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Recent documents in eScholarship@UMMS
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Temporal Organization of Behavioral States through Local Neuromodulation in C. elegans

Fri, 05/05/2017 - 2:59pm

Neuropeptide signaling play critical roles in maintaining distinct behavioral states and orchestrating transitions between them. However, elucidating the mechanisms underlying neuropeptide modulation of neural circuits in vivo remains a major challenge. The nematode Caenorhabditis elegans serves as an excellent model organism to study neuropeptide signaling mechanisms encoded in relatively simple neural circuits. We have used the C. elegans egg-laying circuit as a model to understand how neuropeptide signaling modifies circuit activity to generate opposing behavioral outcomes. C. elegans egg-laying behavior is composed of alternating cycles of two states – short bursts of egg deposition (active phases) and prolonged periods of quiescence (inactive phases). We have identified two neuropeptides (NLP-7 and FLP-11) that are locally released from a group of neurosecretory cells (uv1) and coordinate the temporal organization of egglaying by prolonging the duration of inactive phases. These neuropeptides regulate activity within the core circuit by inhibiting serotonergic transmission between its individual components (HSN motorneurons and Vm2 vulval muscles). This inhibition is achieved at least in part, by reducing synaptic vesicle abundance in the HSN synaptic regions. To identify potential downstream signaling components that mediate the actions of these neuropeptides, we have performed a forward genetic screen and have identified a strong candidate. In addition, we are trying to identify the receptor(s) of these neuropeptides by using a candidate gene approach. Together, we demonstrate that local neuropeptide signaling maintains the periodicity of distinct behavioral states by regulating serotonergic transmission in the core neural circuit.

Emerging Trends in Visual Science Communication: How to create informative and inspiring graphics for journals and presentations

Fri, 05/05/2017 - 2:20pm

Effective science communication is highly dependent on clear, effective and eye-catching visuals. However, most scientists or research organizations do not have the resources to hire professional studios nor have an on-staff design team. Additionally, some research may involve proprietary information that make it difficult to bring on external team members on a whim. Luckily, there are ways to obtain or create an effective image to communicate complex science topics, whether it’s for a journal figure, a keynote presentation, internal team discussions, or the general public.

This webinar will cover some techniques and available tools on how to improve the use and creation of scientific graphics in journals, graphical abstracts, peer-peer communication, or general science communication for the public. Discussion will focus on a few key design and rendering techniques that any non-artist can implement when approaching graphics, schematics, or general presentation of scientific information (including proper layout, basic color or font choices, and when to include images).

Medical Marijuana Education for Medical Students

Fri, 05/05/2017 - 11:38am

As the nationwide discourse on medical marijuana evolves, with 28 out of 50 states approving its use, University of Massachusetts Medical School graduates will need to be prepared to discuss medical marijuana (MMJ) with their patients. There is currently no formal medical school education on MMJ. This project set out to understand the curriculum gap and provide a learning session to interested students. The presentation was created using research done by the author during the first three years of medical school, including visits to private MMJ clinics. Utilizing a pre/post-session online assessment of a group of twenty-six students, we found that student knowledge about Massachusetts’ MMJ law improved by 29%, following a ninety-minute session. In addition, self-assessed confidence in negotiating clinical scenarios involving marijuana improved by 34%. These improvements were statistically significant, with p-values of 0.0033 and 9.5x10-16 respectively. These findings support the formal addition of a sixty- to ninety-minute session focusing on MMJ to the UMMS curriculum.

WooFood Cooks

Fri, 05/05/2017 - 11:24am

As the obesity rates among children have increased examining the causes of this rise is imperative. One of the many reasons for the increase is the amount of meals eaten away from the home and even though young men of color may be less likely to be overweight or obese, chronic diseases associated with poor diets such as diabetes, hypertension, and hyperlipidemia still adversely affect them. Studies show that there is a connection between unhealthy eating and the development of the aforementioned chronic diseases. Therefore, the purpose of this Capstone Project, WooFood Cooks, is to bring high school-aged men of color into the kitchen, expose them to micronutrient rich foods, and teach them to cook healthy meals so that they can take these skills home to their families and employ these into adulthood. By having multiple opportunities to learn about, prepare, cook, and eat meals with fruits, vegetables, and lean meats, this program will hopefully have a long-term positive impact on the health of these young men. After the completion of the classes the young men enjoyed the time in the kitchen and learned new cooking skills that they could implement in their homes. However, this project demonstrated that there is more work to be done in the community with bringing families together into teaching kitchens to help them see a new way of cooking traditional meals. It will also impart the necessary knowledge to parents desiring to best serve the health outcomes and behaviors of their children.

The Use and Efficacy of Comics in Healthcare: A Scoping Review in Graphic Medicine

Fri, 05/05/2017 - 9:04am

Background: Graphic medicine is defined as the “interaction between the medium of comics and the discourse of healthcare”. We seek to understand the ways in which comics are currently being employed in healthcare settings and what effects, if any, these practices have on physician, patient, and their experiences and health outcomes.

Methods: Our scoping review is following the six-stage methodology laid out by Arksey and O’Malley (2005) in order to map the field – an appropriate methodology, as graphic medicine is a relatively new field that thus far lacks clear boundaries. We built, tested, and conducted searches in six databases: (1) PubMed, (2) CINAHL, (3) SCOPUS, (4) ERIC, (5) Web of Science (Core), and (6) Google Scholar.

Preliminary Findings: Search results netted 5,097 unique citations, which highlights a clear problem with current indexing of comics in medical databases, as at least 80% of the citations were in fact NOT comics at all. In-depth screening and analysis of relevant results is ongoing.

Potential Impact: Graphic medicine shows potential as a tool in medical and patient education and may help bridge the health literacy gap.

Next Steps: Our next steps include synthesis of relevant studies and ongoing hand-searching for results outside of typical scholarly publications.

Questions for the MTL Community: How might you make use of comics in your practice and/or praxis?

A predictive model for lack of partial clinical remission in new-onset pediatric type 1 diabetes

Wed, 05/03/2017 - 3:53pm

IMPORTANCE: >50% of patients with new-onset type 1 diabetes (T1D) do not enter partial clinical remission (PCR); early identification of these patients may improve initial glycemic control and reduce long-term complications.

AIM: To determine whether routinely obtainable clinical parameters predict non-remission in children and adolescents with new-onset T1D.

SUBJECTS AND METHODS: Data on remission were collected for the first 36 months of disease in 204 subjects of ages 2-14 years with new-onset type 1 diabetes. There were 86 remitters (age 9.1±3.0y; male 57%), and 118 non-remitters (age 7.0±3.1y; male 40.7%). PCR was defined as insulin-dose adjusted hemoglobin A1c of ≤9.

RESULTS: Non-remission occurred in 57.8% of subjects. Univariable analysis showed that the risk for non-remission was increased 9-fold in patients with 4 diabetes-associated auto-antibodies (OR = 9.90, p = 0.010); 5-fold in patients(odds ratio = 5.38, p = 0.032), 3-fold in those with bicarbonate of/dL at diagnosis (OR = 3.71, p = 0.008). Combined estimates of risk potential for HC03 and the number of autoantibodies by multivariable analysis, adjusted for BMI standard deviation score, showed HC03/dL with a clinically significant 10-fold risk (OR = 10.1, p = 0.074); and the number of autoantibodies with a 2-fold risk for non-remission (OR = 1.9, p = 0.105). Male sex and older age were associated with decreased risk for non-remission. A receiver-operating characteristic curve model depicting sensitivity by 1-specificity for non-remission as predicted by bicarbonate/dL, age3 diabetes-associated autoantibodies had an area under the curve of 0.73.

CONCLUSIONS: More than 50% of children and adolescents with new-onset T1D do not undergo partial clinical remission and are thus at an increased risk for long-term complications of diabetes mellitus. A predictive model comprising of bicarbonate/dL, age3 diabetes-associated autoantibodies has 73% power for correctly predicting non-remission in children and adolescents with new-onset T1D. Early identification of these non-remitters may guide the institution of targeted therapy to limit dysglycemia and reduce the prevalence of long-term deleterious complications.

Targeted Delivery of Glucan Particle Encapsulated Gallium Nanoparticles Inhibits HIV Growth in Human Macrophages

Wed, 05/03/2017 - 12:08pm

Glucan particles (GPs) are hollow, porous 3-5 mum microspheres derived from the cell walls of Baker's yeast (Saccharomyces cerevisiae). The 1,3-beta-glucan outer shell provides for receptor-mediated uptake by phagocytic cells expressing beta-glucan receptors. GPs have been used for macrophage-targeted delivery of a wide range of payloads (DNA, siRNA, protein, small molecules, and nanoparticles) encapsulated inside the hollow GPs or bound to the surface of chemically derivatized GPs. Gallium nanoparticles have been proposed as an inhibitory agent against HIV infection. Here, macrophage targeting of gallium using GPs provides for more efficient delivery of gallium and inhibition of HIV infection in macrophages compared to free gallium nanoparticles.

Case Report of a Child after Hematopoietic Cell Transplantation with Acute Aspergillus Tracheobronchitis as a Cause for Respiratory Failure

Wed, 05/03/2017 - 12:08pm

Rapid respiratory failure due to invasive mycosis of the airways is an uncommon presentation of Aspergillus infection, even in immunocompromised patients, and very few pediatric cases have been reported. Patients with Aspergillus tracheobronchitis present with nonspecific symptoms, and radiologic studies are often noninformative, leading to a delay in diagnosis. Prompt initiation of adequate antifungal therapies is of utmost importance to improve outcome. We report the case of a 9-year-old girl with chronic myelogenous leukemia who developed respiratory distress 41 days after hematopoietic cell transplantation and rapidly deteriorated despite multiple interventions and treatment modalities.

A Novel Protocol for Directed Differentiation of C9orf72-Associated Human Induced Pluripotent Stem Cells Into Contractile Skeletal Myotubes

Wed, 05/03/2017 - 12:08pm

Induced pluripotent stem cells (iPSCs) offer an unlimited resource of cells to be used for the study of underlying molecular biology of disease, therapeutic drug screening, and transplant-based regenerative medicine. However, methods for the directed differentiation of skeletal muscle for these purposes remain scarce and incomplete. Here, we present a novel, small molecule-based protocol for the generation of multinucleated skeletal myotubes using eight independent iPSC lines. Through combinatorial inhibition of phosphoinositide 3-kinase (PI3K) and glycogen synthase kinase 3beta (GSK3beta) with addition of bone morphogenic protein 4 (BMP4) and fibroblast growth factor 2 (FGF2), we report up to 64% conversion of iPSCs into the myogenic program by day 36 as indicated by MYOG+ cell populations. These cells began to exhibit spontaneous contractions as early as 34 days in vitro in the presence of a serum-free medium formulation. We used this protocol to obtain iPSC-derived muscle cells from frontotemporal dementia (FTD) patients harboring C9orf72 hexanucleotide repeat expansions (rGGGGCC), sporadic FTD, and unaffected controls. iPSCs derived from rGGGGCC carriers contained RNA foci but did not vary in differentiation efficiency when compared to unaffected controls nor display mislocalized TDP-43 after as many as 120 days in vitro. This study presents a rapid, efficient, and transgene-free method for generating multinucleated skeletal myotubes from iPSCs and a resource for further modeling the role of skeletal muscle in amyotrophic lateral sclerosis and other motor neuron diseases.

SIGNIFICANCE: Protocols to produce skeletal myotubes for disease modeling or therapy are scarce and incomplete. The present study efficiently generates functional skeletal myotubes from human induced pluripotent stem cells using a small molecule-based approach. Using this strategy, terminal myogenic induction of up to 64% in 36 days and spontaneously contractile myotubes within 34 days were achieved. Myotubes derived from patients carrying the C9orf72 repeat expansion show no change in differentiation efficiency and normal TDP-43 localization after as many as 120 days in vitro when compared to unaffected controls. This study provides an efficient, novel protocol for the generation of skeletal myotubes from human induced pluripotent stem cells that may serve as a valuable tool in drug discovery and modeling of musculoskeletal and neuromuscular diseases.

Menopausal vasomotor symptoms and incident breast cancer risk in the Study of Women's Health Across the Nation

Wed, 05/03/2017 - 12:08pm

PURPOSE: Two case-control studies reported a 50 % decreased breast cancer risk among women who experienced menopausal vasomotor symptoms (VMS), but one cohort study found no association. VMS may be triggered by declining estrogen levels during menopause, whereas elevated estrogen levels have been associated with increased breast cancer risk. VMS may thus be indicative of lower susceptibility to breast cancer.

METHODS: We evaluated this relationship in the longitudinal Study of Women's Health Across the Nation (SWAN), using discrete survival analysis of approximately annual data on VMS and self-reported breast cancer occurrences for up to 13 years of follow-up in 3,098 women who were pre- or early perimenopausal at enrollment.

RESULTS: Over an average 11.4 years of follow-up, 129 incident breast cancer cases were self-reported, and approximately 50 % of participants experienced VMS. Symptomatic women had a reduced risk of breast cancer compared to non-symptomatic women (adjusted HR 0.63, 95 % CI 0.39, 1.00). The association was stronger in the subgroup of women who fully transitioned to postmenopause during follow-up (n = 67 cases, adjusted HR 0.45, 95 % CI 0.26, 0.77).

CONCLUSION: VMS appeared to be a marker of reduced breast cancer risk. Future research is needed to understand the biology underlying this relationship.

Defining an International Standard Set of Outcome Measures for Patients With Hip or Knee Osteoarthritis: Consensus of the International Consortium for Health Outcomes Measurement Hip and Knee Osteoarthritis Working Group

Wed, 05/03/2017 - 12:08pm

OBJECTIVE: To define a minimum Standard Set of outcome measures and case-mix factors for monitoring, comparing, and improving health care for patients with clinically diagnosed hip or knee osteoarthritis (OA), with a focus on defining the outcomes that matter most to patients.

METHODS: An international working group of patients, arthroplasty register experts, orthopedic surgeons, primary care physicians, rheumatologists, and physiotherapists representing 10 countries was assembled to review existing literature and practices for assessing outcomes of pharmacologic and nonpharmacologic OA therapies, including surgery. A series of 8 teleconferences, incorporating a modified Delphi process, were held to reach consensus.

RESULTS: The working group reached consensus on a concise set of outcome measures to evaluate patients' joint pain, physical functioning, health-related quality of life, work status, mortality, reoperations, readmissions, and overall satisfaction with treatment result. To support analysis of these outcome measures, pertinent baseline characteristics and risk factor metrics were defined. Annual outcome measurement is recommended for all patients.

CONCLUSION: We have defined a Standard Set of outcome measures for monitoring the care of people with clinically diagnosed hip or knee OA that is appropriate for use across all treatment and care settings. We believe this Standard Set provides meaningful, comparable, and easy to interpret measures ready to implement in clinics and/or registries globally. We view this set as an initial step that, when combined with cost data, will facilitate value-based health care improvements in the treatment of hip and knee OA.

Light-Mediated Deep-Tissue Theranostics

Wed, 05/03/2017 - 12:08pm

This theme issue provides an overview on recent developments of light-mediated imaging and therapy approaches, with an emphasis on those that transcend the shallow tissue penetration dogma.

Rational design of aptazyme riboswitches for efficient control of gene expression in mammalian cells

Wed, 05/03/2017 - 12:07pm

Efforts to control mammalian gene expression with ligand-responsive riboswitches have been hindered by lack of a general method for generating efficient switches in mammalian systems. Here we describe a rational-design approach that enables rapid development of efficient cis-acting aptazyme riboswitches. We identified communication-module characteristics associated with aptazyme functionality through analysis of a 32-aptazyme test panel. We then developed a scoring system that predicts an aptazymes's activity by integrating three characteristics of communication-module bases: hydrogen bonding, base stacking, and distance to the enzymatic core. We validated the power and generality of this approach by designing aptazymes responsive to three distinct ligands, each with markedly wider dynamic ranges than any previously reported. These aptayzmes efficiently regulated adeno-associated virus (AAV)-vectored transgene expression in cultured mammalian cells and mice, highlighting one application of these broadly usable regulatory switches. Our approach enables efficient, protein-independent control of gene expression by a range of small molecules.

Splenic differentiation and emergence of CCR5+CXCL9+CXCL10+ monocyte-derived dendritic cells in the brain during cerebral malaria

Wed, 05/03/2017 - 12:07pm

Dendritic cells have an important role in immune surveillance. After being exposed to microbial components, they migrate to secondary lymphoid organs and activate T lymphocytes. Here we show that during mouse malaria, splenic inflammatory monocytes differentiate into monocyte-derived dendritic cells (MO-DCs), which are CD11b+F4/80+CD11c+MHCIIhighDC-SIGNhighLy6c+ and express high levels of CCR5, CXCL9 and CXCL10 (CCR5+CXCL9/10+ MO-DCs). We propose that malaria-induced splenic MO-DCs take a reverse migratory route. After differentiation in the spleen, CCR5+CXCL9/10+ MO-DCs traffic to the brain in a CCR2-independent, CCR5-dependent manner, where they amplify the influx of CD8+ T lymphocytes, leading to a lethal neuropathological syndrome.

IL-21 signaling is essential for optimal host resistance against Mycobacterium tuberculosis infection

Wed, 05/03/2017 - 12:07pm

IL-21 is produced predominantly by activated CD4+ T cells and has pleiotropic effects on immunity via the IL-21 receptor (IL-21R), a member of the common gamma chain (gammac) cytokine receptor family. We show that IL-21 signaling plays a crucial role in T cell responses during Mycobacterium tuberculosis infection by augmenting CD8+ T cell priming, promoting T cell accumulation in the lungs, and enhancing T cell cytokine production. In the absence of IL-21 signaling, more CD4+ and CD8+ T cells in chronically infected mice express the T cell inhibitory molecules PD-1 and TIM-3. We correlate these immune alterations with increased susceptibility of IL-21R-/- mice, which have increased lung bacterial burden and earlier mortality compared to WT mice. Finally, to causally link the immune defects with host susceptibility, we use an adoptive transfer model to show that IL-21R-/- T cells transfer less protection than WT T cells. These results prove that IL-21 signaling has an intrinsic role in promoting the protective capacity of T cells. Thus, the net effect of IL-21 signaling is to enhance host resistance to M. tuberculosis. These data position IL-21 as a candidate biomarker of resistance to tuberculosis.

Saturation Mutagenesis of the HIV-1 Envelope CD4 Binding Loop Reveals Residues Controlling Distinct Trimer Conformations

Wed, 05/03/2017 - 12:07pm

The conformation of HIV-1 envelope (Env) glycoprotein trimers is key in ensuring protection against waves of neutralizing antibodies generated during infection, while maintaining sufficient exposure of the CD4 binding site (CD4bs) for viral entry. The CD4 binding loop on Env is an early contact site for CD4 while penetration of a proximal cavity by CD4 triggers Env conformational changes for entry. The role of residues in the CD4 binding loop in regulating the conformation of the trimer and trimer association domain (TAD) was investigated using a novel saturation mutagenesis approach. Single mutations identified, resulted in distinct trimer conformations affecting CD4bs exposure, the glycan shield and the TAD across diverse HIV-1 clades. Importantly, mutations that improve access to the CD4bs without exposing the immunodominant V3 loop were identified. The different trimer conformations identified will affect the specificity and breadth of nabs elicited in vivo and are important to consider in design of Env immunogens for vaccines.

Design and methods for a community-based intervention to reduce sugar-sweetened beverage consumption among youth: H2GO! study

Wed, 05/03/2017 - 12:07pm

BACKGROUND: Reducing sugar-sweetened beverage (SSB) intake is an important dietary target among underserved children at high risk for obesity and associated morbidities. Community-based approaches to reduce SSB intake are needed. The use of narrative-based approaches (presenting messages within the context of a story) can facilitate connection with target health messages and empower children as behavior change agents within their families. The H2GO! program is a community-based behavioral intervention that integrates narrative-based strategies to reduce SSB consumption and promote water intake among school-age youth and parents.

METHODS: Guided by the Social Cognitive Theory and the Social Ecological Model, the H2GO! intervention consists of 6 weekly sessions that target beverage knowledge, attitudes, and behaviors through youth-produced messages and narratives to reduce SSB intake and encourage water intake and parent-child activities. To reach underserved youth and families, we identified Boys and Girls Clubs (BandGC) (youth-based community centers that serve an ethnically diverse and predominantly low socioeconomic status population) as a community partner and study setting. Participants (children ages 9-12 years and their parents) will be recruited from BandGC sites in Massachusetts, USA. Intervention efficacy will be assessed through a site-randomized trial (N = 2 youth-based community sites, pair-matched for size and racial/ethnic composition) with 54 parent-child pairs (N = 108) enrolled per site (N = 216 total). The comparison site will carry on with usual practice. Child and parental SSB and water consumption (primary outcomes) and parent and child beverage knowledge and attitudes (secondary outcomes) will be measured via self-report surveys. Additional outcomes include children's anthropometric data, additional dietary behaviors, and physical activity. Measures will be collected at baseline, 2 and 6 months follow-up. With an estimated 20 % dropout rate, the study will have 80 % power to detect a group difference of 3.9 servings of SSBs per week.

DISCUSSION: Community-based approaches hold potential for decreasing SSB consumption among youth and families, particularly among underserved populations who are at greater obesity risk. This article describes the design and methods of a community-based behavioral intervention designed to reduce SSB consumption among youth and parents/caregivers.

TRIAL REGISTRATION: NCT02890056 . Date of Registration: August 31, 2016.

Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS

Wed, 05/03/2017 - 12:07pm

Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS-STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication is strongly increased in neurons in STING-deficient mice. Interestingly, HSV-infected microglia confer STING-dependent antiviral activities in neurons and prime type I IFN production in astrocytes through the TLR3 pathway. Thus, sensing of HSV-1 infection in the CNS by microglia through the cGAS-STING pathway orchestrates an antiviral program that includes type I IFNs and immune-priming of other cell types.

Recombinant Adeno-Associated Virus Serotype 6 (rAAV6) Potently and Preferentially Transduces Rat Astrocytes In vitro and In vivo

Wed, 05/03/2017 - 12:07pm

Recombinant adeno-associated virus vectors are an increasingly popular tool for gene delivery to the CNS because of their non-pathological nature, low immunogenicity, and ability to stably transduce dividing and non-dividing cells. One of the limitations of rAAVs is their preferential tropism for neuronal cells. Glial cells, specifically astrocytes, appear to be infected at low rates. To overcome this limitation, previous studies utilized rAAVs with astrocyte-specific promoters or assorted rAAV serotypes and pseudotypes with purported selectivity for astrocytes. Yet, the reported glial infection rates are not consistent from study to study. In the present work, we tested seven commercially available recombinant serotypes- rAAV1, 2, and 5 through 9, for their ability to transduce primary rat astrocytes [visualized via viral expression of green fluorescent protein (GFP)]. In cell cultures, rAAV6 consistently demonstrated the highest infection rates, while rAAV2 showed astrocytic transduction in some, but not all, of the tested viral batches. To verify that all rAAV constructs utilized by us were viable and effective, we confirmed high infectivity rates in retinal pigmented epithelial cells (ARPE-19), which are known to be transduced by numerous rAAV serotypes. Based on the in vitro results, we next tested the cell type tropism of rAAV6 and rAAV2 in vivo, which were both injected in the barrel cortex at approximately equal doses. Three weeks later, the brains were sectioned and immunostained for viral GFP and the neuronal marker NeuN or the astrocytic marker GFAP. We found that rAAV6 strongly and preferentially transduced astrocytes (>90% of cells in the virus-infected areas), but not neurons ( approximately 10% infection rate). On the contrary, rAAV2 preferentially infected neurons ( approximately 65%), but not astrocytes ( approximately 20%). Overall, our results suggest that rAAV6 can be used as a tool for manipulating gene expression (either delivery or knockdown) in rat astrocytes in vivo.

Examination of Huntington's disease with atypical clinical features in a Bangladeshi family tree

Wed, 05/03/2017 - 12:07pm

Atypical manifestation of Huntington's disease (HD) could inform ongoing research into HD genetic modifiers not present in the primarily European populations studied to date. This work demonstrates that expanding HD genetic testing into under-resourced healthcare settings can benefit both local communities and ongoing research into HD etiology and new therapies.