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Welcome to the new eScholarship@UMassChan! eScholarship@UMassChan is a freely available digital repository offering worldwide access to the research and scholarly work of the UMass Chan Medical School community. We welcome submissions from our faculty, researchers, staff, and students. eScholarship@UMassChan is a service of the Lamar Soutter Library, Worcester, MA, USA.
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Recently Published
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Lost in Transition: The Journey from Pediatric to Adult Care for Youth with Mental Health ConditionsNearly one out of three (30.6%) young adults (18–25 years) experience mental illness (NIMH). In the United States suicide is the third leading cause of death for young people. Transition age youth (16–25 years) with mental health conditions such as mood disorders, anxiety disorders, and psychotic disorders, experience substantial adversity during the shift from pediatric to adult health care. Research by our team has shown that youth with mental health conditions utilize less outpatient care as they emerge into adulthood. These results echo the American Psychiatric Association position statement that transition age youth are “underserved in current mental health systems”. Understanding provider perspectives to caring for this unique patient population may help to increase health care utilization and quality of care for transition age youth with mental health conditions. This product offers providers real-world tips on what they can do to help and advocate for based on our work.
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Tips to Help People Living with Mental Health Conditions Stop Using Tobacco ProductsApproximately fifty million people living in the U.S. use tobacco products. According to the Massachusetts Department of Public Health, the leading cause of preventable death and disease in the state is smoking. As of 2017, 13.7% of Massachusetts adults were current smokers, with 13.5% of white adults, 15.7% of Black adults, and 18.3% of Hispanic adults reporting smoking cigarettes.1 One study found that an average smoker may attempt to quit 30 or more times before success is achieved with abstinence from smoking for at least one year. This tip sheet provides general and evidence-based tips on how to help individuals living with mental health conditions cease using tobacco products.
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Adulting Shorts: The “TEA” on IEPs Part 2This info-comic is for high school students to help them understand what an Individualized Educational Plan or IEP is, what transition planning is, and the importance of the student being involved in them. This is Part 2 of the story. Find Part 1 here: https://www.umassmed.edu/TransitionsACR/publication/comic/2021/09/tea-on-ieps-part-1/
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Ultrasound in the Acute AbdomenThis presentation is part of the PEER Liberia Radiology Lecture Series. It provides an overview for clinicians of ultrasound in the acute abdomen.
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The Role of Non-Coding Regulatory Elements in Complex Traits and Immune-Mediated DiseaseThe completion of the Human Genome Project ushered in the age of genome-wide association studies (GWAS), which have associated thousands of single nucleotide polymorphisms (SNPs) and other sequence variants with complex traits and diseases. Despite this success, progress bridging these associations to pathophysiologic understanding and new therapeutic interventions has been limited. In large part, this owes to the fact that 90% of GWAS-identified variants are non-coding–they do not impact the structure or function of proteins. Unraveling the impacts of non-coding sequence variants is one of the most significant unsolved problems in biology. Non-coding GWAS variants are enriched within cis-regulatory elements (CREs), sequences of DNA which modulate the expression, rather than the function, of target genes. These include promoters, which are immediately adjacent to the gene they regulate; enhancers, which increase expression of distant genes; silencers, which reduce the expression of distant genes; and insulators, which divide chromatin into domains to regulate interactions between other CREs. The function of CREs is modulated in part by transcription factors (TFs), DNA binding proteins which recognize and bind short characteristic DNA sequences called motifs. TFs and CREs are tissue- and cell type-specific, frequently regulating gene expression in only a few of the thousands of distinct cell and tissue types comprising the human body. Here we present work leveraging deep sequencing data and evolutionary conservation to build comprehensive atlases of cis-regulatory elements and transcription factor binding sites in the human genome, along with work architecting visualization platforms to make these atlases more accessible to, and impactful for, the scientific community. We then illustrate a key role for the sites in our atlases, particularly those evolutionarily constrained throughout the mammalian lineage, in complex traits and diseases. We conclude by presenting two case studies utilizing these datasets: one to better understand the role of non-coding variants in primary sclerosing cholangitis, a rare immune-mediated liver disease, and a second to understand the sequence features underlying strong insulator elements in the human genome.
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Mucosal nanobody IgA as inhalable and affordable prophylactic and therapeutic treatment against SARS-CoV-2 and emerging variantsAnti-COVID antibody therapeutics have been developed but not widely used due to their high cost and escape of neutralization from the emerging variants. Here, we describe the development of VHH-IgA1.1, a nanobody IgA fusion molecule as an inhalable, affordable and less invasive prophylactic and therapeutic treatment against SARS-CoV-2 Omicron variants. VHH-IgA1.1 recognizes a conserved epitope of SARS-CoV-2 spike protein Receptor Binding Domain (RBD) and potently neutralizes major global SARS-CoV-2 variants of concern (VOC) including the Omicron variant and its sub lineages BA.1.1, BA.2 and BA.2.12.1. VHH-IgA1.1 is also much more potent against Omicron variants as compared to an IgG Fc fusion construct, demonstrating the importance of IgA mediated mucosal protection for Omicron infection. Intranasal administration of VHH-IgA1.1 prior to or after challenge conferred significant protection from severe respiratory disease in K18-ACE2 transgenic mice infected with SARS-CoV-2 VOC. More importantly, for cost-effective production, VHH-IgA1.1 produced in Pichia pastoris had comparable potency to mammalian produced antibodies. Our study demonstrates that intranasal administration of affordably produced VHH-IgA fusion protein provides effective mucosal immunity against infection of SARS-CoV-2 including emerging variants.
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GLH/VASA helicases promote germ granule formation to ensure the fidelity of piRNA-mediated transcriptome surveillancepiRNAs function as guardians of the genome by silencing non-self nucleic acids and transposable elements in animals. Many piRNA factors are enriched in perinuclear germ granules, but whether their localization is required for piRNA biogenesis or function is not known. Here we show that GLH/VASA helicase mutants exhibit defects in forming perinuclear condensates containing PIWI and other small RNA cofactors. These mutant animals produce largely normal levels of piRNA but are defective in triggering piRNA silencing. Strikingly, while many piRNA targets are activated in GLH mutants, we observe that hundreds of endogenous genes are aberrantly silenced by piRNAs. This defect in self versus non-self recognition is also observed in other mutants where perinuclear germ granules are disrupted. Together, our results argue that perinuclear germ granules function critically to promote the fidelity of piRNA-based transcriptome surveillance in C. elegans and preserve self versus non-self distinction.
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Building integrative functional maps of gene regulationEvery cell in the human body inherits a copy of the same genetic information. The three billion base pairs of DNA in the human genome, and the roughly 50 000 coding and non-coding genes they contain, must thus encode all the complexity of human development and cell and tissue type diversity. Differences in gene regulation, or the modulation of gene expression, enable individual cells to interpret the genome differently to carry out their specific functions. Here we discuss recent and ongoing efforts to build gene regulatory maps, which aim to characterize all sequences in a genome for their roles in regulating gene expression. Many researchers and consortia have identified such regulatory elements using functional assays and evolutionary analyses; we discuss the results, strengths, and shortcomings of their approaches. We also discuss new techniques the field can leverage and emerging challenges it will face while striving to build gene regulatory maps of ever-increasing resolution and comprehensiveness.
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In vitro Methods to Better Evaluate Drug Responses in CancerEvaluating anti-cancer drugs in vitro is an important aspect of the drug development pipeline. When evaluating anti-cancer drugs, two different measurements are used: relative viability, which scores an amalgam of proliferative arrest and cell death, and fractional viability, which specifically scores the degree of cell killing. These two metrics are often used interchangeably despite measuring different aspects of a drug response. This study explored the relationship between drug-induced growth inhibition and cell death, and found that most drugs affect both proliferation and death, but in different proportions, and with different relative timing. This causes a non-uniform relationship between relative and fractional response measurements. To unify these measurements, I created a data visualization and analysis platform, called drug GRADE, which characterizes the degree to which death contributes to an observed drug response. GRADE captures drug- and genotype-specific responses, which are not captured using traditional pharmaco-metrics. Current in vitro anti-cancer drug evaluation practices measure drug responses with cancer cell lines in mono-culture. However, many cell types in the tumor microenvironment influence cancer’s drug response and disease progression. Therefore, current drug evaluation practices overlook complex cell-cell interactions that influence cancer’s drug response. In this study, I developed a high-throughput assay to study the effect of another cell type (cytotoxic T cells) on cancer viability in co-culture, in vitro. Further, I developed a reference framework to model the complex interaction between cancer cells and cytotoxic T cells, and to model how T cell-mediated cell death is modulated by anti-cancer drug treatment. Taken together, this study highlights two new methods which enable better in vitro evaluation of drug responses in cancer.
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Francis Fontan (1929-2018): Pioneer pediatric cardiac surgeonUp until the mid-1900s, tricuspid atresia - a birth defect of the tricuspid valve, was once categorized as a "death sentence." The challenge of achieving positive health outcomes for affected patients was compounded by a hesitancy to operate on children. The main concern was safely administering anesthesia to young patients who were going through a strenuous operation that was often poorly tolerated. Despite these assumed limitations, Francis Fontan, a pediatric cardiothoracic surgeon at the Hospital of Tondu in Bordeaux, was able to redirect blood flow from the superior and inferior vena cava to the pulmonary arteries in 1971, which elucidated the process of advancing clinical practice in medicine. With the support of mentors and a firm belief in this new technique, Fontan pioneered his eponymous procedure and ultimately paved the way for modern cardiovascular surgical techniques that helped to prolong the life of those with single functioning ventricles. The aim of this study is to examine the genesis and the evolution of the Fontan procedure to elucidate the process of advancing clinical practice in medicine by utilizing personal interviews, Fontan's works, associated primary and secondary sources in the context of 20th century cardiothoracic surgery and innovations.
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Examining Pregnant Veterans' Acceptance and Beliefs Regarding the COVID-19 VaccineBackground: Pregnant persons have received mixed messages regarding whether or not to receive COVID-19 vaccines as limited data are available regarding vaccine safety for pregnant and lactating persons and breastfeeding infants. Objective: The aims of this study were to examine pregnant Veteran's acceptance of COVID-19 vaccines, along with perceptions and beliefs regarding vaccine safety and vaccine conspiracy beliefs. Design and participants: We conducted a cross-sectional survey of pregnant Veterans enrolled in VA care who were taking part in an ongoing cohort study at 15 VA medical centers between January and May 2021. Main measures: Pregnant Veterans were asked whether they had been offered the COVID-19 vaccine during pregnancy, and whether they chose to accept or refuse it. Additional questions focused on perceptions of COVID-19 vaccine safety and endorsements of vaccine knowledge and conspiracy beliefs. Logistic regression was utilized to examine predictors of acceptance of a vaccine during pregnancy. Key results: Overall, 72 pregnant Veterans were offered a COVID-19 vaccine during pregnancy; over two-thirds (69%) opted not to receive a vaccine. Reasons for not receiving a vaccine included potential effects on the baby (64%), side effects for oneself (30%), and immunity from a past COVID-19 infection (12%). Those who received a vaccine had significantly greater vaccine knowledge and less belief in vaccine conspiracy theories. Greater knowledge of vaccines in general (aOR: 1.78; 95% CI: 1.2-2.6) and lower beliefs in vaccine conspiracies (aOR: 0.76; 95% CI: 0.6-0.9) were the strongest predictors of acceptance of a COVID-19 vaccine during pregnancy. Conclusions: Our study provides important insights regarding pregnant Veterans' decisions to accept the COVID-19 vaccine, and reasons why they may choose not to accept the vaccine. Given the high endorsement of vaccine conspiracy beliefs, trusted healthcare providers should have ongoing, open discussions about vaccine conspiracy beliefs and provide additional information to dispel these beliefs.
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Lay Beliefs About Doctors' Knowledge of and Reasons for Recommending COVID-19 VaccinesCommonly cited as the most trusted source of information about COVID-19 vaccines, healthcare providers have an important role in promoting COVID-19 vaccination While a healthcare provider recommendation is associated with greater likelihood of being vaccinated against COVID-193, there is limited understanding of lay beliefs about providers’ knowledge of COVID-19 vaccines and reasons for promoting vaccination.
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Trends in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Seroprevalence in Massachusetts Estimated from Newborn Screening SpecimensBackground: Estimating the cumulative incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential for setting public health policies. We leveraged deidentified Massachusetts newborn screening specimens as an accessible, retrospective source of maternal antibodies for estimating statewide seroprevalence in a nontest-seeking population. Methods: We analyzed 72 117 newborn specimens collected from November 2019 through December 2020, representing 337 towns and cities across Massachusetts. Seroprevalence was estimated for the Massachusetts population after correcting for imperfect test specificity and nonrepresentative sampling using Bayesian multilevel regression and poststratification. Results: Statewide seroprevalence was estimated to be 0.03% (90% credible interval [CI], 0.00-0.11) in November 2019 and rose to 1.47% (90% CI: 1.00-2.13) by May 2020, following sustained SARS-CoV-2 transmission in the spring. Seroprevalence plateaued from May onward, reaching 2.15% (90% CI: 1.56-2.98) in December 2020. Seroprevalence varied substantially by community and was particularly associated with community percent non-Hispanic Black (β = .024; 90% CI: 0.004-0.044); i.e., a 10% increase in community percent non-Hispanic Black was associated with 27% higher odds of seropositivity. Seroprevalence estimates had good concordance with reported case counts and wastewater surveillance for most of 2020, prior to the resurgence of transmission in winter. Conclusions: Cumulative incidence of SARS-CoV-2 protective antibody in Massachusetts was low as of December 2020, indicating that a substantial fraction of the population was still susceptible. Maternal seroprevalence data from newborn screening can inform longitudinal trends and identify cities and towns at highest risk, particularly in settings where widespread diagnostic testing is unavailable.
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Cellular heterogeneity and gene regulatory network coordination during thymic epithelial cell developmentThymic epithelial cells, derived from the pharyngeal endoderm, perform essential functions for establishing a self-tolerant immune system. Unsurprisingly, dysfunction of thymic epithelial cells resulting from maldevelopment of the pharyngeal endoderm causes immunodeficiency or autoimmunity syndromes, some of which cannot be fully explained according to known genetic errors. Despite the functional significance and disease-relevance of pharyngeal endoderm with respect to thymic epithelial cells, we lack a comprehensive understanding of the gene regulatory networks driving pharyngeal endoderm differentiation. To close this gap, we applied transcriptome and chromatin accessibility single cell profiling to generate a multi-omic developmental resource covering pharyngeal differentiation toward organ-specific epithelia in the mouse embryo. We identified cell-type specific gene regulation of developing organ domains and characterized the role of an immunodeficiency-associated forkhead box transcription factor, Foxn1, during early thymus development. Furthermore, analyses of the pharyngeal endoderm multi-omics atlas led us to discover a novel gene associated with thymus development, namely Grainyhead-like3 (Grhl3). We assessed the expression pattern and the functional importance of Grhl3 in the prenatal and postnatal thymus, uncovering a putative role in a specialized medullary thymic subtype. In conclusion, this dissertation provides insight on the molecular basis of pharyngeal endoderm differentiation and subsequent development of the thymus.
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Regulated Gene Therapy Towards Glycosphingolipid Biosynthesis DeficienciesGlycosphingolipids (GSLs) are a group of amphipathic glycolipids essential for maintaining the normal ultrastructure and function of neural and oligodendrocyte cell membranes throughout the mammalian central nervous system (CNS). De novo GSL biosynthesis defects cause severe neurological diseases such as GM3 synthase deficiency (GM3SD) and hereditary sensory and autonomic neuropathy type 1A (HSAN1A), each lacking effective treatment. Here, we developed two distinct potential therapeutic approaches for these neurological diseases. For GM3SD that is caused by loss-of-function mutations in ST3GAL5, we employed a recombinant adeno-associated virus (rAAV)-mediated human ST3GAL5 gene replacement therapy. First, using ST3GAL5 mutant patient iPSC-derived neurons and St3gal5 knock-out mouse models, we have achieved ST3GAL5 gene normalization and restoration of the functional products, cerebral gangliosides. Importantly, we revealed the hepatic toxicity caused by ubiquitous expression of ST3GAL5 and optimized a CNS-restricted rAAV gene replacement therapy for the safe and efficacious rescue of the severe neurodevelopmental phenotypes and early lethality in disease mouse models, given by both intracerebroventricular and intravenous routes of administration. These results support for further clinical development of ST3GAL5 gene therapy. On the other hand, to target gain-of-function SPTLC1 mutation caused HSAN1A, we screened antisense oligonucleotides (ASOs) and achieved efficient reduction of mutant SPTLC1 transcripts and its toxic products in patient-fibroblasts. In summary, this thesis describes the potential of novel rAAV-mediated gene replacement therapy in GM3SD and allele-specific ASO silencing in HSAN1A, highlighting the significance of personalized gene therapy for monogenic neurological disorders.
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Impact of individual and treatment characteristics on wearable sensor-based digital biomarkers of opioid useOpioid use disorder is one of the most pressing public health problems of our time. Mobile health tools, including wearable sensors, have great potential in this space, but have been underutilized. Of specific interest are digital biomarkers, or end-user generated physiologic or behavioral measurements that correlate with health or pathology. The current manuscript describes a longitudinal, observational study of adult patients receiving opioid analgesics for acute painful conditions. Participants in the study are monitored with a wrist-worn E4 sensor, during which time physiologic parameters (heart rate/variability, electrodermal activity, skin temperature, and accelerometry) are collected continuously. Opioid use events are recorded via electronic medical record and self-report. Three-hundred thirty-nine discreet dose opioid events from 36 participant are analyzed among 2070 h of sensor data. Fifty-one features are extracted from the data and initially compared pre- and post-opioid administration, and subsequently are used to generate machine learning models. Model performance is compared based on individual and treatment characteristics. The best performing machine learning model to detect opioid administration is a Channel-Temporal Attention-Temporal Convolutional Network (CTA-TCN) model using raw data from the wearable sensor. History of intravenous drug use is associated with better model performance, while middle age, and co-administration of non-narcotic analgesia or sedative drugs are associated with worse model performance. These characteristics may be candidate input features for future opioid detection model iterations. Once mature, this technology could provide clinicians with actionable data on opioid use patterns in real-world settings, and predictive analytics for early identification of opioid use disorder risk.
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Association Between Patient Portal Use and Perceived Patient-Centered Communication Among Adults With Cancer: Cross-sectional Survey StudyBackground: Patient-centered communication (PCC) plays a vital role in effective cancer management and care. Patient portals are increasingly available to patients and hold potential as a valuable tool to facilitate PCC. However, whether more frequent use of patient portals is associated with increased perceived PCC and which mechanisms might mediate this relationship have not been fully studied. Objective: The goal of this study was to investigate the association between the frequency of access of patient portals and perceived PCC in patients diagnosed with cancer. We further sought to examine whether this association was mediated by patients' self-efficacy in health information-seeking. Methods: We used data from the Health Information National Trend Survey 5 (HINTS 5) cycle 3 (2019) and cycle 4 (2020). This analysis includes 1222 individuals who self-reported having a current or past diagnosis of cancer. Perceived PCC was measured with a 7-item HINTS 5-derived scale and classified as low, medium, or high. Patient portal use was measured by a single item assessing the frequency of use. Self-efficacy about health information-seeking was assessed with a 1-item measure assessing confidence in obtaining health information. We used adjusted multinomial logistic regression models to estimate relative risk ratios (RRRs)/effect sizes of the association between patient portal use and perceived PCC. Mediation by health information self-efficacy was investigated using the Baron and Kenny and Karlson-Holm-Breen methods. Results: A total of 54.5% of the sample reported that they had not accessed their patient portals in the past 12 months, 12.6% accessed it 1 to 2 times, 24.8% accessed it 3 to 9 times, and 8.2% accessed it 10 or more times. Overall, the frequency of accessing the patient portal was marginally associated (P=.06) with perceived PCC in an adjusted multinominal logistic regression model. Patients who accessed their patient portal 10 or more times in the previous 12 months were almost 4 times more likely (RRR 3.8, 95% CI 1.6-9.0) to report high perceived PCC. In mediation analysis, the association between patient portal use and perceived PCC was attenuated adjusting for health information-seeking self-efficacy, but those with the most frequent patient portal use (10 or more times in the previous 12 months) were still almost 2.5 times more likely to report high perceived PCC (RRR 2.4, 95% CI 1.1-5.6) compared to those with no portal use. Conclusions: Increased frequency of patient portal use was associated with higher PCC, and an individual's health information-seeking self-efficacy partially mediated this association. These findings emphasize the importance of encouraging patients and providers to use patient portals to assist in patient-centeredness of cancer care. Interventions to promote the adoption and use of patient portals could incorporate strategies to improve health information self-efficacy.
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Investigating Proteolytic Processing of Ataxin 2, a Neurodegenerative Disease Associated ProteinAtaxin 2 (ATXN2) is a ubiquitously expressed mRNA binding protein involved in the development and progression of spinocerebellar ataxia 2 (SCA2) and amyotrophic lateral sclerosis (ALS). In the context of both neurodegenerative diseases, its N-terminal polyglutamine (polyQ) domain is mutated and expanded in length. Several other polyQ proteins, such as huntingtin (Htt), ataxin 3 (ATXN3), and ataxin 7 (ATXN7), undergo proteolytic processing that produces toxic fragments containing their polyQ domains. Investigating how ATXN2 is regulated by proteolysis is hindered by the lack of available molecular biological tools such as N-terminal ATXN2 antibodies to target and analyze the endogenous N-terminus of ATXN2. To circumvent this challenge, I developed a transient overexpression model of N-terminally tagged ATXN2 in HEK293E cells. Here, I demonstrate that both wild-type and mutant ATXN2 are targets of N-terminal proteolysis. I confirmed that ATXN2 produces an independent polyQ cleavage fragment like other polyQ proteins through basic molecular biology approaches such as Western blotting and immunoprecipitation. Additionally, I identified the specific region that is both necessary and sufficient for cleavage to occur via deletion mapping with multiple truncated ATXN2 mutants and reporter constructs. Further definition of ATXN2 as a target of proteolytic cleavage aligns it with other neurodegenerative polyQ proteins, and proteolysis is currently a less explored avenue of research for ATXN2-related disease development, progression, and therapeutic modalities. This work reveals a novel site that directs cleavage of ATXN2 and provides a potential avenue of investigation for how ATXN2 posttranslational modifications contribute to the progression of SCA2 and ALS.
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UMCCTS Newsletter, August 2022This is the August 2022 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.
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Journal of eScience Librarianship (JeSLIB) Publishing ProcessDescribes the roles and responsibilities, author guidelines, and peer review process for the Journal of eScience Librarianship.
