Drug Deactivation Pouches for Primary Prevention of Opioid Overdose: Perceptions and Attitudes of Community Members.

IMPORTANCE: A substantial number of opioid analgesics dispensed into communities will go unused and be susceptible to diversion for misuse. Convenient, efficient, and environmentally safe mechanisms for disposal are needed to prevent the diversion of unused opioid analgesics. OBJECTIVE: This initiative piloted the feasibility of distributing drug deactivation pouches in a community setting and examined community members' acceptance, intention to use drug deactivation pouches, and their current disposal practices of unused opioid analgesics. Although many studies have examined the benefits of deactivation pouches in preventing drug overdose, few have explored community members' perspectives, the feasibility, and the acceptability of these pouches in disposing of unused medications. METHODS: In the fall of 2017, we piloted the distribution of drug deactivation pouches to assess the overall interest in the pouches at a 3-day community event and continued the second wave of this pilot in the community from the summer of 2018 to the spring of 2019.Our main outcomes and measures included the acceptance of the drug deactivation pouches and the intention to use the pouches. "Acceptance" was defined as study participants physically taking the kit and "Intention" was how participants intended to use the pouch. RESULTS: A total of 170 community members were approached at a community event about the drug deactivation pouches and 116 accepted at least 1 pouch (68.2% acceptance rate). In the second wave, 124 community members were approached by Community Health Workers; 100% accepted the pouch. Overall, the acceptance rate was 81.6%. People mentioned significant interest in using the pouches. Furthermore, surveys that assessed community members' intention to use the deactivation pouches showed that 48% intended to use the pouch. CONCLUSIONS AND RELEVANCE: The distribution of drug deactivation pouches is feasible in a community setting and although community members expressed interest in using drug deactivation pouches to dispose of unused opioid analgesics and other drugs, the majority still disposed of their unused medications through other avenues. This, underscore the need to raise community members' awareness about the importance, benefits, and viability of these pouches as a tool for the primary prevention of opioid overdose because of their ease of use, safety, environmental considerations, and cost-effectiveness.

Naloxone Accessibility by Standing Order in North Carolina Community Pharmacies.

BACKGROUND: According to a standing order in North Carolina (NC), naloxone can be purchased without a provider prescription. OBJECTIVE: The objective of this study is to examine whether same-day naloxone accessibility and cost vary by pharmacy type and rurality in NC. METHODS: A cross-sectional telephone audit of 202 NC community pharmacies stratified by pharmacy type and county of origin was conducted in March and April 2023. Trained "secret shoppers" enacted a standardized script and recorded whether naloxone was available and its cost. We examined the relationship between out-of-pocket naloxone cost, pharmacy type, and rurality. RESULTS: Naloxone could be purchased in 53% of the pharmacies contacted; 26% incorrectly noting that naloxone could be filled only with a provider prescription and 21% did not sell naloxone. Naloxone availability by standing order was statistically different by pharmacy type (chain/independent) (χ2 = 20.58, df = 4, P value < 0.001), with a higher frequency of willingness to dispense according to the standing order by chain pharmacies in comparison to independent pharmacies. The average quoted cost for naloxone nasal spray at chain pharmacies was $84.69; the cost was significantly more ($113.54; P < 0.001) at independent pharmacies. Naloxone cost did not significantly differ by pharmacy rurality (F2,136 = 2.38, P = 0.10). CONCLUSION: Approximately half of NC community pharmacies audited dispense naloxone according to the statewide standing order, limiting same-day access to this life-saving medication. Costs were higher at independent pharmacies, which could be due to store-level policies. Future studies should further investigate these cost differences, especially as intranasal naloxone transitions from a prescription only to over-the-counter product.

Likelihood of Young Adult Engagement in Protective Behavioral Strategies for Alcohol Use across Drinking Contexts: Implications for Adaptive Interventions.

OBJECTIVE: This study examined how young adults' likelihood to engage in protective behavioral strategies (PBS) to reduce alcohol harms varies across physical and social contexts for drinking. METHOD: We conducted an online survey with 514 heavy drinking young adults (Mage = 22.4 years, 52% women, 30% Hispanic/Latin(x), 40% non-White). Participants were asked to rate their likelihood to engage in 26 PBS generally, and specifically in six physical contexts (e.g., bar/club), and six social contexts (e.g., in a large group). We conducted regression analyses to examine the overall effect of context on the likelihood to engage in each PBS and post-hoc Tukey tests to assess pairwise comparisons of the differences in likelihood to engage in each PBS across response options for physical and social context. Analyses were conducted using the full sample, and for men and women separately. RESULTS: There were significant differences in six strategies across physical contexts; likelihood to engage in PBS varied across public and private spaces for different strategies. We also found significant differences in five strategies across social contexts; participants were more likely to engage in PBS among larger numbers of people and those who are intoxicated. There were numerous differences in pairwise comparisons of PBS engagement across physical and social contexts for women, while men demonstrated only two differences in PBS across physical context. CONCLUSIONS: Results suggest that alcohol interventions for young adults that include PBS should consider tailoring strategies to the individual and the specific context of the drinking event.

Development and Evaluation of Messages to Facilitate Secure Storage and Disposal of Prescribed Opioid Medication.

BACKGROUND: Secure storage and disposal is a critical strategy to reduce prescription opioid misuse. We sought to develop effective messages to promote secure storage and disposal of unused opioid medications that can be used in interventions designed to reduce diversion of opioid medications for nonmedical use. METHODS: We used a mixed-method design to develop and evaluate messages. First, we pretested 34 messages in focus group discussions (FGDs; n = 12 FGDs, n = 2-5 participants per FGD; 37 total participants). Then, we tested the 12 most salient messages in an online survey with a nationally representative Qualtrics® panel (n = 1520 participants). A pretest-posttest design was conducted to assess change in beliefs about storage and disposal of opioid medication following message exposure. RESULTS: All 12 messages favorably influenced participants' perceptions related to concerns and risks of retaining unused opioid medications and the importance of and self-efficacy in securely storing and disposing of unused opioid medications. Storage and disposal messages that included the sentence-"Your prescription can become someone else's addiction."-outperformed other messages in encouraging people to safely store or dispose of opioid medication. CONCLUSIONS: This study informs the development of a universal text message intervention using multimodal feedback from the target population that the intervention seeks to serve. The next step is to conduct a randomized controlled trial to assess efficacy of the intervention.

Elucidating determinants of medication disposal programs at retail pharmacies in North Carolina.

BACKGROUND: Pharmacy-based medication disposal programs is one approach to prevent diversion of unused prescription opioids. OBJECTIVE(S): The objective of this study was to assess the extent to which disposal programs have been implemented by retail pharmacies and identify determinants of implementation using the Consolidated Framework for Implementation Research. METHODS: A sequential mixed-method design was used to examine implementation of medication disposal programs at pharmacies in Pitt County, NC. We conducted environmental scans of all retail pharmacies that served community members (N = 31) to assess the extent to which disposal programs had been implemented. Then, we conducted interviews with pharmacists (n = 15; 48.4%) to identify determinants of implementation. The following pharmacy types were represented in the completed interviews: corporate chain (n = 10), small chain (n = 1), independently owned and operated (n = 1), medical (n = 2), and government (n = 1). RESULTS: We found that 32.3% of pharmacies (n = 10) had a medication disposal box and 12.9% (n = 4) had posted a flyer on medication disposal. Pharmacists perceived that patients benefit from disposal boxes and medication disposal is in their purview. Determinants of implementation included the cost of sustaining the intervention, polices of corporate and regional management, variable local control in the decision-making process to implement a disposal box, and experience with having a medication disposal box. CONCLUSION: Our findings highlight one way in which pharmacists can have a vital role in preventing diversion of opioid analgesics and associated consequences. There is a need to expand disposal boxes at pharmacies to increase community member accessibility and use. Future research is needed to determine the cost-effectiveness of expanding the scale of disposal box implementation in community pharmacies.

Cannabinoid home storage practices among a national Qualtrics panel of adult users of cannabinoid products in the USA.

INTRODUCTION: The presence of cannabinoid products in the home may increase the likelihood of unintended adverse consequences for children and adolescents. Secure storage of these products is one prevention method to decrease the risk of diversion and use of cannabinoid products among youth. We sought to examine cannabis, delta-8 tetrahydrocannabinol (THC), and cannabidiol (CBD) storage practices among a sample of adults 18-64 years old residing in the USA. METHODS: In December 2021, we conducted an online cross-sectional survey of 1042 current (past 30 day) users of cannabinoid products (88.3% cannabis, 49.0% delta-8 THC, and 67.2% CBD). Participants were asked about where they typically keep products in their home (ie, in a locked container, unlocked container, or out in the open). We conducted multinomial regression analyses to examine the relationship between sociodemographic characteristics and cannabinoid use behaviours with home storage practices. RESULTS: For all products, participants more frequently reported locking, followed by storing the product in an unlocked but not visible location. Storing the product in an unlocked and visible location was endorsed the least across all three products. Participants reported more frequent endorsement of locking cannabis products as compared with delta-8-THC and CBD. Storage practices varied by biological sex, sexual orientation, ethnicity, educational attainment, having a child who lives in the home, frequency of use, possession of a medical cannabis card and exposure to advertising. CONCLUSIONS: Increasing the prevalence of secure storage practices of cannabinoid products may facilitate prevention of unanticipated consequences associated with diversion of these products.

Alcohol protective behavioral strategies for young adults: a content analysis across drinking contexts and gender.

Background: Protective behavioral strategies (PBS) are specific harm reduction behaviors which mitigate alcohol-related consequences among young adults. Prior work indicates PBS utilization varies according to drinking context and gender, suggesting a need for further research assessing whether young adults employ unidentified PBS according to such factors.Objectives: This study examined alcohol PBS young adults suggest using across drinking contexts and gender to inform alcohol-related harm reduction interventions.Methods: An online survey with 514 young adult heavy drinkers (n = 269 female, Mage = 22.36 years) assessed PBS use generally, and across 12 physical and social contexts. We utilized qualitative content analysis methods to code and derive themes from open-ended responses from a prompt asking participants to state additional PBS used per context. The frequency of each theme's appearance was calculated across the overall sample, by gender, and within each context.Results: PBS endorsement varied across context and gender within each theme. Young adults who reported PBS use most frequently endorsed utilizing strategies related to drink content (18.30%), social support (12.36%), and engaging in other activities (10.34%). Participants infrequently endorsed strategies related to awareness of time (0.23%), standards of behavior (0.78%) and avoiding environments (0.87%).Conclusions: Young adults endorse utilizing additional PBS in varying frequency according to drinking context and gender. Given PBS are often a key component of alcohol harm reduction interventions, monitoring trends in young adult PBS use is crucial to ensure continued relevance and efficacy of such interventions to minimize harms associated with young adult heavy alcohol use.

Associations of gut microbiome with endogenous estrogen levels in healthy postmenopausal women.

PURPOSE: The gut microbiome is a potentially important contributor to endogenous estrogen levels after menopause. In healthy postmenopausal women, we examined associations of fecal microbiome composition with levels of urinary estrogens, their metabolites, and relevant metabolic pathway ratios implicated in breast cancer risk. METHODS: Eligible postmenopausal women (n = 164) had a body mass index (BMI) ≤ 35 kg/m2 and no history of hormone use (previous 6 months) or cancer/metabolic disorders. Estrogens were quantified in spot urine samples with liquid chromatography-high resolution mass spectrometry (corrected for creatinine). Bacterial DNA was isolated from fecal samples and the V1-V2 hypervariable regions of 16S rRNA were sequenced on the Illumina MiSeq platform. We examined associations of gut microbiome's indices of within-sample (alpha) diversity (i.e., Shannon, Chao1, and Inverse Simpson), phylogenetic diversity, and the ratio of the two main phyla (Firmicutes and Bacteroidetes; F/B ratio) with individual estrogens and metabolic ratios, adjusted for age and BMI. RESULTS: In this sample of 164 healthy postmenopausal women, the mean age was 62.9 years (range 47.0-86.0). We found significant inverse associations of observed species with 4-pathway:total estrogens (p = 0.04) and 4-pathway:2-pathway (p = 0.01). Shannon index was positively associated with 2-catechols: methylated 2-catechols (p = 0.04). Chao1 was inversely associated with E1:total estrogens (p = 0.04), and 4-pathway:2-pathway (p = 0.02) and positively associated with 2-pathway:parent estrogens (p = 0.01). Phylogenetic diversity was inversely associated with 4-pathway:total estrogens (p = 0.02), 4-pathway:parent estrogens (p = 0.03), 4-pathway:2-pathway (p = 0.01), and 4-pathway:16-pathway (p = 0.03) and positively associated with 2-pathway:parent estrogens (p = 0.01). F/B ratio was not associated with any of the estrogen measures. CONCLUSION: Microbial diversity was associated with several estrogen metabolism ratios implicated in breast cancer risk. Further studies are warranted to confirm these findings in a larger and more representative sample of postmenopausal women, particularly with enrichment of minority participants.

Clinical and descriptive characteristics associated with high-grade meningioma in a large clinical series.

PURPOSE: We studied 571 patients with intracranial meningioma for clinical characteristics and tumor location associated with high grade meningioma (WHO II/III). MATERIALS AND METHODS: Patients were participants in a multicentre epidemiologic study of risk factors for primary brain tumors including meningioma recruited from September 2005 to November 2019. We included patients 18 or older with a recent diagnosis of a primary intracranial meningioma of any subtype (ICD9/10: 9530-0, 9531-0, 9532-0, 9537-0, 9533-0, 9534-0, 9530-0, 9538-1, 9538-3) who were enrolled at neuro-oncology and neuro-surgery clinics in the southeastern U.S. RESULTS: The median patient age was 58 years (IQR: 48-68) and the majority of patients were female (n = 415; 72.7%) and Caucasian (n = 516; 90.4%). Most patients were symptomatic (n = 460; 80.6%) and their tumours more commonly occurred in a non-skull base location (n = 298; 52.2%). A total of 86 patients (15.0%) had a WHO grade II/III meningioma. Compared to patients with WHO grade I tumours, patients with WHO II/III meningiomas were over 3-times more likely to be male (odds ratio (OR): 3.25; 95% confidence interval (CI): 1.98, 5.35) adjusting for age, race, symptomatic presentation, and skull-based location. Moreover, a WHO grade II/III meningioma was substantially less likely to be observed in asymptomatic patients (OR: 0.15, 95% CI: 0.04, 0.42), and in patients with a skull-based tumour (OR: 0.40, 95% CI: 0.24, 0.66), adjusting for other factors. Male gender, symptomatic tumour, and a non-skull base location were independently associated with WHO grade II/III meningioma. CONCLUSION: These findings may shed additional light on the underlying pathogenesis of meningioma.

The MIF promoter SNP rs755622 is associated with immune activation in glioblastoma.

Intratumoral heterogeneity is a defining hallmark of glioblastoma, driving drug resistance and ultimately recurrence. Many somatic drivers of microenvironmental change have been shown to affect this heterogeneity and, ultimately, the treatment response. However, little is known about how germline mutations affect the tumoral microenvironment. Here, we find that the single-nucleotide polymorphism (SNP) rs755622 in the promoter of the cytokine macrophage migration inhibitory factor (MIF) is associated with increased leukocyte infiltration in glioblastoma. Furthermore, we identified an association between rs755622 and lactotransferrin expression, which could also be used as a biomarker for immune-infiltrated tumors. These findings demonstrate that a germline SNP in the promoter region of MIF may affect the immune microenvironment and further reveal a link between lactotransferrin and immune activation.

Absence of Age Verification for Online Purchases of Cannabidiol and Delta-8: Implications for Youth Access.

PURPOSE: This study assessed the age verification process for purchasing and shipping cannabidiol (CBD) and Delta-8 tetrahydrocannabinol products from online retailers. METHODS: We purchased CBD and Delta-8 products online from 20 brick-and-mortar shops located in the United States that sold products online and shipped products to consumers. We documented online age verifications at the time of purchase and whether identification or a signature was required at delivery. RESULTS: 37.5% of the CBD and 70.0% of the Delta-8 websites required the customer to confirm their age (18 + or 21+ years). Age verification or contact with the customer was not requested at the point of home delivery for all products. DISCUSSION: Methods for age verification at time of purchase are self-reported and easily circumvented. Policies and policy enforcement are needed to prevent youth access to CBD and Delta-8 products from online sources.

Changes in Perceptions of First Responders After Witnessing a Drug Overdose: Individual and Contextual Variations Among People Who Use Opioids in West Virginia.

Introduction: Success of opioid overdose interventions involving first responders is dependent on the comfort level that bystanders have with first responders and their willingness to call for assistance. Positive or negative experiences with first responders following witnessing an overdose may influence a person's willingness to call a first responder for assistance in the future. Purpose: The objective of this study was to examine changes in bystanders' perceptions of first responders following witnessing an overdose attended by emergency medical services or a law enforcement official. It specifically explored perception changes among a sample of individuals residing in Appalachia who use prescription opioids nonmedically. Methods: Individuals from West Virginia who used prescription opioids nonmedically were interviewed to examine changes in perceptions of first responders following witnessing an overdose. The analytic sample (N = 50) consisted of participants who witnessed an overdose for which 911 was called and stayed until a first responder arrived. Chi-square contingency tables and ANOVA were conducted to assess relationships between individual and contextual characteristics with changes in perceptions. Results: Findings indicate that the majority (63%) had improved perceptions of first responders, 6% had diminished perceptions, and 24% were unchanged. Changes in perceptions varied by income, presence during substance use, and prior concerns about first responders. Implications: Individuals who reported experiencing a positive interaction with first a responder after witnessing an overdose may be more likely to call 911 during an overdose and support other interventions by first responders (e.g., referral to syringe service programs or treatment with medications for opioid use disorder).

Rates and correlates of medicine disposal program implementation at pharmacies in North Carolina: A longitudinal study, 2016-2021.

BACKGROUND: Unused prescription opioids from family and friends continue to be the primary access point to prescription opioids for nonmedical use among youth. Implementation of medicine disposal boxes at pharmacies is one approach to facilitate removal of unused prescription opioids from the home to prevent diversion. OBJECTIVES: We sought to examine the implementation rates of disposal boxes at pharmacies in North Carolina from 2016 to 2021 and place-based health disparities in availability. METHODS: We identified pharmacies with a disposal box in 2016, 2018, and 2021 among licensed pharmacies in North Carolina in 2018 (N = 2587). We computed descriptive statistics to describe disposal box implementation rates over time and used geographic information systems to identify spatial trends. We used separate logistic regression models in 2018 and 2021 to assess the relationship between neighborhood characteristics and the likelihood of a pharmacy implementing a disposal box. RESULTS: We found an increase in disposal boxes over time with 43 pharmacies (1.7%) in 2016, 144 (5.6%) in 2018, and 350 (13.5%) in 2021 implementing a disposal box. In 2018, independent pharmacies were more likely than chains to have a disposal box. In 2021, medical-affiliated and pharmacies defined as "other" were less likely than chains to have a disposal box. In both 2018 and 2021, pharmacies in census tracts with a higher percentage of the population below the federal poverty line were more likely to have a disposal box. In 2021, pharmacies in tracts with a higher percentage of the population unemployed were less likely to have a disposal box. In 2018, pharmacies located in counties with a greater number of opioid overdose deaths were more likely to have a disposal box. CONCLUSION: Our findings highlight the growth of disposal boxes in North Carolina over time and the potential for continued expansion to provide opportunities to prevent prescription opioid diversion.

Conducting clinical trials in persons with Down syndrome: summary from the NIH INCLUDE Down syndrome clinical trials readiness working group.

The recent National Institute of Health (NIH) INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) initiative has bolstered capacity for the current increase in clinical trials involving individuals with Down syndrome (DS). This new NIH funding mechanism offers new opportunities to expand and develop novel approaches in engaging and effectively enrolling a broader representation of clinical trials participants addressing current medical issues faced by individuals with DS. To address this opportunity, the NIH assembled leading clinicians, scientists, and representatives of advocacy groups to review existing methods and to identify those areas where new approaches are needed to engage and prepare DS populations for participation in clinical trial research. This paper summarizes the results of the Clinical Trial Readiness Working Group that was part of the INCLUDE Project Workshop: Planning a Virtual Down Syndrome Cohort Across the Lifespan Workshop held virtually September 23 and 24, 2019.

Prospective investigation of herpesvirus infection and risk of glioma.

Glioma is an aggressive neoplasm of the brain with poorly understood etiology. A limited number of pathogens have been examined as glioma risk factors, but data from prospective studies with infection status determined before disease are lacking. Herpesviruses comprise a large family of DNA viruses that infect humans and are linked to a range of chronic diseases. We conducted a prospective evaluation of the association between antibody to six human herpesviruses and glioma risk in the Janus Serum Bank (Janus) and the Cancer Prevention Study-II (CPS-II). In Janus and CPS-II, the risk for glioma was not related to seroprevalence of herpes simplex virus-1, varicella zoster virus, or human herpes viruses 6A or 6B. In Janus, seropositivity to either the Epstein Barr virus (EBV) EA[D] or VCAp18 antigen was associated with a lower risk of glioma (ORs: 0.55 [95% CI 0.32-0.94] and 0.57 [95% CI 0.38-0.85]). This inverse association was consistent by histologic subtype and was observed for gliomas diagnosed up to two decades following antibody measurement. In Janus, seropositivity to at least one of three examined cytomegalovirus (CMV) antigens (pp150, pp52, pp28) was associated with an increased risk of nonglioblastoma (OR: 2.08 [95% CI 1.07-4.03]). This association was limited to tumors diagnosed within 12 years of antibody measurement. In summary, we report evidence of an inverse association between exposure to EBV and glioma. We further report that CMV exposure may be related to a higher likelihood of the nonglioblastoma subtype.

Associations of established breast cancer risk factors with urinary estrogens in postmenopausal women.

PURPOSE: Circulating estrogens are an established risk factor for postmenopausal breast cancer (BCa). We describe the distribution of urinary estrogens, their metabolites, and relevant metabolic pathway ratios among healthy postmenopausal women and examine associations of several known BCa factors with these estrogen measures. METHODS: Eligible postmenopausal women (n = 167) had no history of hormone use (previous 6 months) and cancer/metabolic disorders and had a body mass index (BMI) ≤ 35 kg/m2. Estrogens were quantified in spot urine samples with liquid chromatography-high-resolution mass spectrometry and corrected for creatinine. We assessed overall distributions of estrogens and associations of age, BMI, race/ethnicity, parity/age at first birth, age at menarche, alcohol, and smoking with log-transformed estrogen measures using multivariate regression. RESULTS: BMI was positively associated with estrone (ß per unit = 0.04, 95% Confidence Interval [CI] 0.00; 0.07), combined parent estrogens (ß = 0.04, 95% CI 0.01; 0.07), and E2:total estrogens (ß = 0.04, 95% CI 0.02; 0.06), and inversely associated with 4-MeOE1 (ß = - 0.17, 95% CI - 0.33; - 0.02), E3:parent estrogens (ß = - 0.04, 95% CI - 0.07; - 0.00), and 16-pathway:parent (ß = - 0.04, 95% CI - 0.07; - 0.01). Being African American vs. white was associated with higher levels of 4-MeOE1 (ß = 3.41, 95% CI 0.74; 6.08), 17-epiE3 (ß = 1.19, 95% CI 0.07; 2.31), 2-pathway:parent (ß = 0.54, 95% CI 0.04; 1.04), and lower levels of E2:total estrogens (ß = - 0.48, 95% CI - 0.83; - 0.13). Having < 7 alcohol drinks/week vs. none was associated with higher levels of 16-ketoE2 (ß = 1.32, 95% CI 0.36; 2.27), 16-epiE3 (ß = 1.02, 95% CI 0.24; 1.79), and 17-epiE3 (ß = 0.55, 95% CI 0.02; 1.08). Smoking was positively associated with E3:parent (ß = 0.29, 95% CI 0.01; 0.57), 16-pathway:parent (ß = 0.25, 95% CI 0.01; 0.49), and inversely associated with estradiol (ß = - 0.52, 95% CI - 0.93; - 0.10). As compared to nulliparous, parous women with age at first birth ≥ 25 years had lower levels of estrone, combined parent estrogens, 2-OHE1, and 2-OHE2. CONCLUSION: Our findings suggest that BMI, race/ethnicity, and some reproductive and lifestyle factors may contribute to postmenopausal BCa through their effects on circulating estrogens.

Mitochondrial DNA sequence variation and risk of glioma.

BACKGROUND: Malignant gliomas are the most common primary adult brain tumors, with a poor prognosis and ill-defined etiology. Mitochondrial DNA (mtDNA) sequence variation has been linked with certain cancers; however, research on glioma is lacking. METHODS: We examined the association of common (minor allele frequency ≥ 5%) germline mtDNA variants and haplogroups with glioma risk in 1,566 glioma cases and 1,017 controls from a US case-control study, and 425 glioma cases and 1,534 matched controls from the UK Biobank cohort (UKB). DNA samples were genotyped using the UK Biobank array that included a set of common and rare mtDNA variants. Risk associations were examined separately for glioblastoma (GBM) and lower grade tumors (non-GBM). RESULTS: In the US study, haplogroup W was inversely associated with glioma when compared with haplogroup H (OR = 0.43, 95%CI: 0.23-0.79); this association was not demonstrated in the UKB (OR = 1.07, 95%CI: 0.47-2.43). In the UKB, the variant m.3010G > A was significantly associated with GBM (OR = 1.32; 95%CI: 1.01-1.73; p = 0.04), but not non-GBM (1.23; 95%CI: 0.78-1.95; p = 0.38); no similar association was observed in the US study. In the US study, the variant m.14798 T > C, was significantly associated with non-GBM (OR = 0.72; 95%CI: 0.53-0.99), but not GBM (OR = 0.86; 95%CI: 0.66-1.11), whereas in the UKB, a positive association was observed between this variant and GBM (OR = 1.46; 95%CI: 1.06-2.02) but not non-GBM (OR = 0.92; 95%CI: 0.52-1.63). None of these associations were significant after adjustment for multiple testing. CONCLUSION: The association of inherited mtDNA variation, including rare and singleton variants, with glioma risk merits further study.

A prospective study of pre-diagnostic circulating tryptophan and kynurenine, and the kynurenine/tryptophan ratio and risk of glioma.

BACKGROUND: Conversion of tryptophan to kynurenine may promote glioma growth and suppress antitumor immune response through activation of the aryl hydrocarbon receptor. Expression of the enzymes indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase-2 in the glioma microenvironment has been shown to mediate tryptophan catabolism, and the ratio between kynurenine and tryptophan is considered an indirect measure of this enzyme activity. METHODS: We explored whether tryptophan, kynurenine, and the ratio of kynurenine to tryptophan (KTR) in pre-diagnostic blood samples was related to risk of glioma in a nested case-control study of 84 cases and 168 matched controls from two cohort studies - the Nurses' Health Study, and the Health Professionals Follow-Up Study. Tryptophan and kynurenine were measured by liquid chromatography-tandem mass spectrometry. Conditional logistic regression models were used to estimate risk ratios (RRs) and 95% confidence intervals (95%CI) for the associations between tertiles of these analytes and glioma risk. RESULTS: We observed no significant associations for either analyte or the ratio for risk of glioma overall. The RR for the highest KTR tertile compared to the lowest for all gliomas was 0.74 (95% CI: 0.34-1.59). All results were essentially unchanged in lagged analyses excluding the first two or four years of follow up, though data were sparse. CONCLUSION: Our findings do not provide support for an association between pre-diagnostic circulating KTR and risk of glioma.

Mitochondrial DNA sequence variation and risk of meningioma.

BACKGROUND: Risk factors for meningioma include female gender, African American race, high body mass index (BMI), and exposure to ionizing radiation. Although genome-wide association studies (GWAS) have identified two nuclear genome risk loci for meningioma (rs12770228 and rs2686876), the relation between mitochondrial DNA (mtDNA) sequence variants and meningioma is unknown. METHODS: We examined the association of 42 common germline mtDNA variants (minor allele frequency ≥ 5%), haplogroups, and genes with meningioma in 1080 controls and 478 meningioma cases from a case-control study conducted at medical centers in the southeastern United States. Associations were examined separately for meningioma overall and by WHO grade (n = 409 grade I and n = 69 grade II/III). RESULTS: Overall, meningioma was significantly associated with being female (OR 2.85; 95% CI 2.21-3.69), self-reported African American race (OR 2.38, 95% CI 1.41-3.99), and being overweight (OR 1.48; 95% CI 1.11-1.97) or obese (OR 1.70; 95% CI 1.25-2.31). The variant m.16362T > C (rs62581341) in the mitochondrial control region was positively associated with grade II/III meningiomas (OR 2.33; 95% CI 1.14-4.77), but not grade I tumors (OR 0.99; 95% CI 0.64-1.53). Haplogroup L, a marker for African ancestry, was associated with meningioma overall (OR 2.92; 95% CI 1.01-8.44). However, after stratifying by self-reported race, this association was only apparent among the few self-reported Caucasians with this haplogroup (OR 6.35; 95% CI 1.56-25.9). No other mtDNA variant, haplogroup, or gene was associated with meningioma. CONCLUSION: Common mtDNA variants and major mtDNA haplogroups do not appear to have associations with the odds of developing meningioma.