Understanding Factors Affecting Health Providers' Perceptions of Pharmacist Roles in HPV Vaccine Administration.

Human papillomavirus (HPV) is a viral infection that sexually active females and males may be exposed to in their lifetime. The HPV vaccine is highly recommended especially among children to protect them before their anticipated exposure to HPV, however, vaccination uptake in Hawai'i remains low. As of 2017, legislation allows pharmacists to vaccinate for adolescent vaccines with the potential to increase access and opportunities for patients to complete the HPV vaccine series. Physicians in Hawai'i were surveyed to examine physicians' awareness of this law, their perceptions of the role of pharmacists, and willingness to send adolescent patients to pharmacies; 137 responses were received and analyzed. Overall, 72% (n=99) of respondents were willing while 28% (n=38) were unwilling to send patients to pharmacies for vaccines. Physicians view pharmacists' role as helpful but have concerns regarding correct administration and tracking doses given. Results show potential for more physician-pharmacist collaborations through further education and trainings for pharmacists and health providers to increase physician referrals for adolescent vaccine services in pharmacies.

Stem cell plasticity, acetylation of H3K14, and de novo gene activation rely on KAT7.

In the conventional model of transcriptional activation, transcription factors bind to response elements and recruit co-factors, including histone acetyltransferases. Contrary to this model, we show that the histone acetyltransferase KAT7 (HBO1/MYST2) is required genome wide for histone H3 lysine 14 acetylation (H3K14ac). Examining neural stem cells, we find that KAT7 and H3K14ac are present not only at transcribed genes but also at inactive genes, intergenic regions, and in heterochromatin. KAT7 and H3K14ac were not required for the continued transcription of genes that were actively transcribed at the time of loss of KAT7 but indispensable for the activation of repressed genes. The absence of KAT7 abrogates neural stem cell plasticity, diverse differentiation pathways, and cerebral cortex development. Re-expression of KAT7 restored stem cell developmental potential. Overexpression of KAT7 enhanced neuron and oligodendrocyte differentiation. Our data suggest that KAT7 prepares chromatin for transcriptional activation and is a prerequisite for gene activation.

Loss of TIP60 (KAT5) abolishes H2AZ lysine 7 acetylation and causes p53, INK4A, and ARF-independent cell cycle arrest.

Histone acetylation is essential for initiating and maintaining a permissive chromatin conformation and gene transcription. Dysregulation of histone acetylation can contribute to tumorigenesis and metastasis. Using inducible cre-recombinase and CRISPR/Cas9-mediated deletion, we investigated the roles of the histone lysine acetyltransferase TIP60 (KAT5/HTATIP) in human cells, mouse cells, and mouse embryos. We found that loss of TIP60 caused complete cell growth arrest. In the absence of TIP60, chromosomes failed to align in a metaphase plate during mitosis. In some TIP60 deleted cells, endoreplication occurred instead. In contrast, cell survival was not affected. Remarkably, the cell growth arrest caused by loss of TIP60 was independent of the tumor suppressors p53, INK4A and ARF. TIP60 was found to be essential for the acetylation of H2AZ, specifically at lysine 7. The mRNA levels of 6236 human and 8238 mouse genes, including many metabolism genes, were dependent on TIP60. Among the top 50 differentially expressed genes, over 90% were downregulated in cells lacking TIP60, supporting a role for TIP60 as a key co-activator of transcription. We propose a primary role of TIP60 in H2AZ lysine 7 acetylation and transcriptional activation, and that this fundamental role is essential for cell proliferation. Growth arrest independent of major tumor suppressors suggests TIP60 as a potential anti-cancer drug target.

Loss of TAF8 causes TFIID dysfunction and p53-mediated apoptotic neuronal cell death.

Mutations in genes encoding general transcription factors cause neurological disorders. Despite clinical prominence, the consequences of defects in the basal transcription machinery during brain development are unclear. We found that loss of the TATA-box binding protein-associated factor TAF8, a component of the general transcription factor TFIID, in the developing central nervous system affected the expression of many, but notably not all genes. Taf8 deletion caused apoptosis, unexpectedly restricted to forebrain regions. Nuclear levels of the transcription factor p53 were elevated in the absence of TAF8, as were the mRNAs of the pro-apoptotic p53 target genes Noxa, Puma and Bax. The cell death in Taf8 forebrain regions was completely rescued by additional loss of p53, but Taf8 and p53 brains failed to initiate a neuronal expression program. Taf8 deletion caused aberrant transcription of promoter regions and splicing anomalies. We propose that TAF8 supports the directionality of transcription and co-transcriptional splicing, and that failure of these processes causes p53-induced apoptosis of neuronal cells in the developing mouse embryo.

Monitoring Behaviors of Patients With Late-Stage Dementia Using Passive Environmental Sensing Approaches: A Case Series.

OBJECTIVE: To show the feasibility of using different unobtrusive activity-sensing technologies to provide objective behavioral markers of persons with dementia (PwD). DESIGN: Monitored the behaviors of two PwD living in memory care unit using the Oregon Center for Aging & Technology (ORCATECH) platform, and the behaviors of two PwD living in assisted living facility using the Emerald device. SETTING: A memory care unit in Portland, Oregon and an assisted living facility in Framingham, Massachusetts. PARTICIPANTS: A 63-year-old male with Alzheimer's disease (AD), and an 80-year-old female with frontotemporal dementia, both lived in a memory care unit in Portland, Oregon. An 89-year-old woman with a diagnosis of AD, and an 85-year-old woman with a diagnosis of major neurocognitive disorder, Alzheimer's type with behavioral symptoms, both resided at an assisted living facility in Framingham, Massachusetts. MEASUREMENTS: These include: sleep quality measured by the bed pressure mat; number of transitions between spaces and dwell times in different spaces measured by the motion sensors; activity levels measured by the wearable actigraphy device; and couch usage and limb movements measured by the Emerald device. RESULTS: Number of transitions between spaces can identify the patient's episodes of agitation; activity levels correlate well with the patient's excessive level of agitation and lack of movement when the patient received potentially inappropriate medication and neared the end of life; couch usage can detect the patient's increased level of apathy; and periodic limb movements can help detect risperidone-induced side effects. This is the first demonstration that the ORCATECH platform and the Emerald device can measure such activities. CONCLUSION: The use of technologies for monitoring behaviors of PwD can provide more objective and intensive measurements of PwD behaviors.

Contactless In-Home Monitoring of the Long-Term Respiratory and Behavioral Phenotypes in Older Adults With COVID-19: A Case Series.

Currently, there is a limited understanding of long-term outcomes of COVID-19, and a need for in-home measurements of patients through the whole course of their disease. We study a novel approach for monitoring the long-term trajectories of respiratory and behavioral symptoms of COVID-19 patients at home. We use a sensor that analyzes the radio signals in the room to infer patients' respiration, sleep and activities in a passive and contactless manner. We report the results of continuous monitoring of three residents of an assisted living facility for 3 months, through the course of their disease and subsequent recovery. In total, we collected 4,358 measurements of gait speed, 294 nights of sleep, and 3,056 h of respiration. The data shows differences in the respiration signals between asymptomatic and symptomatic patients. Longitudinally, we note sleep and motor abnormalities that persisted for months after becoming COVID negative. Our study represents a novel phenotyping of the respiratory and behavioral trajectories of COVID recovery, and suggests that the two may be integral components of the COVID-19 syndrome. It further provides a proof-of-concept that contactless passive sensors may uniquely facilitate studying detailed longitudinal outcomes of COVID-19, particularly among older adults.

A Report on the Impact of the COVID-19 Pandemic on the Health and Social Welfare of the Filipino Population in Hawai'i.

Hawai'i's Filipino community has been deeply impacted by coronavirus disease 2019 (COVID-19). This article reports the findings for the Filipino population from the Hawai'i Emergency Management Agency (HI-EMA) Community Care Outreach Unit (CCO) Unit evaluation assessment of the impact of COVID-19 on the health and social welfare of individuals across the state. The survey was conducted from August-September 2020. We propose recommendations to mitigate the impact of the pandemic on this community, including the following actions: (1) developing linguistically and culturally appropriate support for all COVID-19 related services, especially for the high number of older Filipinos with limited English proficiency, (2) providing support and resource information in locations that are accessible to Filipino communities, and (3) supporting those already doing work to address the deep and diverse needs in the Filipino community with funding. Building partnerships between existing Filipino organizations, health and social service providers, and state agencies will contribute to sustainability over time.

Disaggregating Data to Measure Racial Disparities in COVID-19 Outcomes and Guide Community Response - Hawaii, March 1, 2020-February 28, 2021.

Native Hawaiian and Pacific Islander populations have been disproportionately affected by COVID-19 (1-3). Native Hawaiian, Pacific Islander, and Asian populations vary in language; cultural practices; and social, economic, and environmental experiences,† which can affect health outcomes (4).§ However, data from these populations are often aggregated in analyses. Although data aggregation is often used as an approach to increase sample size and statistical power when analyzing data from smaller population groups, it can limit the understanding of disparities among diverse Native Hawaiian, Pacific Islander, and Asian subpopulations¶ (4-7). To assess disparities in COVID-19 outcomes among Native Hawaiian, Pacific Islander, and Asian populations, a disaggregated, descriptive analysis, informed by recommendations from these communities,** was performed using race data from 21,005 COVID-19 cases and 449 COVID-19-associated deaths reported to the Hawaii State Department of Health (HDOH) during March 1, 2020-February 28, 2021.†† In Hawaii, COVID-19 incidence and mortality rates per 100,000 population were 1,477 and 32, respectively during this period. In analyses with race categories that were not mutually exclusive, including persons of one race alone or in combination with one or more races, Pacific Islander persons, who account for 5% of Hawaii's population, represented 22% of COVID-19 cases and deaths (COVID-19 incidence of 7,070 and mortality rate of 150). Native Hawaiian persons experienced an incidence of 1,181 and a mortality rate of 15. Among subcategories of Asian populations, the highest incidences were experienced by Filipino persons (1,247) and Vietnamese persons (1,200). Disaggregating Native Hawaiian, Pacific Islander, and Asian race data can aid in identifying racial disparities among specific subpopulations and highlights the importance of partnering with communities to develop culturally responsive outreach teams§§ and tailored public health interventions and vaccination campaigns to more effectively address health disparities.

Cannabinoids for Agitation in Alzheimer's Disease.

Agitation is a common neuropsychiatric symptom of Alzheimer's disease (AD) that greatly impacts quality of life and amplifies caregiver burden. Agitation in AD may be associated with volume loss in the anterior cingulate cortex, posterior cingulate cortex, insula, amygdala, and frontal cortex, as well as with degeneration of monoaminergic neurotransmission, disrupted circadian rhythms, and frailty. Current pharmacologic options have troubling safety concerns and only modest efficacy. There is increasing interest in cannabinoids as promising agents due to preclinical and early clinical research that suggest cannabinoids can elicit anxiolytic, antidepressant, and/or anti-inflammatory effects. Cannabinoids may relieve agitation by regulating neurotransmitters, improving comorbidities and circadian rhythms, and increasing cerebral circulation. Here we discuss the possible contributory mechanisms for agitation in AD and the therapeutic relevance of cannabinoids, including CBD and THC.

Development of Plasmodium-specific liver-resident memory CD8+ T cells after heat-killed sporozoite immunization in mice.

Malaria remains a major cause of mortality in the world and an efficient vaccine is the best chance of reducing the disease burden. Vaccination strategies for the liver stage of disease that utilise injection of live radiation-attenuated sporozoites (RAS) confer sterile immunity, which is mediated by CD8+ memory T cells, with liver-resident memory T cells (TRM ) being particularly important. We have previously described a TCR transgenic mouse, termed PbT-I, where all CD8+ T cells recognize a specific peptide from Plasmodium. PbT-I form liver TRM cells upon RAS injection and are capable of protecting mice against challenge infection. Here, we utilize this transgenic system to examine whether nonliving sporozoites, killed by heat treatment (HKS), could trigger the development of Plasmodium-specific liver TRM cells. We found that HKS vaccination induced the formation of memory CD8+ T cells in the spleen and liver, and importantly, liver TRM cells were fewer in number than that induced by RAS. Crucially, we showed the number of TRM cells was significantly higher when HKS were combined with the glycolipid α-galactosylceramide as an adjuvant. In the future, this work could lead to development of an antimalaria vaccination strategy that does not require live sporozoites, providing greater utility.

Plasmodium berghei Hsp90 contains a natural immunogenic I-Ab-restricted antigen common to rodent and human Plasmodium species.

Thorough understanding of the role of CD4 T cells in immunity can be greatly assisted by the study of responses to defined specificities. This requires knowledge of Plasmodium-derived immunogenic epitopes, of which only a few have been identified, especially for the mouse C57BL/6 background. We recently developed a TCR transgenic mouse line, termed PbT-II, that produces CD4+ T cells specific for an MHC class II (I-Ab)-restricted Plasmodium epitope and is responsive to both sporozoites and blood-stage P. berghei. Here, we identify a peptide within the P. berghei heat shock protein 90 as the cognate epitope recognised by PbT-II cells. We show that C57BL/6 mice infected with P. berghei blood-stage induce an endogenous CD4 T cell response specific for this epitope, indicating cells of similar specificity to PbT-II cells are present in the naïve repertoire. Adoptive transfer of in vitro activated TH1-, or particularly TH2-polarised PbT-II cells improved control of P. berghei parasitemia in C57BL/6 mice and drastically reduced the onset of experimental cerebral malaria. Our results identify a versatile, potentially protective MHC-II restricted epitope useful for exploration of CD4 T cell-mediated immunity and vaccination strategies against malaria.

Clinical Trials and Tribulations in the COVID-19 Era.

Advances in treating and preventing Alzheimer disease and other neurocognitive disorders of aging arise from rigorous preclinical and clinical research, with randomized controlled treatment trials as the last and definitive test. The COVID-19 pandemic has greatly disrupted ongoing interventional studies and researchers are scrambling to find ways to safely continue this critical work amidst rapidly shifting guidelines from sponsors, institutions, and state and federal guidelines. Here the authors describe novel approaches and work-flow adaptations to study visits, drug delivery and interim and endpoint safety and outcomes assessments to avoid sacrificing years of preparation and substantial financial investments, to work in the best interest of participants and their caregivers, and to continue on the path toward discovering disease-modifying treatments for the millions of individuals impacted by major neurocognitive disorders.

Glycolipid-peptide vaccination induces liver-resident memory CD8+ T cells that protect against rodent malaria.

Liver resident-memory CD8+ T cells (TRM cells) can kill liver-stage Plasmodium-infected cells and prevent malaria, but simple vaccines for generating this important immune population are lacking. Here, we report the development of a fully synthetic self-adjuvanting glycolipid-peptide conjugate vaccine designed to efficiently induce liver TRM cells. Upon cleavage in vivo, the glycolipid-peptide conjugate vaccine releases an MHC I-restricted peptide epitope (to stimulate Plasmodium-specific CD8+ T cells) and an adjuvant component, the NKT cell agonist α-galactosylceramide (α-GalCer). A single dose of this vaccine in mice induced substantial numbers of intrahepatic malaria-specific CD8+ T cells expressing canonical markers of liver TRM cells (CD69, CXCR6, and CD101), and these cells could be further increased in number upon vaccine boosting. We show that modifications to the peptide, such as addition of proteasomal-cleavage sequences or epitope-flanking sequences, or the use of alternative conjugation methods to link the peptide to the glycolipid improved liver TRM cell generation and led to the development of a vaccine able to induce sterile protection in C57BL/6 mice against Plasmodium berghei sporozoite challenge after a single dose. Furthermore, this vaccine induced endogenous liver TRM cells that were long-lived (half-life of ~425 days) and were able to maintain >90% sterile protection to day 200. Our findings describe an ideal synthetic vaccine platform for generating large numbers of liver TRM cells for effective control of liver-stage malaria and, potentially, a variety of other hepatotropic infections.

Radio Signal Sensing and Signal Processing to Monitor Behavioral Symptoms in Dementia: A Case Study.

OBJECTIVES: Alzheimer's Disease (AD)-related behavioral symptoms (i.e. agitation and/or pacing) develop in nearly 90% of AD patients. In this N = 1 study, we provide proof-of-concept of detecting changes in movement patterns that may reflect underlying behavioral symptoms using a highly novel radio sensor and identifying environmental triggers. METHODS: The Emerald device is a Wi-Fi-like box without on-body sensors, which emits and processes radio-waves to infer patient movement, spatial location and activity. It was installed for 70 days in the room of patient 'E', exhibiting agitated behaviors. RESULTS: Daily motion episode aggregation revealed motor activity fluctuation throughout the data collection period which was associated with potential socio-environmental triggers. We did not detect any adverse events attributable to the use of the device. CONCLUSION: This N-of-1 study suggests the Emerald device is feasible to use and can potentially yield actionable data regarding behavioral symptom management. No active or potential device risks were encountered.

HPV vaccination prevalence, parental barriers and motivators to vaccinating children in Hawai'i.

Objective: To determine the prevalence and barriers to human papillomavirus (HPV) vaccine uptake among 11-18 year olds in the Hawai'i's four major ethnic groups-Native Hawaiians, Filipinos, Japanese, and Caucasians. Study design: A telephone survey assessed parents' knowledge of HPV and the HPV vaccine, status of their child's HPV vaccine uptake, variables operationalizing the Health Belief Model, and barriers and motivators to uptake. Results: Across the groups, 799 parents completed the survey. About 35% of daughters and 19% of sons had received all three shots. Although ethnic differences in vaccine uptake were seen in bivariate analysis (with significantly lower uptake in Filipino youth), in multivariable logistic regression analysis, only Caucasian parents were significantly less likely to start their sons on the HPV vaccine series compared with Japanese parents (reference group). Having heard about the vaccine, believing in its effectiveness, and older age of the child were also associated with vaccine uptake. Motivators for HPV vaccination were physician's recommendation and wanting to protect one's child. The primary barrier to uptake was lack of knowledge about the vaccine. Conclusions: Findings reinforce the fact that a physician's recommendation and receipt of information about the vaccine are strong motivators for parents to vaccinate their children, regardless of ethnicity.

HBO1 (KAT7) Does Not Have an Essential Role in Cell Proliferation, DNA Replication, or Histone 4 Acetylation in Human Cells.

HBO1 (MYST2/KAT7) is essential for histone 3 lysine 14 acetylation (H3K14ac) but is dispensable for H4 acetylation and DNA replication in mouse tissues. In contrast, previous studies using small interfering RNA (siRNA) knockdown in human cell lines have suggested that HBO1 is essential for DNA replication. To determine if HBO1 has distinctly different roles in immortalized human cell lines and normal mouse cells, we performed siRNA knockdown of HBO1. In addition, we used CRISPR/Cas9 to generate 293T, MCF7, and HeLa cell lines lacking HBO1. Using both techniques, we show that HBO1 is essential for all H3K14ac in human cells and is unlikely to have a direct effect on H4 acetylation and only has minor effects on cell proliferation. Surprisingly, the loss of HBO1 and H3K14ac in HeLa cells led to the secondary loss of almost all H4 acetylation after 4 weeks. Thus, HBO1 is dispensable for DNA replication and cell proliferation in immortalized human cells. However, while cell proliferation proceeded without HBO1 and H3K14ac, HBO1 gene deletion led to profound changes in cell adhesion, particularly in 293T cells. Consistent with this phenotype, the loss of HBO1 in both 293T and HeLa principally affected genes mediating cell adhesion, with comparatively minor effects on other cellular processes.

Rates of Current Tobacco and Electronic Smoking Device Use Among Filipinos in Hawai'i.

Tobacco use continues to damage the health of Filipinos. In Hawai'i, Filipinos have the second highest rate of smoking among adults and they are the fastest growing minority population. Electronic smoking devices are becoming popular and accessible. This study explored attitudes and practices of Filipinos in Hawai'i who use electronic smoking devices (ESDs), as well their knowledge of the effect of smoking and/or vaping on health and their awareness and motivations use smoking cessation programs. A convenience sample of 178 Filipinos who reported that they smoked and/or vaped responded to the online survey from January to March 2018. Reasons for starting to use ESDs included liking the different flavors (43%), being curious about vaping (38%), and viewing vaping as healthier than cigarettes (30%). Among respondents, 12% said they would like to quit smoking and 11% wanted to quit vaping, and very few felt that smoking and/or vaping behaviors impacted their health. They also demonstrated limited knowledge of cessation methods and products. Tobacco and vaping cessation programs for the Filipino community in Hawai'i are much needed because this population is at risk of developing smoking-related diseases.

Divergence between genes but limited allelic polymorphism in two MHC class II A genes in Leach's storm-petrels Oceanodroma leucorhoa.

The major histocompatibility complex (MHC) is critical to host-pathogen interactions. Class II MHC is a heterodimer, with α and ß subunits encoded by different genes. The peptide-binding groove is formed by the first domain of both subunits (α1 and ß1), but studies of class II variation or natural selection focus primarily on the ß subunit and II B genes. We explored MHC II A in Leach's storm-petrel, a seabird with two expressed, polymorphic II B genes. We found two II A genes, Ocle-DAA and Ocle-DBA, in contrast to the single II A gene in chicken and duck. In exon 2 which encodes the α1 domain, the storm-petrel II A genes differed strongly from each other but showed little within-gene polymorphism in 30 individuals: just one Ocle-DAA allele, and three Ocle-DBA alleles differing from each other by single non-synonymous substitutions. In a comparable sample, the two II B genes had nine markedly diverged alleles each. Differences between the α1 domains of Ocle-DAA and Ocle-DBA showed signatures of positive selection, but mainly at non-peptide-binding site (PBS) positions. In contrast, positive selection within and between the II B genes corresponded to putative PBS codons. Phylogenetic analysis of the conserved α2 domain did not reveal deep or well-supported lineages of II A genes in birds, in contrast to the pronounced differentiation of DQA, DPA, and DRA isotypes in mammals. This uncertain homology complicates efforts to compare levels of functional variation and modes of evolution of II A genes across taxa.

MOZ directs the distal-less homeobox gene expression program during craniofacial development.

Oral clefts are common birth defects. Individuals with oral clefts who have identical genetic mutations regularly present with variable penetrance and severity. Epigenetic or chromatin-mediated mechanisms are commonly invoked to explain variable penetrance. However, specific examples of these are rare. Two functional copies of the MOZ (KAT6A, MYST3) gene, encoding a MYST family lysine acetyltransferase chromatin regulator, are essential for human craniofacial development, but the molecular role of MOZ in this context is unclear. Using genetic interaction and genomic studies, we have investigated the effects of loss of MOZ on the gene expression program during mouse development. Among the more than 500 genes differentially expressed after loss of MOZ, 19 genes had previously been associated with cleft palates. These included four distal-less homeobox (DLX) transcription factor-encoding genes, Dlx1, Dlx2, Dlx3 and Dlx5 and DLX target genes (including Barx1, Gbx2, Osr2 and Sim2). MOZ occupied the Dlx5 locus and was required for normal levels of histone H3 lysine 9 acetylation. MOZ affected Dlx gene expression cell-autonomously within neural crest cells. Our study identifies a specific program by which the chromatin modifier MOZ regulates craniofacial development.

Loss of p53 Causes Stochastic Aberrant X-Chromosome Inactivation and Female-Specific Neural Tube Defects.

Neural tube defects (NTDs) are common birth defects in humans and show an unexplained female bias. Female mice lacking the tumor suppressor p53 display NTDs with incomplete penetrance. We found that the combined loss of pro-apoptotic BIM and p53 caused 100% penetrant, female-exclusive NTDs, which allowed us to investigate the female-specific functions of p53. We report that female p53-/- embryonic neural tube samples show fewer cells with inactive X chromosome markers Xist and H3K27me3 and a concomitant increase in biallelic expression of the X-linked genes, Huwe1 and Usp9x. Decreased Xist and increased X-linked gene expression was confirmed by RNA sequencing. Moreover, we found that p53 directly bound response elements in the X chromosome inactivation center (XIC). Together, these findings suggest p53 directly activates XIC genes, without which there is stochastic failure in X chromosome inactivation, and that X chromosome inactivation failure may underlie the female bias in neural tube closure defects.