Rare variants in pharmacogenes influence clozapine metabolism in individuals with schizophrenia.

Clozapine is the only licensed medication for treatment-resistant schizophrenia (TRS). Few predictors for variation in response to clozapine have been identified, but clozapine metabolism is known to influence therapeutic response and adverse side effects. Here, we expand on genome-wide studies of clozapine metabolism, previously focused on common genetic variation, by analysing whole-exome sequencing data from 2062 individuals with schizophrenia taking clozapine in the UK. We investigated whether rare genomic variation in genes and gene sets involved in the clozapine metabolism pathway influences plasma concentrations of clozapine metabolites, assessed through the longitudinal analysis of 6585 pharmacokinetic assays. We observed a statistically significant association between the burden of rare damaging coding variants (MAF ≤ 1 %) in gene sets broadly related to drug pharmacokinetics and lower clozapine (ß = -0.054, SE = 0.019, P-value = 0.005) concentrations in plasma. We estimate that the effects in clozapine plasma concentrations of a single damaging allele in this gene set are akin to reducing the clozapine dose by about 35 mg/day. The gene-based analysis identified rare variants in CYP1A2, which encodes the enzyme responsible for converting clozapine to norclozapine, as having the strongest effects of any gene on clozapine metabolism (ß = 0.324, SE = 0.124, P = 0.009). Our findings support the hypothesis that rare genetic variants in known drug-metabolising enzymes and transporters can markedly influence clozapine plasma concentrations; these results suggest that pharmacogenomic efforts trying to predict clozapine metabolism and personalise drug therapy could benefit from the inclusion of rare damaging variants in pharmacogenes beyond those already identified and catalogued as PGx star alleles.

Facilitators and Barriers to Implementing COVID-19 Prevention Strategies in K-12 Public Schools.

To meet the educational needs of students, most schools in the United States (U.S.) reopened for in-person instruction during the 2021-2022 school year implementing a wide range of COVID-19 prevention strategies (e.g., mask requirements). To date, there have been limited studies examining facilitators and barriers to implementing each of the recommended COVID-19 prevention strategies in schools. Twenty-one semistructured interviews were conducted with public school staff from across the U.S. responsible for overseeing prevention strategy implementation. MAXQDA was used for thematic analysis. Findings identified key facilitators including utilizing Centers for Disease Control and Prevention guidance and district policies to guide decision-making at the school level, possessing financial resources to purchase supplies, identifying key staff for implementation, and having school health services infrastructure in place. Key barriers included staff shortages, limited resources, and community opposition. Findings from this study provide important insight into how schools can prepare for future public health emergencies.

Violence Victimization, Homelessness, and Severe Mental Illness Among People Who Use Opioids in Three U.S. Cities.

This study examined the associations between violence victimization, homelessness, and severe mental illness (SMI) among people who use opioids (PWUOs) in three U.S. cities. We analyzed data from a cross-sectional survey conducted from May 2019 to February 2020 across three study sites: Los Angeles, CA; Las Vegas, NV; and Atlanta, GA. We used multivariable regressions to examine how multiple victimizations and housing situation are associated with SMI. Based on K-6 scale, nearly half (44.2%) were screened positive for SMI. Meanwhile, 69.7% of the participants reported experiencing some kind of violence in their lifetime, and more than half (51.9%) reported experiencing recent violence (in the past 6 months). The most common form of lifetime violence was emotional (59.5%), followed by physical and intimate partner violence (IPV) (56.1 and 34.9%, respectively), and 34.9% of all participants reported experiencing multiple forms of victimization in the past 6 months. Participants who reported homelessness were more likely to report having experienced recent violence victimization (p < .001). In multivariable models, experiencing recent victimization was significantly associated with SMI (adjusted odds ratio (AOR) = 1.85, 95% confidence interval [CI] [1.46, 2.38]), as was homelessness (AOR = 1.57, 95% CI [1.15, 2.14]), after adjusting for study covariates. Among those with moderate and SMI (n = 927), only 22% were currently receiving mental health services, and those who reported having experienced any forms of violence in the past 6 months were more likely to utilize mental health services than those who had not experienced any recent violence victimization (25 vs. 17.9%, p < .05). To improve mental health and wellness among this high priority population, mental health facilities and syringe service programs may consider screening for experiences of violence and using trauma-informed mental health approaches. Harm reduction interventions must be responsive to the diverse individual and structural-level needs of PWUOs, especially those experiencing homelessness and housing insecurity. Holistic strategies and services are needed to meet the social and structural needs of this population.

Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample: a longitudinal analysis and genome-wide association study using UK clinical monitoring data.

BACKGROUND: The antipsychotic, clozapine, is the only licensed drug against the treatment-resistant symptoms that affect 20-30% of people with schizophrenia. Clozapine is markedly underprescribed, partly because of concerns about its narrow therapeutic range and adverse drug reaction profile. Both concerns are linked to drug metabolism, which varies across populations globally and is partly genetically determined. Our study aimed to use a cross-ancestry genome-wide association study (GWAS) design to investigate variations in clozapine metabolism within and between genetically inferred ancestral backgrounds, to discover genomic associations to clozapine plasma concentrations, and to assess the effects of pharmacogenomic predictors across different ancestries. METHODS: In this GWAS, we analysed data from the UK Zaponex Treatment Access System clozapine monitoring service as part of the CLOZUK study. We included all available individuals with clozapine pharmacokinetic assays requested by their clinicians. We excluded people younger than 18 years, or whose records contained clerical errors, or with blood drawn 6-24 h after dose, a clozapine or norclozapine concentration less than 50 ng/mL, a clozapine concentration of more than 2000 ng/mL, a clozapine-to-norclozapine ratio outside of the 0·5-3·0 interval, or a clozapine dose of more than 900 mg/day. Using genomic information, we identified five biogeographical ancestries: European, sub-Saharan African, north African, southwest Asian, and east Asian. We did pharmacokinetic modelling, a GWAS, and a polygenic risk score association analysis using longitudinal regression analysis with three primary outcome variables: two metabolite plasma concentrations (clozapine and norclozapine) and the clozapine-to-norclozapine ratio. FINDINGS: 19 096 pharmacokinetic assays were available for 4760 individuals in the CLOZUK study. After data quality control, 4495 individuals (3268 [72·7%] male and 1227 [27·3%] female; mean age 42·19 years [range 18-85]) linked to 16 068 assays were included in this study. We found a faster average clozapine metabolism in people of sub-Saharan African ancestry than in those of European ancestry. By contrast, individuals with east Asian or southwest Asian ancestry were more likely to be slow clozapine metabolisers than those with European ancestry. Eight pharmacogenomic loci were identified in the GWAS, seven with significant effects in non-European groups. Polygenic scores generated from these loci were associated with clozapine outcome variables in the whole sample and within individual ancestries; the maximum variance explained was 7·26% for the metabolic ratio. INTERPRETATION: Longitudinal cross-ancestry GWAS can discover pharmacogenomic markers of clozapine metabolism that, individually or as polygenic scores, have consistent effects across ancestries. Our findings suggest that ancestral differences in clozapine metabolism could be considered for optimising clozapine prescription protocols for diverse populations. FUNDING: UK Academy of Medical Sciences, UK Medical Research Council, and European Commission.

Genomic Stratification of Clozapine Prescription Patterns Using Schizophrenia Polygenic Scores.

BACKGROUND: Treatment-resistant schizophrenia affects approximately 30% of individuals with the disorder. Clozapine is the medication of choice in treatment-resistant schizophrenia, but optimizing administration and dose titration is complex. The identification of factors influencing clozapine prescription and response, including genetics, is of interest in a precision psychiatry framework. METHODS: We used linear regression models accounting for demographic, pharmacological, and clinical covariates to determine whether a polygenic risk score (PRS) for schizophrenia would be associated with the highest dose recorded during clozapine treatment. Analyses were performed across 2 independent multiancestry samples of individuals from a UK patient monitoring system, CLOZUK2 (n = 3133) and CLOZUK3 (n = 909), and a European sample from a Norwegian therapeutic drug monitoring service (n = 417). In a secondary analysis merging both UK cohorts, logistic regression models were used to estimate the relationship between schizophrenia PRSs and clozapine doses classified as low, standard, or high. RESULTS: After controlling for relevant covariates, the schizophrenia PRS was correlated with the highest clozapine dose on record for each individual across all samples: CLOZUK2 (ß = 12.22, SE = 3.78, p = .001), CLOZUK3 (ß = 12.73, SE = 5.99, p = .034), and the Norwegian cohort (ß = 46.45, SE = 18.83, p = .014). In a secondary analysis, the schizophrenia PRS was associated with taking clozapine doses >600 mg/day (odds ratio = 1.279, p = .006). CONCLUSIONS: The schizophrenia PRS was associated with the highest clozapine dose prescribed for an individual in records from 3 independent samples, suggesting that the genetic liability for schizophrenia might index factors associated with therapeutic decisions in cohorts of patients with treatment-resistant schizophrenia.

Utilization of HIV Prevention, Care, and Treatment Services Among Young Men Who Have Sex With Men and Transgender Persons of Color in the U.S. South: A Qualitative Analysis.

To better understand utilization of HIV prevention, care, and treatment services by young men who have sex with men (YMSM) and young transgender persons (YTG), of Black race or Hispanic/Latino/Latina ethnicity in the U.S. South, we conducted semi-structured interviews with 127 clients at one of four community based organizations (CBOs) in Miami, Atlanta, New Orleans/Baton Rouge, or Columbia, South Carolina. Across sites, the service that most commonly drew respondents into the CBO was HIV and STD testing. Other services commonly used included HIV/STI treatment, counseling services/support groups, and PrEP services. Social/organizational/structural facilitators of service utilization include the welcoming climate/culture of the CBOs, ease of access to the services, and transportation services to reach the CBOs. Suggested service enhancements include broader range of comprehensive, navigational-type services beyond HIV testing and service co-location. Research on how to reduce stigma in the surrounding communities may help reduce health disparities experienced by these populations.

U.S. Vietnamese Mothers' HPV Vaccine Decision-Making for Their Adolescents: A Qualitative Study.

U.S. Vietnamese experience HPV-related cancer disparities and HPV vaccine underutilization. We explored practice-, provider-, and patient-level influences on U.S. Vietnamese mothers' HPV vaccine decision-making for their female and male adolescent children. Using purposive sampling, we conducted 32 interviews among U.S. Vietnamese mothers. Data were analyzed using a hybrid thematic analysis approach. Findings indicated that practice-level barriers included limited clinic-based HPV promotion materials in Vietnamese and challenges in appointment scheduling. While provider recommendation emerged as a key facilitator of vaccine uptake, several mothers received either no recommendation or a low-quality recommendation. We found diverging patterns of vaccine acceptance following recommendation receipt. Patient-level barriers included misconceptions regarding the vaccine (particularly eligibility for males to get the vaccine), lack of health care utilization, perceived sexual inactivity, and safety concerns. We discuss the need for interventions addressing modifiable multilevel barriers to HPV vaccine acceptance and uptake among U.S. Vietnamese.

Acceptability of injectable pre-exposure prophylaxis among people who inject drugs in three urban U.S. settings.

BACKGROUND: Outbreaks of new HIV transmission among people who inject drugs (PWID) are a major public health concern. Oral daily PrEP, has been identified as a critical addition to the biomedical toolkit for this population. However, limited research on the acceptability of long-acting injectable PrEP has been conducted with this population. METHODS: We conducted a cross sectional multi-site survey with 1127 participants from May 2019-February 2020 to assess the acceptability of novel PrEP regimens. We computed bivariate and multivariable logistic regressions to evaluate correlates of the outcome variable: acceptability of 3-month injectable-PrEP. SAS v.9.4 was used to conduct statistical analysis. RESULTS: Limited knowledge of or use of PrEP, past or present, was evident within the sample. Injection drug use in the past six months was significantly associated with LA injectable PrEP acceptability, with the odds of acceptability being 1.885 (CI: 1.376, 2.582) times greater than those who did not inject drugs. After adjusting for confounders, injection drug use was significantly associated with the outcome, such that the odds of acceptability of LA injectable PrEP were 1.705 (CI: 1.198, 2.427) times greater among PWID compared to those who did not inject drugs (p < 0.03). The results demonstrate acceptability (38.2%) in a durable (3-month) injectable PrEP modality among participants who also identified as PWID. CONCLUSIONS: PrEP promotion efforts among PWID to increase access to long-acting injectable PrEP are necessary. Through efforts to increase acceptance and regular use of long-acting injectable PrEP, public health strategies may be able to effectively lessen chances of future HIV outbreaks among PWID.

Vaccine confidence among people who use drugs: A cross-sectional survey.

Adult immunization coverage remains low in the US, particularly for people who use drugs (PWUD), a population that experiences a disproportionate burden of vaccine-preventable diseases. The extent of and characteristics associated with vaccine confidence (VC) held by PWUD is poorly understood. As VC strongly correlates with vaccine uptake, this cross-sectional study identifies mutable factors associated with VC and quantifies its relationship to immunization status within a highly vulnerable, underimmunized population of PWUD. Using a community-engaged research strategy with select partner organizations hosting syringe exchange programs in Atlanta, Los Angeles, and Las Vegas, USA, we surveyed participants ages 18-69 years served by these organizations from 2019 to 2020. Survey measures included sociodemographics, health behavior including immunization receipt, and vaccine confidence in adult vaccinations using a modified Emory Vaccine Confidence Index (EVCI). The findings reflect relatively low VC among the 1,127 recruited participants, with 56% expressing low VC (EVCI 0-12), 35% medium (EVCI 13-20) and 10% high (EVCI 21-24). EVCI varied by city, with lowest confidence in Atlanta and highest in Las Vegas. VC was associated with past receipt of specific vaccines, including hepatitis A, MMR, Tdap, and influenza. VC varied by specific sociodemographic correlates such as housing insecurity (reduced confidence) and receipt of public benefits or disability (increased confidence). This study identified correlates associated with VC based on site and sociodemographic characteristics for this priority population, highlighting the need for specific interventions to raise VC among PWUD, especially among those experiencing housing insecurity and without public benefits.

Caregivers of Adolescents' Motivators and Barriers to Vaccinating Children Against Human Papillomavirus.

In the United States (US), acceptance of adolescent vaccines, as measured by vaccine uptake in adolescents, is high amongst caregivers. However, this does not routinely extend to Human Papillomavirus (HPV) vaccination. In the US state of Georgia, HPV vaccine coverage rates remain suboptimal, especially when compared to other adolescent vaccines. Our study aims to identify and examine caregivers' motivators and barriers towards vaccinating their adolescents against HPV. We conducted nine focus groups with caregivers (n = 75) throughout the state. Using MAXQDA for thematic analysis, we identified common motivators and barriers related to adolescent HPV vaccine uptake amongst caregivers. Barriers reported include caregivers' inability to develop a trusting patient-provider relationship and HPV vaccine message framing issues. Motivators reported include caregivers' intrinsic need to protect their adolescents and trust their healthcare provider. Trust in healthcare providers was a key theme identified towards mitigating barriers and reinforcing motivators related to HPV vaccine acceptance and uptake. By improving patient-provider relationships throughout Georgia and streamlining digestible, representative vaccine information sharing across reputable sources, caregivers may become more receptive to vaccinating their adolescents.

Health Behavior Survey Among People Who Use Opioids: Protocol for Implementing Technology-Based Rapid Response Surveillance in Community Settings.

BACKGROUND: In 2018, 2 million Americans met the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition diagnostic criteria for an opioid use disorder, and 9.9 million Americans had misused prescription pain relievers the previous year. Despite a rapid increase in opioid misuse, opioid use disorders, and overdoses, data are limited on the behavioral and contextual risks as well as the protective factors fueling the opioid epidemic in some hard hit US cities-Atlanta, Los Angeles, and Las Vegas. Opioid use also contributes to the risk of other health problems such as HIV and hepatitis C virus infections or mental health disorders and is linked to behavioral and environmental risks (eg, homelessness, experiences of violence, involvement in the justice system). Knowledge of the relationships between these linked vulnerabilities and how they influence service utilization is critical to effective policy and interventions. OBJECTIVE: This survey explores the relationships between demographic and economic characteristics, behavioral and environmental risk factors, and service utilization of people who use opioids to inform public health practice, policy, and future efforts to mitigate the risks faced by this population experiencing multiple health, social, and economic vulnerabilities. The results of this survey will be used to identify needs and intervention points for people who use drugs currently served by public health organizations. METHODS: We implemented a community-engaged strategy that involved development and execution of a two-stage purposive sampling plan involving selection of partner organizations (syringe exchange programs in urban settings) and recruitment and enrollment of participants aged 18-69 years served by these organizations in Atlanta, Los Angeles, and Las Vegas from 2019 to 2020. The recruited participants completed a survey, including a variety of measures to assess health (physical and mental) and health behaviors such as sexual behavior, vaccine receipt, and HIV/ hepatitis C virus infection testing. Additional items assessed drug use and misuse, syringe exchange and health service utilization, sex exchange, histories of interpersonal violence, and vaccine confidence. RESULTS: This protocol was successfully implemented despite challenges such as real-time technology issues and rapidly finding and surveying a difficult-to-reach population. We sampled 1127 unique participants (248 in Atlanta, 465 in Los Angeles, and 414 in Las Vegas). CONCLUSIONS: The establishment and utilization of strong community partnerships enabled the rapid collection of data from a typically difficult-to-reach population. Local efforts such as these are needed to develop policies and practices that promote harm reduction among people who use opioids. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/25575.

Clozapine Metabolism is Associated With Absolute Neutrophil Count in Individuals With Treatment-Resistant Schizophrenia.

Up to one-third of those with schizophrenia fail to respond to standard antipsychotics and are considered to have treatment-resistant schizophrenia, a condition for which clozapine is the only evidence-based medication. While up to 60% of treated individuals obtain therapeutic benefits from clozapine, it is currently underprescribed worldwide, partly because of concerns related to its broad adverse effect profile. In particular, the potential effects of clozapine on the immune system have gained relevance after a recent study showed that drug plasma concentrations were inversely correlated with neutrophil counts in individuals routinely undergoing treatment. Seeking to investigate this relationship in more detail, we extracted metabolic, immune, and genetic data from a UK cohort of long-term clozapine users linked to a clozapine monitoring service, CLOZUK2 (N = 208). Whilst a correlation analysis was compatible with the original results, a multiple linear regression accounting for dose and other confounding factors additionally allowed us to estimate the decrease in absolute neutrophil counts to approximately 141 cells/mm3 for every 0.1 mg/L increase in clozapine concentration. However, this association was attenuated after controlling for the metabolic ratio between clozapine and its main metabolite, norclozapine, which was itself negatively associated with neutrophil concentrations. Further analyses revealed that these relationships are likely moderated by genetic factors, as three pharmacogenomic SNPs previously associated to norclozapine plasma concentrations and the metabolic ratio (rs61750900, rs2011425 and rs1126545) were shown to be independently associated with a variation in neutrophil counts of about 400 cells/mm3 per effect allele. Such results are compatible with an effect of norclozapine, but not necessarily clozapine, on immune cell counts, and highlight the need for further investigations into the potential role of genetic determinants of clozapine pharmacokinetics in the occurrence of adverse effects during treatment.

Identifying Missed Opportunities for Routine Vaccination among People Who Use Drugs.

In the US, adult immunization coverage remains low, especially among vulnerable populations, as recent hepatitis A outbreaks have demonstrated. We studied the vaccination history variation among the US adults who use drugs by implementing a community-engaged research survey to identify reported immunization coverage, missed opportunities (MO), and places where immunizations might be delivered. Our analysis of a sample of 1127 participants recruited at community syringe exchanges in three cities identified higher overall vaccination receipt in Los Angeles compared to Atlanta or Las Vegas (e.g., HAV receipt 52.2% LA, 42.1% LV, 41.4% Atlanta). Overall, fewer participants reported having received HAV (45.9%), HBV (47.5%), or influenza (47.6%) vaccines than MMR (57.1%) or Td/Tdap (61.1%). Across sites, HAV receipt was higher for participants incarcerated ≥ 5 years (54.2% vs. 43.6% for those incarcerated < 5 years, 49.4% no incarceration history, p = 0.02). HBV receipt was higher among participants who were not intravenous drug users (56.1% vs. 46.0%, p = 0.03). Additionally, income >$20k predicted higher rates of MMR receipt (67.0% vs. 56.5%, p = 0.009), as did stable housing (62.8% vs. 54.3%, p = 0.01). To address the need to expand vaccine coverage among vulnerable adults, delivering vaccine at sites where persons who use drugs access services, or in correctional facilities, may be warranted.

HPV Vaccine Promotion: The church as an agent of change.

Vaccination to prevent human papillomavirus (HPV) infections and associated cancers has been recommended for use in the US since 2006; however, vaccine uptake remains suboptimal. Many sociodemographic factors have been evaluated with regard to HPV vaccine uptake but there has been less focus on the role of religion and religiosity. Our qualitative case study aimed to identify community perceptions of HPV and HPV vaccination via seven focus group discussions (FGDs) with leaders and members of an African Methodist Episcopal (AME) church in metro-Atlanta, Georgia from April 2018 to July 2018. A Social and Behavior Change Communication (SBCC) conceptual framework was used to identify potential avenues to strengthen communication and health promotion strategies in the church community. Results showed diverse perceptions about HPV vaccine amongst the church community, ranging from viewing the HPV vaccine as essential to unnecessary for adolescents. Two key barriers to the HPV vaccine that may be addressed through the SBCC strategies were identified: 1) general mistrust in the healthcare system and 2) the expectation of abstinence among adolescents. For future HPV prevention opportunities, congregants highlighted they would be more receptive to receiving HPV vaccine promotion messages from pre-established trustworthy sources. Church leaders hold the trust of their congregation, therefore implementation of a church-based intervention utilizing the SBCC strategies has considerable potential to transform perceptions of the HPV vaccine and increase vaccination uptake. These findings may be implemented in future HPV vaccine promotion strategies within faith-based communities to promote safe and open dialogue for health communication messages to be disseminated in a familiar and trusted setting.

Practice-, provider- and patient-level facilitators of and barriers to HPV vaccine promotion and uptake in Georgia: a qualitative study of healthcare providers' perspectives.

Georgia experiences higher human papillomavirus (HPV)-associated cancer burden and lower HPV vaccine uptake compared with national estimates. Using the P3 model that concomitantly assesses practice-, provider- and patient-level factors influencing health behaviors, we examined facilitators of and barriers to HPV vaccine promotion and uptake in Georgia. In 2018, we conducted six focus groups with 55 providers. Questions focused on multilevel facilitators of and barriers to HPV vaccine promotion and uptake. Our analysis was guided by the P3 model and a deductive coding approach. We found that practice-level influences included organizational priorities of vaccinations, appointment scheduling, immunization registries/records, vaccine availability and coordination with community resources. Provider-level influences included time constraints, role, vaccine knowledge, self-efficacy to discuss HPV vaccine and vaccine confidence. Patient-level influences included trust, experiences with vaccine-preventable diseases, perceived high costs, perceived side effects and concerns with sexual activity. Findings suggest that interventions include incentives to boost vaccine rates and incorporate appointment scheduling technology. An emphasis should be placed on the use of immunization registries, improving across-practice information exchange, and providing education for providers on HPV vaccine. Patient-provider communication and trust emerge as intervention targets. Providers should be trained in addressing patient concerns related to costs, side effects and sexual activity.

Presentation of caregiver-specific vaccine-related information on National Cancer Institute designated cancer center websites.

BACKGROUND: Household-based caregivers serve an important role in protecting the health of cancer patients, who may be vulnerable to infectious diseases due to their cancer treatments. Caregiver preventive care should be prioritized to maintain continuity of care and to reduce potential for transmission of infectious diseases to cancer patients. Uptake of vaccines, such as influenza vaccine, is suboptimal in the United States in general, as well as among caregivers for cancer patients. Little is known about the types of information about vaccination and prevention of infectious diseases (e.g. influenza) presented to caregivers of cancer patients. METHODS: A qualitative content review of NCI cancer center websites (N = 70), searching for vaccine-related information and the need for and availability of vaccines for caregivers, and comparison of the availability of this information to that for caregiver support groups and general preventative health information (e.g. diet, exercise) for caregivers or patients was conducted. RESULTS: While 53 of 70 (76%) cancer centers routinely presented general preventative health information for caregivers or patients, only eight (11%) cancer centers had any information about vaccinations for caregivers or patients. Of these eight cancer center websites, only one had information about vaccinations for caregivers or family contacts. CONCLUSIONS: As vaccinations confer both individual and community-level protection against infectious diseases, promotion of routine vaccination for caregivers should be considered as part of caregiver support resources provided by cancer centers. This can include changes such as including this information on cancer center websites or adding to caregiver support resource documents.

Understanding the impact of state vaccination laws on exemption rates.

PURPOSE OF REVIEW: This review summarizes the current state of school-entry vaccination requirements and related exemption policies in the United States and examines recent changes to these policies. RECENT FINDINGS: With recent infectious disease outbreaks in the United States, there has been heightened awareness on unvaccinated individuals, and the state-level policies that allow individuals to be exempted from school-entry vaccination requirements. Between 2015 and 2017, there have been eleven states that have altered their policies regarding school-entry vaccination requirements and related reporting for which no formal evaluations have been published. One policy change during that period, California SB 277, which became law in 2016, reduced the nonmedical exemption and increased the childhood vaccination coverage rate in that state, though with some evidence of exemption replacement through the use of medical exemptions. Through September 2019, five additional state law changes have been enacted. SUMMARY: The large number of heterogeneous changes to state-level policies for school-entry vaccination requirements in recent years need rigorous evaluation to identify best practices for balancing public health authority and parental autonomy while seeking to achieve the highest level of infectious disease prevention for children.

Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism.

OBJECTIVE: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. METHODS: The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics. RESULTS: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data. CONCLUSIONS: Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia.

Human Papillomavirus Vaccination in Georgia: Evaluating the Georgia HPV Work Group.

HPV-related cancers can be prevented through HPV vaccination, however uptake and completion of the vaccination in the state of Georgia remains suboptimal. The research team conducted two online focus groups with members of the Georgia Cancer Control Consortium HPV Work Group in efforts to better understand the role that the working group could have on increasing vaccination uptake and completion in the state of Georgia. Analysis of the focus groups was completed using a Grounded Theory approach. Various aspects of the Working Group were discussed throughout the focus groups with a number of key points for growth identified both by the participants during the discussion, and by the research team during analysis. Predominantly, a primary point for growth of the Working Group lies in building its capacity to collectively conduct HPV vaccination-related activities. An online webportal specifically designed for the Working Group was identified as a tool for improving Working Group communication, sharing best practices and resources, and to collectively develop activities, research projects, and HPV vaccine promotion events in a culturally competent and age appropriate manner in efforts to improve vaccine uptake and completion throughout the state of Georgia.