The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities.

Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in the All of Us cohort. The European ancestry subgroup showed the highest overall rate of pathogenic variation, with 2.26% of participants having a pathogenic variant. Other ancestry groups had lower rates of pathogenic variation, including 1.62% for the African ancestry group and 1.32% in the Latino/Admixed American ancestry group. Pathogenic variants were most frequently observed in genes related to Breast/Ovarian Cancer or Hypercholesterolemia. Variant frequencies in many genes were consistent with the data from the public gnomAD database, with some notable exceptions resolved using gnomAD subsets. Differences in pathogenic variant frequency observed between ancestral groups generally indicate biases of ascertainment of knowledge about those variants, but some deviations may be indicative of differences in disease prevalence. This work will allow targeted precision medicine efforts at revealed disparities.

Building coping skills to relieve distress and physical symptoms: Findings from a quality improvement project of a five-week group psychoeducational program for cancer patients.

To examine the effectiveness of Mind Over Matter (MOM), a group psychosocial intervention based on CBT, ACT, and mind-body interventions, from data collected during a quality improvement project. MOM was offered in person prior to COVID-19 and via telehealth after COVID-19 began.Distress, as measured by anxiety, depression, the severity of physical symptoms and the impact of physical symptoms on daily functioning, was measured pre- and post-MOM.The sample included 46 participants with an experience of cancer ranging in age from 31 to 75.Overall, there were significant differences in anxiety, depression, and physical symptom severity and interference pre and post MOM. The in-person intervention showed significant differences in anxiety, depression, and physical symptom interference. There were significant differences in anxiety and physical symptom severity reported in the telehealth groups.MOM may be an effective psychosocial intervention for addressing cancer-related physical and emotional challenges making it a valuable resource for institutions trying to meet needs identified by distress screenings.

Improved Pathologic response to chemoradiation in MGMT methylated locally advanced rectal cancer.

Background and Purpose: With the growing interest in total neoadjuvant treatment for locally advanced rectal adenocarcinoma (LARC) there is an urgent unmet need to identify predictive markers of response to long-course neoadjuvant concurrent chemoradiotherapy (LCRT). O6-Methylguanine (O6-MG)-DNA-methyltransferase (MGMT) gene methylation has been associated in some malignancies with response to concurrent chemoradiotherapy. We attempted to find if pathologic response to LCRT was associated with MGMT promoter hypermethylation (MGMTh). Materials and Methods: Patients were identified with LARC, available pre-treatment biopsy specimens, and at least 1 year of follow-up who received LCRT followed by surgical resection within 6 months. Biopsies were tested for MGMTh using a Qiagen pyrosequencing kit (Catalog number 970061). The primary outcome of LCRT responsiveness was based on tumor regression grade (TRG), with grades of 0-1 considered to have excellent response and grades of 2-3 considered to be non-responders. Secondary outcomes included overall survival (OS) and recurrence free survival (RFS). Results: Of 96 patients who met inclusion criteria, 76 had samples which produced reliable assay results. MGMTh corresponded with higher grade and age of the biopsy specimen. The percentage of responders to LCRT was higher amongst the MGMTh patients than the MGMTn patients (60.0% vs 27.5%, p value = 0.0061). MGMTh was not significantly associated with improved OS (2-year OS of 96.0% vs 98.0%, p = 0.8102) but there was a trend for improved RFS (2-year RFS of 87.6% vs 74.2%, p = 0.0903). Conclusion: Significantly greater tumor regression following LCRT was seen in MGMTh LARC. Methylation status may help identify good candidates for close observation without surgery following LCRT.

Indiana Parental Perceptions of the Acceptability of General and HPV-Specific State Vaccine Requirements.

State vaccine requirements are a tool for improving child and adolescent vaccination immunization coverage, but to be effective, parental buy-in is needed. The objective of this study was to assess the demographic, healthcare characteristics, and health beliefs associated with parental acceptance of general and HPV-specific state vaccine requirements. Indiana parents (N = 601) with children ages 11-17 years old completed a survey during March 2020.Results showed that 47.2% and 43.1% of parents believed there should always be general and HPV-specific state vaccine requirements, respectively. In multivariable analysis, higher odds of parental support for general state vaccine requirements were associated with being unsure whether HPV-associated cancer is a problem in the participant's county and having higher perceived benefits of HPV vaccines. Lower odds were associated with private insurance, having less than a bachelor's degree, and having less confidence in vaccines. In comparison, parents had higher odds of agreeing with HPV-specific state vaccine requirements if they reported higher interpersonal altruism and higher perceived benefits of HPV vaccines; they had lower odds if they were non-Hispanic White. Findings indicate that while similar percentages of parents agreed with general and HPV-specific state vaccine requirements, there were different characteristics associated with acceptance of each. Results can inform the development of tailored interventions for improving parental support for general and HPV-specific state vaccine requirements.

Dental patients' communication preferences for learning about HPV-related topics.

Oropharyngeal cancer (OPC) has the highest incidence of any cancer caused by human papillomavirus (HPV). Oral health providers are urged to support the use of the HPV vaccine, which was approved by the US Food and Drug Administration for the prevention of OPC in 2020. This study evaluated the preferences of dental patients regarding 11 modalities for learning about HPV-related topics from their oral health providers. An online survey was administered to US adults aged 18 to 45 years (n = 285) to assess their communication modality preferences, prior experience discussing HPV with oral health providers, and demographic characteristics. Multiple items were combined to obtain preference scores for each modality. Preference scores were compared using 2 × 3 mixed analysis of variance. Age, sex, income, and HPV vaccination status were assessed as potential confounders. One-on-one discussions were the most preferred modality for learning about HPV-related topics; however, the preference scores differed based on whether the patient had prior HPV-related discussions with oral health providers (partial η2 = 0.054). Patients who had prior discussions showed a weaker preference for one-on-one discussions than did patients who had not had prior discussions. Oral health providers are called on to promote HPV vaccination, which will require increasing communication on this subject with patients. To assure greater acceptance of their recommendations, providers will need to match their communication styles to those desired by their patients. As part of a comprehensive HPV prevention strategy that includes administration of the vaccine, oral health providers should be educated on how to confidently discuss HPV-related issues with their patients.

The third international hackathon for applying insights into large-scale genomic composition to use cases in a wide range of organisms.

In October 2021, 59 scientists from 14 countries and 13 U.S. states collaborated virtually in the Third Annual Baylor College of Medicine & DNANexus Structural Variation hackathon. The goal of the hackathon was to advance research on structural variants (SVs) by prototyping and iterating on open-source software. This led to nine hackathon projects focused on diverse genomics research interests, including various SV discovery and genotyping methods, SV sequence reconstruction, and clinically relevant structural variation, including SARS-CoV-2 variants. Repositories for the projects that participated in the hackathon are available at https://github.com/collaborativebioinformatics.

The changing dynamics of community care and support in rural Malawi: The impact on Women's health and wellbeing at end of life.

In this critical ethnographic study, we examined women's end of life experiences in Malawi, one of the few countries in the world with a national palliative care policy. Specifically, we explored how women's and their caregivers' experiences were shaped by family and community care, and material needs. Interviews and observations with female clients of a non-governmental organization in rural Central Malawi, and with their caregivers, revealed that community-level support was both precarious and critical. We found three main themes: (1) I stay with them well, (2) we eat together, and (3) everyone is for themselves. The analysis illustrates the centrality of community care, social in/exclusion, and availability of stable food, shelter, medical, and caregiving resources on health and wellbeing at end of life. We provide recommendations to strengthen community care opportunities and women's resource bases.

A qualitative study exploring the relationship between mothers' vaccine hesitancy and health beliefs with COVID-19 vaccination intention and prevention during the early pandemic months.

Vaccine hesitancy is a top ten global health threat that can negatively impact COVID-19 vaccine uptake. It is assumed that vaccine refusers hold deep, negative beliefs, while acceptors hold strong, positive beliefs. However, vaccine hesitancy exists along a continuum and is multidimensional, varying by time, place, vaccine, subgroup, and person. Guided by the Health Belief Model and vaccine hesitancy frameworks, the study purpose was to qualitatively explore maternal COVID-19 threat perceptions and willingness to accept a COVID-19 vaccine in light of their expressed vaccine hesitancy toward past school required and routinely recommended vaccines and the HPV vaccine for their children. Researchers conducted twenty-five interviews with US Midwestern mothers during the early COVID-19 pandemic months. Mothers were grouped by vaccine hesitancy categories and thematic analysis was used to analyze the data within and across categories. Results showed that prior vaccine hesitancy attitudes and behavior did not fully capture maternal acceptance of COVID-19 vaccine or perception of COVID-19 threat. Perceptions of COVID-19 threat did influence mothers' decisions about COVID-19 protective behaviors (e.g., handwashing, mask wearing, and distancing). However, mothers were hesitant to accept the COVID-19 vaccine across vaccine hesitancy categories, primarily citing concerns about safety, efficacy, and confusion over conflicting information as barriers to immediate COVID-19 vaccine acceptance. Findings indicate that mothers cannot be grouped together based on hesitancy about, or acceptance of, other vaccines for purposes of assuming COVID-19 preventive behavior adherence or anticipated COVID-19 vaccine acceptance.

Improved local control in p16 negative oropharyngeal cancers with hypermethylated MGMT.

INTRODUCTION: Patients with oropharyngeal cancers that are p16 negative (p16-) have worse outcomes than those who are p16 positive (p16+) and there is an unmet need for prognostic markers in this population. O6-Methylguanine (O6-MG)-DNA-methyltransferase (MGMT) gene methylation has been associated with response to chemoradiotherapy (CRT) in glioblastoma. We sought to find if MGMT promoter methylation was associated with outcomes of locally advanced oropharyngeal and oral cavity squamous cell carcinoma (OOSCC) in patients treated with definitive concurrent CRT. METHODS: Patients were identified with primary OOSCC, known p16 status, retrievable pre-treatment biopsies, and at least 6 months of follow-up who received definitive concurrent CRT from 2004 to 2015. Biopsies were tested for MGMT hypermethylation (MGMT+) using a Qiagen pyrosequencing kit (Catalog number 970061). Outcomes were subsequently recorded and analyzed. RESULTS: Fifty-eight patients were included with a median follow up of 78 (range 6-196) months. Fourteen patients (24.1%) had oral cavity cancer and 44 (75.9%) had oropharyngeal cancer. A significant difference was found for local recurrence free survival (LRFS) by combined MGMT and p16 status (p = 0.0004). Frequency of LR in MGMT+/p16+, MGMT+/p16-, MGMT-/p16+, and MGMT-p16- patients was 14.3%, 14.3%, 13.0%, and 69.2%, respectively (p = 0.0019). A significant difference was not found for distant recurrence free survival (p = 0.6165) or overall survival (p = 0.1615). LRFS remained significant on analysis restricted to oropharyngeal cancer patients (p-value = 0.0038). CONCLUSION: Patients who are p16- and MGMT+ with oropharyngeal and oral cavity squamous cell carcinoma have significantly better LC with definitive CRT than those who are p16- and MGMT-. Prospective studies are needed to verify these findings.

"We fear the unknown": Emergence, route and transfer of hesitancy and misinformation among HPV vaccine accepting mothers.

Although licensed since 2006, US HPV vaccination rates remain suboptimal. Since mothers are decision-makers for young adults' vaccination, assessing ongoing knowledge deficits and misunderstanding among parents is important for determining the content and mode of interventions to reach parents. Guided by the social-ecological model and health belief model, 30 interviews with vaccine accepting mothers in the U.S. Midwest were conducted from January through June 2020. Researchers examined ecological determinants of acceptance, perceptions of vaccination barriers, and perceived cues to action for empowering other mothers to vaccinate their children. Data were analyzed using thematic analysis. Results found vaccine accepting mothers exhibited ongoing misconceptions and negative attitudes toward HPV vaccine. Physicians, peers and the media were identified as primary pro-HPV vaccine sources, yet hesitancy and misinformation occurred with each source. Trust in provider recommendation was the primary source for decision-making, yet trust was still lacking. While mothers looked to the media for HPV information, the media were identified as the main source of confusion and distrust. Results show that parents who accept the HPV vaccine can still be hesitant. Thus, mothers who have vaccinated their children for HPV may still need attitudinal and educational training prior to establishing them as role models in interventions for empowering other parents to vaccinate their children. Results showing that the media sow confusion and hesitancy also call for more attention to social media policies to guard against misinformation about the HPV vaccine.

The role of the media on maternal confidence in provider HPV recommendation.

BACKGROUND: Despite a growing understanding of the importance of provider HPV recommendation on parental acceptance, U.S. HPV vaccination rates remain suboptimal. Given the prevalence and use of the media for health decisions, this study examined the relationship between the media and provider HPV recommendation on maternal HPV vaccine hesitancy. METHODS: Thirty individual interviews with HPV vaccine-accepting mothers in the Midwest U.S. were conducted to examine their feelings of hesitancy around the decision to accept HPV vaccination at the time of provider recommendation and their suggestions for improving the recommendation experience by addressing media concerns. RESULTS: Media exposure was an antecedent to hesitancy for three main vaccination concerns: safety, protection/efficacy and sexual stigma. Although mothers accepted vaccination, they continued to feel confused and hesitant about HPV vaccination. They had several recommendations for how providers could combat hesitancy to improve confidence in HPV vaccine acceptance. CONCLUSIONS: Providers' approach to HPV vaccination recommendation must consider concerns reported in the media with delivery techniques modified to adjust to maternal fears absorbed from adverse media information.

Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms.

Cancer-induced immune responses affect tumour progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages that define 'immune subtypes' of triple-negative breast cancer (TNBC), including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumour-intrinsic pathways and mutual regulation between macrophages (or monocytes) and neutrophils contribute to the development of a dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells), is resistant to ICB, and contains a minority of macrophages that seem to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.

The Role of Dental Providers in Preventing HPV-Related Diseases: A Systems Perspective.

Successfully educating dental providers and patients about the link between human papillomavirus (HPV) and oropharyngeal cancer requires coordinated efforts to increase HPV-related prevention practices. The aim of this study was to identify, using a systems perspective, the multi-level determinants related to how dental providers can promote HPV prevention in dental practices. Data for this qualitative study were collected in 2015-16 from focus groups with dentists (four focus groups, n=33), focus groups with dental hygienists (four focus groups, n=48), and in-depth interviews with dental opinion leaders (n=13). Results were triangulated and mapped along micro, meso, and macro system levels. At the micro level, participants identified patient characteristics and low self-efficacy as influential determinants when discussing HPV prevention. At the meso level, relationships among dentists, dental hygienists, and the physical practice environment were factors affecting dental providers' HPV prevention efforts. At the macro level, professional organizations impacted how dental providers interacted with their patients on this topic. These results suggest that improving HPV prevention among dental providers requires a multi-level approach that considers the distinctive context of dental settings, dental training, and perceptions of professional roles. The findings suggested that the macro- and meso-level determinants may be challenging to modify due to the distinctive culture and practice models of dentistry. Nevertheless, the association between HPV and oral cancer requires an expansion of prevention strategies used in dental practices. Improving dental providers' self-efficacy to communicate HPV prevention through continuing education and integration of skill-guided training in dental and dental hygiene curricula could facilitate this process.

USA dental health providers' role in HPV vaccine communication and HPV-OPC protection: a systematic review.

Background. Improving human papilloma virus (HPV) vaccination coverage in the US will require healthcare providers to recommend the vaccine more effectively. To inform quality improvement efforts, we systematically reviewed studies of dental provider communication about HPV vaccination. Methods. We searched MEDLINE, CINAHL, ScienceDirect, PsycINFO and JSTOR in August 2018 to identify studies of dental provider knowledge, perceived role and communication about HPV, HPV vaccination and HPV-associated oropharyngeal cancer (HPV-OPC). Results. We identified 10 qualitative and quantitative studies. Results of the primarily descriptive studies showed that although there were some deficiencies in knowledge about HPV-related outcomes and its effect on the male population, most providers understand HPV as a sexually transmitted infection and know the HPV vaccine is available, yet many are not discussing the HPV-OPC link or recommending vaccination. Providers were less often to recommend HPV vaccination if they were uncomfortable discussing sex, perceived parents as hesitant, or believed patients to be low risk. Studies reported mixed results on providers' perceived role in expanded HPV vaccination and HPV-OPC education, but indicated support for the role of professional organizations in promoting awareness. Conclusion. Interventions are needed to help dental providers perceive their role to deliver effective recommendations within the complex communication environment surrounding HPV vaccination and HPV-OPC education.

HPV and Oral Cancer: The Need to Integrate Oral Health Practices Into Nursing Education.

BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal cancer has increased in recent decades. With a shortage of dental professionals, nurses may be key in detecting oral cancer and educating patients. OBJECTIVES: The aim of this study is to assess students in nursing and dental programs for their oral and oropharyngeal cancer knowledge and perceptions of responsibility and capability of performing oral screenings and HPV counseling. METHODS: 158 surveys were completed by students attending nursing and dental programs at a midwestern university. The chi-squared test and analysis of variance were used to calculate differences in frequencies of categorical and interval data. FINDINGS: Many students across programs were unaware of the potential effectiveness of the HPV vaccination in reducing oropharyngeal cancer. Nursing and nurse practitioner students were less likely to believe they could perform an examination or that it was within their perceived scope of practice.

College Students' Knowledge Concerning Oropharyngeal Cancer, Human Papillomavirus, and Intent Toward Being Examined.

The purpose of this study was to assess college students' knowledge of oral/oropharyngeal cancer and the relationship of human papillomavirus (HPV) to oropharyngeal cancer. Data were also collected to determine their perceived susceptibility to oropharyngeal cancer and awareness of emotions toward and intentions to receive an oral cancer examination in order to design tailored messages for promoting oropharyngeal cancer prevention on college campuses. Two hundred ten baccalaureate students in nonhealth majors from a public southeastern university were surveyed. Descriptive statistics were calculated, and multiple regression analysis was conducted to determine the predictors of knowledge of oral/oropharyngeal cancer and the HPV and intentions to be examined. Results indicated most were unaware of oropharyngeal cancer, did not understand the purpose of an oral cancer examination, and could not affirm they had received one or had one explained to them. Results also indicated poor understanding of some of the signs and risk factors of oropharyngeal cancer, especially HPV. In addition, oral/oropharyngeal cancer knowledge and negative emotions were predictors of examination intentions, confirming current behavioral theories that postulate rational decisions require collaboration from both cognitive and affective systems. Recommendations are offered for tailored educational communications and strategies about oropharyngeal cancer on college campuses.

Characterizing reduced coverage regions through comparison of exome and genome sequencing data across 10 centers.

PURPOSE: As massively parallel sequencing is increasingly being used for clinical decision making, it has become critical to understand parameters that affect sequencing quality and to establish methods for measuring and reporting clinical sequencing standards. In this report, we propose a definition for reduced coverage regions and describe a set of standards for variant calling in clinical sequencing applications. METHODS: To enable sequencing centers to assess the regions of poor sequencing quality in their own data, we optimized and used a tool (ExCID) to identify reduced coverage loci within genes or regions of particular interest. We used this framework to examine sequencing data from 500 patients generated in 10 projects at sequencing centers in the National Human Genome Research Institute/National Cancer Institute Clinical Sequencing Exploratory Research Consortium. RESULTS: This approach identified reduced coverage regions in clinically relevant genes, including known clinically relevant loci that were uniquely missed at individual centers, in multiple centers, and in all centers. CONCLUSION: This report provides a process road map for clinical sequencing centers looking to perform similar analyses on their data.

Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation.

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of ß-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.