Perceptions of the Addictiveness of Low-Nicotine Cigarettes Versus Typical Cigarettes and Exposure to Tobacco Industry-Sponsored Corrective Campaign.

BACKGROUND: In 2017, the U.S. Food and Drug Administration (FDA) announced a regulatory plan to reduce the nicotine content of cigarettes. This study examines the association of exposure to industry-sponsored corrective statements on perceptions of the addictiveness of low-nicotine cigarettes relative to typical cigarettes within the general US population. METHODS: The study comprised 4975 US adult respondents of the 2019 Health Information National Trends Survey (HINTS 5, Cycle 3). Multinomial logistic regression models were used to examine associations between exposure to tobacco industry corrective messages and perceptions of the addictiveness of low-nicotine cigarettes relative to typical cigarettes. RESULTS: In the overall population, 4.1% reported that low-nicotine cigarettes were much more addictive than typical cigarettes, 67.5% said they were equally addictive, while 28.4% reported they were slightly/much less addictive. Adults exposed to industry-sponsored corrective messages had higher odds of perceiving low-nicotine cigarettes as equally addictive as typical cigarettes (aOR 1.57; 95% CI, 1.13-2.19) than those who saw no corrective messages. Those exposed to the corrective messages specifically about the addictiveness of smoking and nicotine had higher odds of perceiving low-nicotine cigarettes as equally addictive as typical cigarettes (aOR, 1.73; 95% CI, 1.07-2.81) compared to those who saw no corrective message. CONCLUSIONS: Our findings suggest that exposure to court-ordered tobacco industry corrective statements may have reinforced perceptions on the addictive potential of nicotine. However, study findings indicate a need for campaigns specifically tailored to address misperceptions observed in this study.

67.5% of US adults perceived low-nicotine cigarettes and typical cigarettes as being equally addictiveExposure to court-ordered corrective statements increased the odds of equal addictiveness perceptionExposure to corrective statements specifically tailored to addiction increased the odds of equal addictiveness perception.

Genetic variations associated with telomere length predict the risk of recurrence of non-oropharyngeal head and neck squamous cell carcinoma.

Genetic factors underlying lymphocyte telomere length (LTL) may provide insights into genomic stability and integrity, with direct links to susceptibility to cancer recurrence. Polymorphisms in telomere-associated genes are strongly associated with LTL and cancer risk, while few large studies have explored the associations between LTL-related polymorphisms and recurrence risk of non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC). Totally 1403 non-OPHNSCC patients were recruited and genotyped for 16 LTL-related polymorphisms identified by genome-wide association studies. Univariate and multivariate analyzes were performed to evaluate associations between the polymorphisms and non-OPHNSCC recurrence risk. Patients carrying rs755017 GA/GG, rs2487999 TC/TT, rs2736108 TC/TT, or rs6772228 AT/AA genotypes exhibited shorter DFS than those with the rs755017 AA, rs2487999 CC, rs2736108 CC, or s6772228 TT genotypes, respectively (all log-rank p < 0.05). Multivariable analysis confirmed an increased risk of recurrence for patients carrying rs755017 GA/GG, rs2487999 TC/TT, rs2736108 TC/TT, or rs6772228 AT/AA genotypes (adjusted hazard ratio [aHR]: 1.66, 95% confidence interval [CI]: 1.32-2.07; aHR: 1.77, 95% CI: 1.41-2.23; aHR: 1.56, 95% CI: 1.22-1.99; aHR: 1.52, 95% CI: 1.20-1.93, respectively). Further stratified analysis revealed stronger associations between these genotypes and recurrence risk in ever-smokers and patients undergoing chemoradiotherapy. The similar but particularly pronounced results were observed for the combined risk genotypes of the four significant polymorphisms. This is the first large study on non-OPHNSCC patients showing that LTL-related polymorphisms may modify risk of non-OPHNSCC recurrence individually and jointly, particularly when analyzed in the context of smoking status and personized treatment. Larger studies are needed to validate these results.

What do cancer genetic providers want us to know about variant reclassification and recontact that we are not asking? A thematic analysis of open-ended survey responses.

BACKGROUND: Accurate variant classification and relaying reclassified results to patients is critical for hereditary cancer care delivery. Over a 5- to 10-year period, 6%-15% of variants undergo reclassification. As the frequency of reclassifications increases, the issue of whether, how, when, and which providers should recontact patients becomes important but remains contentious. METHODS: The authors used inductive thematic analysis to analyze open-ended comments offered by oncologists and genetic counselors (GCs) from a large national survey. RESULTS: Of the 634 oncologists and cancer GCs, 126 (20%) offered substantive free-text comments. Four thematic areas emerged: 1) ambiguity over professional responsibility to recontact, 2) logistical challenges with recontact, 3) importance of inter-institutional communication, and 4) suggested solutions. Some oncologists felt that laboratories, not them, are responsible for recontact; others believed that ordering providers/GCs were responsible; GCs readily acknowledged their own responsibility in recontact but added important caveats. Besides the lack of up-to-date patient contact information, providers raised unique challenges with recontact: financial instability of laboratories, lack of clinical resources, contacting family members, and accumulating burden of reclassifications. There were numerous calls for developing practice guidelines on prioritizing variants for recontact and discussion on whether duty for recontact may be fulfilled via unidirectional, low touch modalities. Potential solutions to recontact including national databases and patient facing databases were discussed. CONCLUSIONS: The authors confirm previous themes of stakeholder opinions and add previously unreported contextual details to qualify those themes. Clarifying provider responsibilities through professional guidelines for reclassification and recontact addressing the subthemes identified here will better serve all constituencies.

Potentially functional variants of CHMP4A and PANX1 in the pyroptosis-related pathway predict survival of patients with non-oropharyngeal head and neck squamous cell carcinoma.

BACKGROUND: Pyroptosis has been implicated in the advancement of various cancers. Triggering pyroptosis within tumors amplifies the immune response, thereby fostering an antitumor immune environment. Nonetheless, few published studies have evaluated associations between functional variants in the pyroptosis-related genes and clinical outcomes of patients with non-oropharyngeal head and neck squamous cell carcinoma (NON-ORO HNSCC). METHODS: We conducted an association study of 985 NON-ORO HNSCC patients who were randomly divided into two groups: the discovery group of 492 patients and the replication group of 493 patients. We used Cox proportional hazards regression analysis to examine associations between genetic variants of the pyroptosis-related genes and survival of patients with NON-ORO HNSCC. Bayesian false discovery probability (BFDP) was used for multiple testing correction. Functional annotation was applied to the identified survival-associated genetic variants. RESULTS: There are 8254 single-nucleotide polymorphisms (SNPs) located in 82 pyroptosis-related genes, of which 202 SNPs passed multiple testing correction with BFDP < 0.8 in the discovery and six SNPs retained statistically significant in the replication. In subsequent stepwise multivariable Cox regression analysis, two independent SNPs (CHMP4A rs1997996 G > A and PANX1 rs56175344 C > G) remained significant with an adjusted hazard ratios (HR) of 1.31 (95% confidence interval [CI] = 1.09-1.57, p = 0.004) and 0.65 (95% CI = 0.51-0.83, p = 0.0005) for overall survival (OS), respectively. Further analysis of the combined genotypes revealed progressively worse OS associated with the number of unfavorable genotypes (ptrend < 0.0001 and 0.021 for OS and disease-specific survival, respectively). Moreover, both PANX1 rs56175344G and CHMP4A rs1997996A alleles were correlated with reduced mRNA expression levels. CONCLUSIONS: Genetic variants in the pyroptosis pathway genes may predict the survival of NON-ORO HNSCC patients, likely by reducing the gene expression, but our findings need to be replicated by larger studies.

Smoking Cessation After Initial Treatment Failure With Varenicline or Nicotine Replacement: A Randomized Clinical Trial.

Importance: Most people who smoke do not quit on their initial attempt. Objective: To determine the best subsequent strategy for nonabstinence following initial treatment with varenicline or combined nicotine replacement therapy (CNRT). Design, Setting, and Participants: Using a double-blind, placebo-controlled, sequential multiple assignment randomized trial, 490 volunteers were randomized to receive 6 weeks of varenicline or CNRT. After 6 weeks, nonabstainers were rerandomized to continue, switch, or increase medication dosage for 6 additional weeks. The study was conducted from June 2015 through October 2019 in a Texas tobacco treatment clinic. Interventions: The initial treatment was 2 mg/d of varenicline or the combined replacement therapy of a 21-mg patch plus 2-mg lozenge. The rerandomized participants either continued with their initial therapies, switched between varenicline and CNRT, or increased dosages either to 3-mg or more of varenicline or to a 42-mg patch and lozenges. All received weekly brief counseling. Main Outcomes and Measures: Biochemically verified 7-day point prevalence abstinence at the end of treatment at 12 weeks. Results: The 490 randomized participants (210 female [43%], 287 non-Hispanic White [58%], mean age, 48.1 years) smoked an average of 20 cigarettes per day. After the first phase, 54 participants in the CNRT group were abstinent and continued their therapy; of the 191 who were not abstinent, 151 were rerandomized, and the 40 who did not return for rerandomization were assigned to continue their initial CNRT condition in phase 2. The end-of-treatment abstinence rate for the 191 phase 1 nonabstainers was 8% (95% credible interval [CrI], 6% to 10%) for the 90 (47%) who continued at the dosage condition, 14% (CrI, 10% to 18%) for the 50 (33%) who increased their dosage, and 14% (95% CrI, 10% to 18%) for the 51 (34%) who switched to varenicline (absolute risk difference [RD], 6%; 95% CrI, 6% to 11%) with more than 99% posterior probability that either strategy conferred benefit over continuing the initial dosage. After the first phase, 88 participants in the varenicline group were abstinent and continued their therapy; of the 157 who were not abstinent, 122 were rerandomized and 35 who did not return for rerandomization were assigned to continue with the varenicline condition. The end-of-treatment abstinence rate for the 157 phase 1 nonabstainers was 20% (95% CrI, 16% to 26%) for the 39 (32%) who increased their varenicline dosage, 0 (95% CrI, 0 to 0) for the 41 (34%) who switched CNRT, and 3% (95% CrI, 1% to 4%) for the 77 (49%) who were assigned to the continued varenicline condition (absolute RD, -3%; 95% CrI, -4% to -1%) with more than 99% posterior probability that continuing varenicline at the initial dosage was worse than switching to a higher dosage. Furthermore, increasing the varenicline dosage had an absolute RD of 18% (95% CrI, 13% to 24%) and a more than 99% posterior probability of conferring benefit. The secondary outcome of continuous abstinence at 6 months indicated that only increased dosages of the CNRT and varenicline provided benefit over continuation of the initial treatment dosages. Conclusions and Relevance: For individuals who smoked but did not achieve abstinence after treatment with varenicline, increasing the dosage enhanced abstinence vs continuing, whereas for nonabstainers initially treated with CNRT, a dosage increase or switch to varenicline enhanced abstinence and may be viable rescue strategies. Trial Registration: ClinicalTrials.gov Identifier: NCT02271919.

Exome sequencing implicates ancestry-related Mendelian variation at SYNE1 in childhood-onset essential hypertension.

Childhood-onset essential hypertension (COEH) is an uncommon form of hypertension that manifests in childhood or adolescence and, in the United States, disproportionately affects children of African ancestry. The etiology of COEH is unknown, but its childhood onset, low prevalence, high heritability, and skewed ancestral demography suggest the potential to identify rare genetic variation segregating in a Mendelian manner among affected individuals and thereby implicate genes important to disease pathogenesis. However, no COEH genes have been reported to date. Here, we identify recessive segregation of rare and putatively damaging missense variation in the spectrin domain of spectrin repeat containing nuclear envelope protein 1 (SYNE1), a cardiovascular candidate gene, in 3 of 16 families with early-onset COEH without an antecedent family history. By leveraging exome sequence data from an additional 48 COEH families, 1,700 in-house trios, and publicly available data sets, we demonstrate that compound heterozygous SYNE1 variation in these COEH individuals occurred more often than expected by chance and that this class of biallelic rare variation was significantly enriched among individuals of African genetic ancestry. Using in vitro shRNA knockdown of SYNE1, we show that reduced SYNE1 expression resulted in a substantial decrease in the elasticity of smooth muscle vascular cells that could be rescued by pharmacological inhibition of the downstream RhoA/Rho-associated protein kinase pathway. These results provide insights into the molecular genetics and underlying pathophysiology of COEH and suggest a role for precision therapeutics in the future.

Culturally Competent Education and Human Papillomavirus Self-Sampling Achieves Healthy People 2030 Cervical Screening Target Among Low-Income Non-Hispanic Black and Hispanic Women.

PURPOSE: Disparities in cervical cancer screening, incidence, and mortality exist in the United States. Cervical cancer incidence and mortality rates in Texas are 20% and 32% higher, respectively, than national averages. Within Texas, these rates are significantly higher among non-Hispanic (NH) Black and Hispanic women. Cervical cancer screening uptake is lower among NH Black and Hispanic women (72.9% and 75.9%, respectively) compared with White women (85.5%) in Texas. METHODS: During March-August 2023, we conducted a pilot study that offered culturally competent education and human papillomavirus (HPV) self-sampling kits to women in two public housing projects in Houston, TX, that have predominantly NH Black or Hispanic residents. Among those eligible for cervical cancer screening, 35% (n = 24) of the NH Black and 34% (n = 16) of the Hispanic women were found to be underscreened per the US Preventive Services Task Force Guideline. We recruited 40 (24 NH Black and 16 Hispanic) eligible women for our study. The study was approved by the MD Anderson institutional review board and registered with ClinicalTrials.gov (NCT04614155-March 11, 2020). RESULTS: Seventy-five percent of the NH Black and 87% of the Hispanic participants completed the HPV self-sampling procedures per protocol. Samples of 17% NH Black and 12% Hispanic participants showed a performance error. Overall, cervical cancer screening uptake improved from 65% to 91% among NH Black and from 66% to 96% among Hispanic participants. CONCLUSION: Culturally competent education and HPV self-sampling resulted in remarkable improvement in cervical cancer screening uptake among underscreened NH Black and Hispanic women residents of Houston public housing projects. Implementing this strategy could significantly reduce cervical cancer incidence and mortality among similar populations in the United States and globally.

Immune-related adverse event in the emergency department: methodology of the immune-related emergency disposition index (IrEDi).

For many cancer patients, immune checkpoint inhibitors (ICIs) can be life-saving. However, the immune-related adverse events (irAEs) from ICIs can be debilitating and can quickly become severe or even be fatal. Often, irAEs will precipitate visits to the emergency department (ED). Therefore, early recognition and the decision to admit, observe, or discharge these patients from the ED can be key to a cancer patient's morbidity and mortality. ED clinicians typically make their decision for disposition (admit, observe, or discharge) within 2-6 h from their patient's ED presentation. However, irAEs are particularly challenging in the ED because of atypical presentations, the absence of classic symptoms, the delayed availability of diagnostic tests during the ED encounter, and the fast pace in the ED setting. At present, there is no single sufficiently large ED data source with clinical, biological, laboratory, and imaging data that will allow for the development of a tool that will guide early recognition and appropriate ED disposition of patients with potential irAEs. We describe an ongoing federally funded project that aims to develop an immune-related emergency disposition index (IrEDi). The project capitalizes on a multi-site collaboration among 4 members of the Comprehensive Oncologic Emergency Research Network (CONCERN): MD Anderson Cancer Center, Ohio State University, Northwestern University, and University of California San Diego. If the aims are achieved, the IrEDi will be the first risk stratification tool derived from a large racial/ethnically and geographically diverse population of cancer patients. The future goal is to validate irEDi in general EDs to improve emergency care of cancer patients on ICIs.

The TELEhealth Shared decision-making Coaching and Navigation in Primary carE (TELESCOPE) intervention: a study protocol for delivering shared decision-making for lung cancer screening by patient navigators.

Background: Lung cancer screening (LCS) can reduce lung cancer mortality but has potential harms for patients. A shared decision-making (SDM) conversation about LCS is required by the Centers for Medicare & Medicaid Services (CMS) for LCS reimbursement. To overcome barriers to SDM in primary care, this protocol describes a telehealth decision coaching intervention for LCS in primary care clinics delivered by patient navigators. The objective of the study is to evaluate the effectiveness of the intervention and its implementation potential, compared with an enhanced usual care (EUC) arm. Methods: Patients (n = 420) of primary care clinicians (n = 120) are being recruited to a cluster randomized controlled trial. Clinicians are randomly assigned to 1) TELESCOPE intervention: prior to an upcoming non-acute clinic visit, patients participate in a telehealth decision coaching session about LCS delivered by trained patient navigators and nurse navigators place a low-dose CT scan (LDCT) order for each TELESCOPE patient wanting LCS, or 2) EUC: patients receive enhanced usual care from a clinician. Usual care is enhanced by providing clinicians in both arms with access to a Continuing Medical Education (CME) webinar about LCS and an LCS discussion guide. Patients complete surveys at baseline and 1-week after the scheduled clinic visit to assess quality of the SDM process. Re-navigation is attempted with TELESCOPE patients who have not completed the LDCT within 3 months. One month before being due for an annual screening, TELESCOPE patients whose initial LCS showed low-risk findings are randomly assigned to receive a telehealth decision coaching booster session with a navigator or no booster. Electronic health records are abstracted at 6, 12 and 18 months after the initial decision coaching session (TELESCOPE) or clinic visit (EUC) to assess initial and annual LCS uptake, imaging results, follow-up testing for abnormal findings, cancer diagnoses, treatment, and tobacco treatment referrals. This study will evaluate factors that facilitate or interfere with program implementation using mixed methods. Discussion: We will assess whether a decision coaching and patient navigation intervention can feasibly support high-quality SDM for LCS and guideline-concordant LCS uptake for patients in busy primary care practices serving diverse patient populations. Trial Registration: This study was registered at ClinicalTrials.gov (NCT05491213) on August 4, 2022.

TGF-ß1 and TGF-ßR1 variants are associated with clinical outcomes in smoking-related head and neck cancer patients treated with chemoradiation through modulating microRNA-mediated regulation.

TGF-ß1 and TGF-ßR1 play important roles in immune and inflammatory responses. Genetic variants of TGF-ß1 rs1800470 and TGF-ßR1 rs334348 have emerged as potentially prognostic biomarkers for HPV-related head and neck cancer, while their prognostic effect on survival of smoking-related head and neck cancer remains unknown. This study included 1403 patients with smoking-related head and neck cancer, and all these patients were genotyped for TGF-ß1 rs1800470 and TGF-ßR1 rs334348. Both univariate and multivariate analyses were performed to evaluate associations between the two functional genetic variants in microRNA binding sites of TGF-ß1 and TGF-ßR1 and survivals. Patients with TGF-ß1 rs1800470 CT or CC genotype had 30-35% risk reductions for OS, DSS, and DFS compared to patients with TT genotype among overall patients, ever smokers, and patients administered chemoradiation. Furthermore, patients with TGF-ßR1 rs334348 GA or GG genotype had significant 50-60% risk reductions for OS, DSS, and DFS compared to patients with AA genotype among overall patients and patients administered chemoradiation; among ever smokers, the risk reductions even reached 60-70%. The TCGA dataset was used for validation. These findings suggest that TGF-ß1 rs1800470 and TGF-ßR1 rs334348 significantly affect survival outcomes in patients with smoking-related head and neck cancer, especially in the subgroups of ever smokers and patients treated with chemoradiation. These genetic variants may serve as prognostic indicators for patients with smoking-related head and neck cancer and could play a role in advancing the field of personalized chemoradiation, thereby improving patient survival and quality of life.

Approaches to estimate bidirectional causal effects using Mendelian randomization with application to body mass index and fasting glucose.

Mendelian randomization (MR) is an epidemiological framework using genetic variants as instrumental variables (IVs) to examine the causal effect of exposures on outcomes. Statistical methods based on unidirectional MR (UMR) are widely used to estimate the causal effects of exposures on outcomes in observational studies. To estimate the bidirectional causal effects between two phenotypes, investigators have naively applied UMR methods separately in each direction. However, bidirectional causal effects between two phenotypes create a feedback loop that biases the estimation when UMR methods are naively applied. To overcome this limitation, we proposed two novel approaches to estimate bidirectional causal effects using MR: BiRatio and BiLIML, which are extensions of the standard ratio, and limited information maximum likelihood (LIML) methods, respectively. We compared the performance of the two proposed methods with the naive application of UMR methods through extensive simulations of several scenarios involving varying numbers of strong and weak IVs. Our simulation results showed that when multiple strong IVs are used, the proposed methods provided accurate bidirectional causal effect estimation in terms of median absolute bias and relative median absolute bias. Furthermore, compared to the BiRatio method, the BiLIML method provided a more accurate estimation of causal effects when weak IVs were used. Therefore, based on our simulations, we concluded that the BiLIML should be used for bidirectional causal effect estimation. We applied the proposed methods to investigate the potential bidirectional relationship between obesity and diabetes using the data from the Multi-Ethnic Study of Atherosclerosis cohort. We used body mass index (BMI) and fasting glucose (FG) as measures of obesity and type 2 diabetes, respectively. Our results from the BiLIML method revealed the bidirectional causal relationship between BMI and FG in across all racial populations. Specifically, in the White/Caucasian population, a 1 kg/m2 increase in BMI increased FG by 0.70 mg/dL (95% confidence interval [CI]: 0.3517-1.0489; p = 8.43×10-5), and 1 mg/dL increase in FG increased BMI by 0.10 kg/m2 (95% CI: 0.0441-0.1640; p = 6.79×10-4). Our study provides novel findings and quantifies the effect sizes of the bidirectional causal relationship between BMI and FG. However, further studies are needed to understand the biological and functional mechanisms underlying the bidirectional pathway.

Deep sequencing of candidate genes identified 14 variants associated with smoking abstinence in an ethnically diverse sample.

Despite the large public health toll of smoking, genetic studies of smoking cessation have been limited with few discoveries of risk or protective loci. We investigated common and rare variant associations with success in quitting smoking using a cohort from 8 randomized controlled trials involving 2231 participants and a total of 10,020 common and 24,147 rare variants. We identified 14 novel markers including 6 mapping to genes previously related to psychiatric and substance use disorders, 4 of which were protective (CYP2B6 (rs1175607105), HTR3B (rs1413172952; rs1204720503), rs80210037 on chr15), and 2 of which were associated with reduced cessation (PARP15 (rs2173763), SCL18A2 (rs363222)). The others mapped to areas associated with cancer including FOXP1 (rs1288980) and ZEB1 (rs7349). Network analysis identified significant canonical pathways for the serotonin receptor signaling pathway, nicotine and bupropion metabolism, and several related to tumor suppression. Two novel markers (rs6749438; rs6718083) on chr2 are flanked by genes associated with regulation of bodyweight. The identification of novel loci in this study can provide new targets of pharmacotherapy and inform efforts to develop personalized treatments based on genetic profiles.

Barriers to the assessment and recommendation of HPV vaccination among healthcare providers in Texas.

Background: Healthcare providers (HCPs) recommendations for HPV vaccination plays a critical role in increasing vaccination uptake. This study assesses the prevalence of reported barriers to HPV vaccination assessment and recommendation among HCPs in Texas. Methods: Study data were obtained from a population-based survey of HCPs currently practicing in Texas. Participants were asked about their HPV vaccination assessment and recommendation practices and the reasons for not assessing or recommending the vaccine. Barriers were stratified by HCP characteristics including age, sex, race/ethnicity, location of practice, provider type, and type of facility. Results: Among the 826 HCPs included in this study, 47.3 % never, 49.6 % sometimes, and 3.0 % often/always assessed a patient's HPV vaccination status. Similarly, 36.0 % never, 36.2 % sometimes, and 27.9 % often/always recommended HPV vaccination. The most frequently reported barriers to assessment and recommendation of HPV vaccination were time constraints (22.9 %), delegating the task to others (15.0 %), lack of effective tools and information to give patients (12.0 %), and requiring additional training (9.2 %). HCPs who were female, less than 35 years old, non-Hispanic black, and nonphysician HCPs (Physician Assistant, Nurse Practitioner) most frequently reported lacking effective tools and information and a need for additional training. Conclusion: The assessment and recommendation for HPV vaccination among HCPs in Texas is suboptimal. Barriers reported varied based on the provider's characteristics. Addressing these barriers, such as by providing more effective tools and information and offering additional training to HCPs, could potentially increase HPV vaccination rates in Texas. The findings also suggest that interventions should be tailored to specific demographic groups.

HPV vaccination in Africa in the COVID-19 era: a cross-sectional survey of healthcare providers' knowledge, training, and recommendation practices.

Introduction: Although the burden of cervical cancer in Africa is highest, HPV vaccination coverage remains alarmingly low in this region. Providers' knowledge and recommendation are key drivers of HPV vaccination uptake. Yet, evidence about providers' knowledge and recommendation practices about the HPV vaccine against a backdrop of emerging vaccine hesitancy fueled by the COVID-19 pandemic is lacking in Africa. Methods: A cross-sectional study was conducted in 2021-2022 among healthcare providers involved in cervical cancer prevention activities in Africa. They were invited to report prior training, the availability of the HPV vaccine in their practice, whether they recommended the HPV vaccine, and, if not, the reasons for not recommending it. Their knowledge about the HPV vaccine was assessed through self-reporting (perceived knowledge) and with three pre-tested knowledge questions (measured knowledge). Results: Of the 153 providers from 23 African countries who responded to the survey (mean age: 38.5 years, SD: 10.1), 75 (54.0%) were female and 97 (63.4%) were based In countries with national HPV immunization programs. Overall, 57 (43.8%) reported having received prior training on HPV vaccine education/counseling, and 40 (37.4%) indicated that the HPV vaccine was available at the facility where they work. Most respondents (109, 83.2%) reported recommending the HPV vaccine in their practice. Vaccine unavailability (57.1%), lack of effective communication tools and informational material (28.6%), and need for adequate training (28.6%) were the most commonly reported reasons for not recommending the HPV vaccine. While 63 providers (52.9%) reported that their knowledge about HPV vaccination was adequate for their practice, only 9.9% responded correctly to the 3 knowledge questions. Conclusion: To increase HPV vaccination coverage and counter misinformation about this vaccine in Africa, adequate training of providers and culturally appropriate educational materials are needed to improve their knowledge of the HPV vaccine and to facilitate effective communication with their patients and the community.

An Approach to Identifying Spatial Variability in Observed Infectious Disease Spread in a Prospective Time-Space Series with Applications to COVID-19 and Dengue Incidence.

Most of the growing prospective analytic methods in space-time disease surveillance and intended functions of disease surveillance systems focus on earlier detection of disease outbreaks, disease clusters, or increased incidence. The spread of the virus such as SARS-CoV-2 has not been spatially and temporally uniform in an outbreak. With the identification of an infectious disease outbreak, recognizing and evaluating anomalies (excess and decline) of disease incidence spread at the time of occurrence during the course of an outbreak is a logical next step. We propose and formulate a hypergeometric probability model that investigates anomalies of infectious disease incidence spread at the time of occurrence in the timeline for many geographically described populations (e.g., hospitals, towns, counties) in an ongoing daily monitoring process. It is structured to determine whether the incidence grows or declines more rapidly in a region on the single current day or the most recent few days compared to the occurrence of the incidence during the previous few days relative to elsewhere in the surveillance period. The new method uses a time-varying baseline risk model, accounting for regularly (e.g., daily) updated information on disease incidence at the time of occurrence, and evaluates the probability of the deviation of particular frequencies to be attributed to sampling fluctuations, accounting for the unequal variances of the rates due to different population bases in geographical units. We attempt to present and illustrate a new model to advance the investigation of anomalies of infectious disease incidence spread by analyzing subsamples of spatiotemporal disease surveillance data from Taiwan on dengue and COVID-19 incidence which are mosquito-borne and contagious infectious diseases, respectively. Efficient R programs for computation are available to implement the two approximate formulae of the hypergeometric probability model for large numbers of events.

Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification.

BACKGROUND: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. METHODS: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. RESULTS: Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12-3.50, P-value = 4.13 × 10-15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99-2.49, P-value = 5.70 × 10-46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72-0.74). CONCLUSIONS: Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.

Awareness and interest in cannabis use for cancer management among cancer survivors.

BACKGROUND: We examined the awareness, interest, and information sources relating to cannabis use for cancer management (including management of cancer symptoms and treatment-related side effects) and determined factors associated with cancer survivors' awareness and interest in learning about cannabis use for cancer management. METHODS: This was a cross-sectional study of adult cancer survivors (N = 1886) receiving treatment at a comprehensive cancer center. Weighted prevalence and multivariable logistic regression analyses were conducted. RESULTS: Among cancer survivors, 88% were aware and 60% were interested in learning about cannabis use for cancer management. Common sources of information to learn about cannabis use for cancer management were cancer doctors/nurses (82%), other patients with cancer (27%), websites/blogs (26%), marijuana stores (20%), and family/friends (18%). The odds of being aware of cannabis use for cancer management was lower among male compared to female survivors (adjusted odds ratio [AOR]: 0.61; 95% confidence interval [CI]: 0.41-0.90), non-Hispanic Blacks compared to non-Hispanic Whites (AOR: 0.36; 95% CI: 0.21-0.62), and survivors who do not support the legalization of cannabis for medical use compared to those who do (AOR: 0.10; 95% CI: 0.04-0.23). On the other hand, the odds of being interested in cannabis use for cancer management was higher among non-Hispanic Blacks compared to non-Hispanic Whites (AOR: 1.65; 95% CI: 1.04-2.62), and among cancer survivors actively undergoing cancer treatment compared to patients on non-active treatment (AOR: 2.25; 95% CI: 1.74-2.91). CONCLUSION: Awareness of cannabis use for cancer management is high within the cancer survivor population. Results indicated health care providers are leading information source and should receive continued medical education on cannabis-specific guidelines. Similarly, tailored educational interventions are needed to guide survivors on the benefits and risks of cannabis use for cancer management.

Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies.

BACKGROUND: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. METHODS: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. RESULTS: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior. CONCLUSIONS: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies. IMPACT: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.

Acceptability of Personalized Lung Cancer Screening Program Among Primary Care Providers.

Current lung cancer screening (LCS) guidelines rely on age and smoking history. Despite its benefit, only 5%-15% of eligible patients receive LCS. Personalized screening strategies select individuals based on their lung cancer risk and may increase LCS's effectiveness. We assess current LCS practices and the acceptability of personalized LCS among primary care providers (PCP) in Texas. We surveyed 32,983 Texas-based PCPs on an existing network (Protocol 2019-1257; PI: Dr. Shete) and 300 attendees of the 2022 Texas Academy of Family Physicians (TAFP) conference. We analyzed the responses by subgroups of interest. Using nonparametric bootstrap, we derived an enriched dataset to develop logistic regression models to understand current LCS practices and acceptability of personalized LCS. Response rates were 0.3% (n = 91) and 15% (n = 60) for the 2019-1257 and TAFP surveys, respectively. Most (84%) respondents regularly assess LCS in their practice. Half of the respondents were interested in adopting personalized LCS. The majority (66%) of respondents expressed concerns regarding time availability with the personalized LCS. Most respondents would use biomarkers as an adjunct to assess eligibility (58%), or to help guide indeterminate clinical findings (63%). There is a need to enhance the engagement of Texas-based PCPs in LCS. Most of the respondents expressed interest in personalized LCS. Time availability was the main concern related to personalized LCS. Findings from this project highlight the need for better education of Texas-based PCPs on the benefits of LCS, and the development of efficient decision tools to ensure successful implementation of personalized LCS. PREVENTION RELEVANCE: Personalized LCS facilitated by a risk model and/or a biomarker test is proposed as an alternative to existing programs. Acceptability of personalized approach among PCPs is unknown. The goal of this study is to assess the acceptability of personalized LCS among PCPs.

Identification of genetically predicted DNA methylation markers associated with non-small cell lung cancer risk among 34,964 cases and 448,579 controls.

BACKGROUND: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated. METHODS: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways. RESULTS: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10-6 ) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10-3 ), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified. CONCLUSIONS: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby. PLAIN LANGUAGE SUMMARY: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non-small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer.