, and non-Latino Other. We also conducted racial/ethnic-specific geospatial analyses to assess whether there was within-group geographic variation in naloxone receipt rates for each racial/ethnic group. Results Non-Latino Black residents had the highest median quarterly naloxone receipt rate of 41.8 per 100,000 residents, followed by Latino residents (22.0 per 100,000), non-Latino White (13.6 per 100,000) and non-Latino Other residents (13.3 per 100,000). In our multivariable analysis, compared with non-Latino White residents, non-Latino Black residents had a significantly higher receipt rate, and non-Latino Other residents had a significantly lower receipt rate. In the geospatial analyses, both Latino and non-Latino Black residents had the most within-group geographic variation in naloxone receipt rates compared to non-Latino White and Other residents. Conclusions This study found significant racial/ethnic differences in naloxone receipt from NYC OOPPs. We observed substantial variation in naloxone receipt for non-Latino Black and Latino residents across neighborhoods, indicating relatively poorer access in some neighborhoods and opportunities for new approaches to address geographic and structural barriers in these locations.

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor‐negative, ER − ) from four independent cohorts. RANK protein expression was more frequent in ER − tumors, where it associated with poor outcome and poor response to chemotherapy. In ER − breast cancer patient‐derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER − breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK + ER − tumors after menopause. Synopsis The analyses of RANK and RANKL expression in large cohorts of breast cancer samples and functional studies in RANK+ breast cancer patient‐derived xenografts (PDXs) revealed a key role for RANK in postmenopausal women with estrogen receptor negative (ER ‐ ) breast cancer. RANK biology and prognostic value in breast cancer is determined by ER status and menopause. RANK protein expression in tumor cells is associated with ER ‐ breast cancer and poor survival in ER ‐ and postmenopausal ER ‐ breast cancer patients. RANK protein expression in tumor cells is associated with poor survival in postmenopausal breast cancer patients independent of ER expression, tumor grade, stage and size. RANK expression associates with poor response to chemotherapy in ER ‐ breast cancer and RANKL inhibition improves response to taxanes in ER ‐ breast PDXs. Graphical Abstract The analyses of RANK and RANKL expression in large cohorts of breast cancer samples and functional studies in RANK+ breast cancer patient‐derived xenografts (PDXs) revealed a key role for RANK in postmenopausal women with estrogen receptor negative ER ‐ breast cancer.

Background We examined the association of non-cigarette tobacco use on chronic obstructive pulmonary disease (COPD) risk in the Population Assessment of Tobacco and Health (PATH) Study. Methods There were 13,752 participants ≥ 40 years with Wave 1 (W1) data for prevalence analyses, including 6945 adults without COPD for incidence analyses; W1–5 (2013–2019) data were analyzed. W1 tobacco use was modeled as 12 mutually-exclusive categories of past 30-day (P30D) single and polyuse, with two reference categories (current exclusive cigarette and never tobacco). Prevalence and incidence ratios of self-reported physician-diagnosed COPD were estimated using weighted multivariable Poisson regression. Results W1 mean (SE) age was 58.1(0.1) years; mean cigarette pack-years was similar for all categories involving cigarettes and exclusive use of e-cigarettes (all > 20), greater than exclusive cigar users (< 10); and COPD prevalence was 7.7%. Compared to P30D cigarette use, never tobacco, former tobacco, and cigar use were associated with lower COPD prevalence (RR = 0.33, (95% confidence interval—CI) [0.26, 0.42]; RR = 0.57, CI [0.47, 0.70]; RR = 0.46, CI [0.28, 0.76], respectively); compared to never tobacco use, all categories except cigar and smokeless tobacco use were associated with higher COPD prevalence (RR former = 1.72, CI [1.33, 2.23]; RR cigarette = 3.00, CI [2.37, 3.80]; RR e-cigarette = 2.22, CI [1.44, 3.42]; RR cigarette + e-cigarette = 3.10, CI [2.39, 4.02]; RR polycombusted = 3.37, CI [2.44, 4.65]; RR polycombusted plus noncombusted = 2.75, CI]1.99, 3.81]). COPD incidence from W2-5 was 5.8%. Never and former tobacco users had lower COPD risk compared to current cigarette smokers (RR = 0.52, CI [0.35, 0.77]; RR = 0.47, CI [0.32, 0.70], respectively). Compared to never use, cigarette, smokeless, cigarette plus e-cigarette, and polycombusted tobacco use were associated with higher COPD incidence (RR = 1.92, CI [1.29, 2.86]; RR = 2.08, CI [1.07, 4.03]; RR = 1.99, CI [1.29, 3.07]; RR = 2.59, CI [1.60, 4.21], respectively); exclusive use of e-cigarettes was not (RR = 1.36, CI [0.55, 3.39]). Conclusions E-cigarettes and all use categories involving cigarettes were associated with higher COPD prevalence compared to never use, reflecting, in part, the high burden of cigarette exposure in these groups. Cigarette—but not exclusive e-cigarette—use was also strongly associated with higher COPD incidence. Compared to cigarette use, only quitting tobacco was protective against COPD development.

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10 −4 in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 ( P = 2.5 × 10 −13 overall; P = 6.9 × 10 −12 replication), and rs16892766, at 8q23.3 ( P = 3.3 × 10 −18 overall; P = 9.6 × 10 −17 replication), which tags a plausible causative gene, EIF3H . These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.

We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation=1.29 [95% CI 1.25–1.33], P=3×10−72). For BRCA2, the strongest association was with overall BC PRS (HR=1.31 [95% CI 1.27–1.36], P=7×10−50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR=1.32 [95% CI 1.25–1.40], P=3×10−22) and BRCA2 (HR=1.44 [95% CI 1.30–1.60], P=4×10−12) carriers. The associations in the prospective cohort were similar. Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

BackgroundAZD0156 and AZD6738 are potent and selective inhibitors of ataxia-telangiectasia-kinase (ATM) and ataxia-telangiectasia-mutated and Rad3-related (ATR), respectively, important sensors/signallers of DNA damage.MethodsWe used multiplexed targeted-mass-spectrometry to select pRAD50(Ser635) as a pharmacodynamic biomarker for AZD0156-mediated ATM inhibition from a panel of 45 peptides, then developed and tested a clinically applicable immunohistochemistry assay for pRAD50(Ser635) detection in FFPE tissue.ResultsWe found moderate pRAD50 baseline levels across cancer indications. pRAD50 was detectable in 100% gastric cancers (n = 23), 99% colorectal cancers (n = 102), 95% triple-negative-breast cancers (TNBC) (n = 40) and 87.5% glioblastoma-multiformes (n = 16). We demonstrated AZD0156 target inhibition in TNBC patient-derived xenograft models; where AZD0156 monotherapy or post olaparib treatment, resulted in a 34–72% reduction in pRAD50. Similar inhibition of pRAD50 (68%) was observed following ATM inhibitor treatment post irinotecan in a colorectal cancer xenograft model. ATR inhibition, using AZD6738, increased pRAD50 in the ATM-proficient models whilst in ATM-deficient models the opposite was observed, suggesting pRAD50 pharmacodynamics post ATR inhibition may be ATM-dependent and could be useful to determine ATM functionality in patients treated with ATR inhibitors.ConclusionTogether these data support clinical utilisation of pRAD50 as a biomarker of AZD0156 and AZD6738 pharmacology to elucidate clinical pharmacokinetic/pharmacodynamic relationships, thereby informing recommended Phase 2 dose/schedule.

In 2013–2014, nearly 28% of adults in the United States (U.S.) were current tobacco users with cigarettes the most common product used and with nearly 40% of tobacco users using two or more tobacco products. We describe overall change in prevalence of tobacco product use and within-person transitions in tobacco product use in the U.S. between 2013–2014 and 2014–2015 for young adults (18–24 years) and older adults (25+ years). Data from Wave 1 (W1, 2013–2014) and Wave 2 (W2, 2014–2015) of the Population Assessment of Tobacco and Health (PATH) Study were analyzed (N = 34,235). Tobacco product types were categorized into: (1) combustible (cigarettes, cigars, pipe tobacco, hookah), (2) noncombustible (smokeless tobacco, snus pouches, dissolvable tobacco), and (3) electronic nicotine delivery systems (ENDS). Transitions for individual combustible-product types, and for single- and multiple-product use, were also considered. Overall prevalence of current tobacco use decreased from 27.6% to 26.3%. Among W1 non-tobacco users, 88.7% of young adults and 95.8% of older adults were non-tobacco users at W2. Among W1 tobacco users, 71.7% of young adults transitioned, with 20.7% discontinuing use completely, and 45.9% of older adults transitioned, with 12.5% discontinuing use completely. Continuing with/transitioning toward combustible product(s), particularly cigarettes, was more common than continuing with/transitioning toward ENDS. Tobacco use behaviors were less stable among young adults than older adults, likely reflecting greater product experimentation among young adults. Relative stability of cigarette use compared to other tobacco products (except older adult noncombustible use) demonstrates high abuse liability for cigarettes.