As part of the mini-symposium entitled "Interdiscipllinary Mobile Health and Sensing Research," this presentation discusses use of a novel smartphone app for cardiovascular screening in rural India.
As part of the mini-symposium entitled "Biomechanical Gait Analysis for Improving Clinical Outcomes: Applications for Orthopedics, Geriatrics and Community Based Research," this presentation discusses the importance of patient reported outcomes (PRO) in clinical research and the PRO/physical activity translational research in osteoarthritis and and total joint replacement at UMass Medical School.
This is the moderator's introductory presentation for the mini-symposium entitled "Innovations for Vulnerable Populations in Massachusetts," in which she places the session presentations in the context of an ongoing collaboration between Commonwealth Medicine, a division of the University of Massachusetts Medical School, and MassHealth.
As part of the mini-symposium entitled "Biomechanical Gait Analysis for Improving Clinical Outcomes: Applications for Orthopedics, Geriatrics and Community Based Research," this presentation explores research on gait analysis and pain for patients with knee osteoarthritis.
As part of the mini-symposium entitled "Innovations for Vulnerable Populations in Massachusetts," this presentation explores research into expanding the State’s existing risk models to include social determinants of health variables. Potential variables for inclusion in payment models (such as unstable housing, defined as having three or more addresses during a calendar year) have been identified. These models are being developed in support of alternative payment mechanisms for integrated delivery systems.
This is the Research Retreat's Keynote presentation by Vasan S. Ramachandran, MD, who is Principal Investigator and Co-Director, Echocardiography/Vascular Laboratory, Framingham Heart Study. Dr. Ramachandran is also Chief, Section of Preventive Medicine and Epidemiology and Professor of Medicine, Boston University School of Medicine. Dr. Ramachandran discusses the future of cardiovascular epidemiology, including the roles of: cHealth (community), sHealth (social), mHealth (mobile), eHealth (electronic), and gHealth (genomic).
Katherine Luzuriaga, MD, is PI and Director, UMass Center for Clinical and Translational Science and Vice Provost, Clinical and Translational Research at UMass Medical School. Dr. Luzuriaga is also the UMass Memorial Health Care Chair in Biomedical Research and Professor, Program in Molecular Medicine, Pediatrics and Medicine. In her presentation, she reviews the history, goals, programs and achievements of the UMass Center for Clinical and Translational Science.
Dr. Flotte, who is Dean, Provost and Executive Deputy Chancellor at the University of Massachusetts Medical School, discusses the value of physician-scientists to the mission of academic medicine, and the challenges and rewards. Specific purposeful mechanisms must be developed to ensure the ongoing viability of the physician-scientist role.
Mini Symposia Program for the 6th annual UMass Center for Clinical and Translational Science Research Retreat, held Friday, May 20, 2016 at the University of Massachusetts Medical School, Worcester, MA.
Agenda for the 6th annual UMass Center for Clinical and Translational Science Research Retreat, held Friday, May 20, 2016 at the University of Massachusetts Medical School, Worcester, MA.
Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a sizable economic cost. Adeno-associated viral (AAV) vectors have emerged as an effective platform for CNS gene therapy and have shown early promise in clinical trials. These trials involve direct infusion into brain parenchyma, an approach that may be suboptimal for treatment of neurodegenerative disorders, which often involve more than a single structure in the CNS. However, overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. We have developed novel capsids AAV-AS and AAV-B1 that lead to widespread gene delivery throughout the brain and spinal cord, particularly to neuronal populations. Both transduce the adult mouse brain >10-fold more efficiently than the clinical gold standard AAV9 upon intravascular infusion, with gene transfer to multiple neuronal sub-populations. These vectors are also capable of neuronal transduction in a normal cat. We have demonstrated the efficacy of AAV-AS in the context of Huntington's disease by knocking down huntingtin mRNA 33-50% after a single intravenous injection, which is better than what can be achieved by AAV9 at the particular dose. AAVB1 additionally transduces muscle, beta cells, pulmonary alveoli and retinal vasculature at high efficiency, and has reduced sensitivity to neutralizing antibodies in human sera. Generation of this vector toolbox represents a major step towards gaining genetic access to the entire CNS, and provides a platform to develop new gene therapies for neurodegenerative disorders.
Systematic Dissection of Roles for Chromatin Regulators in Dynamics of Transcriptional Response to Stress in Yeast: A Dissertation
The following work demonstrates that chromatin regulators play far more pronounced roles in dynamic gene expression than they do in steady-state. Histone modifications have been associated with transcription activity. However, previous analyses of gene expression in mutants affecting histone modifications show limited alteration. I systematically dissected the effects of 83 histone mutants and 119 gene deletion mutants on gene induction/repression in response to diamide stress in yeast. Importantly, I observed far more changes in gene induction/repression than changes in steady-state gene expression. The extensive dynamic gene expression profile of histone mutants and gene deletion mutants also allowed me to identify specific interactions between histone modifications and chromatin modifiers. Furthermore, by combining these functional results with genome-wide mapping of several histone modifications in the same time course, I was able to investigate the correspondence between histone modification occurrence and function. One such observation was the role of Set1-dependent H3K4 methylation in the repression of ribosomal protein genes (RPGs) during multiple stresses. I found that proper repression of RPGs in stress required the presence, but not the specific sequence, of an intron, an element which is almost unique to this gene class in Saccharomyces cerevisiae. This repression may be related to Set1’s role in antisense RNA-mediated gene silencing. Finally, I found a potential role for Set1 in producing or maintaining uncapped mRNAs in cells through a mechanism that does not involved nuclear exoribonucleases. Thus, deletion of Set1 in xrn1Δ suppresses the accumulation of uncapped transcripts observed in xrn1Δ. These findings reveal that Set1, along with other chromatin regulators, plays important roles in dynamic gene expression through diverse mechanisms and thus provides a coherent means of responding to environmental cues.
Purpose: The purpose of this study was to explore the experiences of distracted practice across the healthcare team.
Definition: Distracted practice is the diversion of a portion of available cognitive resources that may be needed to effectively perform/carry out the current activity.
Background: Distracted practice is the result of individuals interacting with the healthcare team, the environment and technology in the performance of their jobs. The resultant behaviors can lead to error and affect patient safety.
Methods: A qualitative descriptive (QD) approach was used that integrated observations with semi-structured interviews. The conceptual framework was based on the distracted driving model and a completed concept analysis.
Results: There were 22 observation sessions and 32 interviews (12 RNs, 11 MDs, and 9 Pharmacists) completed between December, 2014 and July 2015. Results suggested that distracted practice is based on the main theme of cognitive resources which varies by the subthemes of individual differences; environmental disruptions; team awareness; and “rush mode”/time pressure.
Conclusions and Implications: Distracted practice is an individual human experience that occurs when there are not enough cognitive resources available to effectively complete the task at hand. In that moment an individual shifts from thinking critically, being able to complete their current task without error, to not thinking critically and working in an automatic mode. This is when errors occur. Additional research is needed to evaluate intervention strategies to reduce and prevent distracted practice.
Techniques in distal access of wide-necked giant intracranial aneurysms during treatment with flow diversion
BACKGROUND: Accessing the normal distal vessel in treatment of wide-necked giant intracranial aneurysms with flow diversion can be difficult.
CASE DESCRIPTION: Through illustrative cases, the authors present several useful techniques in distal access of wide-necked giant aneurysms during flow diversion treatment. Obtaining an optimal projection that separates the outflow limb from the aneurysm is most critical. Each of the three techniques described enabled the distal access to giant intracranial aneurysms during treatment with flow diversion.
CONCLUSION: The looped-around technique, balloon-assisted technique, and retrograde access are valuable strategies in crossing the aneurysm if direct distal access cannot be obtained.
Biosimilars are now a reality in rheumatology. Although analytical and non-clinical procedures to establish similarity have evolved significantly, clinical trials demonstrating equivalent efficacy and safety are absolutely required for all biosimilars. The design of such trials, including equivalence and non-inferiority statistical approaches, are discussed. Clinical evidence on biosimilars that have been approved recently or are presently being developed for use in rheumatology is also reviewed and contrasted with that available for biomimics (or intended copies), which are non-innovator biologics that are marketed in several countries but have not undergone review according to a regulatory pathway for biosimilars.
Curcumin Ingestion Inhibits Mastocytosis and Suppresses Intestinal Anaphylaxis in a Murine Model of Food Allergy
IgE antibodies and mast cells play critical roles in the establishment of allergic responses to food antigens. Curcumin, the active ingredient of the curry spice turmeric, has anti-inflammatory properties, and thus may have the capacity to regulate Th2 cells and mucosal mast cell function during allergic responses. We assessed whether curcumin ingestion during oral allergen exposure can modulate the development of food allergy using a murine model of ovalbumin (OVA)-induced intestinal anaphylaxis. Herein, we demonstrate that frequent ingestion of curcumin during oral OVA exposure inhibits the development of mastocytosis and intestinal anaphylaxis in OVA-challenged allergic mice. Intragastric (i.g.) exposure to OVA in sensitized BALB/c mice induced a robust IgE-mediated response accompanied by enhanced OVA-IgE levels, intestinal mastocytosis, elevated serum mMCP-1, and acute diarrhea. In contrast, mice exposed to oral curcumin throughout the experimental regimen appeared to be normal and did not exhibit intense allergic diarrhea or a significant enhancement of OVA-IgE and intestinal mast cell expansion and activation. Furthermore, allergic diarrhea, mast cell activation and expansion, and Th2 responses were also suppressed in mice exposed to curcumin during the OVA-challenge phase alone, despite the presence of elevated levels of OVA-IgE, suggesting that curcumin may have a direct suppressive effect on intestinal mast cell activation and reverse food allergy symptoms in allergen-sensitized individuals. This was confirmed by observations that curcumin attenuated the expansion of both adoptively transferred bone marrow-derived mast cells (BMMCs), and inhibited their survival and activation during cell culture. Finally, the suppression of intestinal anaphylaxis by curcumin was directly linked with the inhibition of NF-kappaB activation in curcumin-treated allergic mice, and curcumin inhibited the phosphorylation of the p65 subunit of NF-kappaB in BMMCs. In summary, our data demonstrates a protective role for curcumin during allergic responses to food antigens, suggesting that frequent ingestion of this spice may modulate the outcome of disease in susceptible individuals.
Endometriosis is a benign gynecological condition characterized by specific histological, molecular, and clinical findings. It affects 5%-10% of premenopausal women, is a cause of infertility, and has been implicated as a precursor for certain types of ovarian cancer. Advances in technology, primarily the ability for whole genome sequencing, have led to the discovery of new mutations and a better understanding of the function of previously identified genes and pathways associated with endometriosis associated ovarian cancers (EAOCs) that include PTEN, CTNNB1 (beta-catenin), KRAS, microsatellite instability, ARID1A, and the unique role of inflammation in the development of EAOC. Clinically, EAOCs are associated with a younger age at diagnosis, lower stage and grade of tumor, and are more likely to occur in premenopausal women when compared with other ovarian cancers. A shift from screening strategies adopted to prevent EAOCs has resulted in new recommendations for clinical practice by national and international governing bodies. In this paper, we review the common histologic and molecular characteristics of endometriosis and ovarian cancer, risks associated with EAOCs, clinical challenges and give recommendations for providers.
Decade-long trends (1999-2009) in the characteristics, management, and hospital outcomes of patients hospitalized with acute myocardial infarction with prior diabetes and chronic kidney disease
BACKGROUND: Despite the increasing magnitude and impact, there are limited data available on the clinical management and in-hospital outcomes of patients who have diabetes mellitus (DM) and chronic kidney disease (CKD) at the time of hospitalization for acute myocardial infarction (AMI). The objectives of our population-based observational study in residents of central Massachusetts were to describe decade-long trends (1999-2009) in the characteristics, in-hospital management, and hospital outcomes of AMI patients with and without these comorbidities.
METHODS: We reviewed the medical records of 6,018 persons who were hospitalized for AMI on a biennial basis between 1999 and 2009 at all eleven medical centers in central Massachusetts. Our sample consisted of the following four groups: DM with CKD (n=587), CKD without DM (n=524), DM without CKD (n=1,442), and non-DM/non-CKD (n=3,465).
RESULTS: Diabetic patients with CKD were more likely to have a higher prevalence of previously diagnosed comorbidities, to have developed heart failure acutely, and to have a longer hospital stay compared with non-DM/non-CKD patients. Between 1999 and 2009, there were marked increases in the prescribing of beta-blockers, statins, and aspirin for patients with CKD and DM as compared to those without these comorbidities. In-hospital death rates remained unchanged in patients with DM and CKD, while they declined markedly in patients with CKD without DM (20.2% dying in 1999; 11.3% dying in 2009).
CONCLUSION: Despite increases in the prescribing of effective cardiac medications, AMI patients with DM and CKD continue to experience high in-hospital death rates.
The origin of glutamatergic synaptic inputs controls synaptic plasticity and its modulation by alcohol in mice nucleus accumbens
It is widely accepted that long-lasting changes of synaptic strength in the nucleus accumbens (NAc), a brain region involved in drug reward, mediate acute and chronic effects of alcohol. However, our understanding of the mechanisms underlying the effects of alcohol on synaptic plasticity is limited by the fact that the NAc receives glutamatergic inputs from distinct brain regions (e.g., the prefrontal cortex (PFCx), the amygdala and the hippocampus), each region providing different information (e.g., spatial, emotional and cognitive). Combining whole-cell patch-clamp recordings and the optogenetic technique, we examined synaptic plasticity, and its regulation by alcohol, at cortical, hippocampal and amygdala inputs in fresh slices of mouse tissue. We showed that the origin of synaptic inputs determines the basic properties of glutamatergic synaptic transmission, the expression of spike-timing dependent long-term depression (tLTD) and long-term potentiation (LTP) and long-term potentiation (tLTP) and their regulation by alcohol. While we observed both tLTP and tLTD at amygadala and hippocampal synapses, we showed that cortical inputs only undergo tLTD. Functionally, we provide evidence that acute Ethyl Alcohol (EtOH) has little effects on higher order information coming from the PFCx, while severely impacting the ability of emotional and contextual information to induce long-lasting changes of synaptic strength.
FIB/SEM technology and high-throughput 3D reconstruction of dendritic spines and synapses in GFP-labeled adult-generated neurons
The fine analysis of synaptic contacts is usually performed using transmission electron microscopy (TEM) and its combination with neuronal labeling techniques. However, the complex 3D architecture of neuronal samples calls for their reconstruction from serial sections. Here we show that focused ion beam/scanning electron microscopy (FIB/SEM) allows efficient, complete, and automatic 3D reconstruction of identified dendrites, including their spines and synapses, from GFP/DAB-labeled neurons, with a resolution comparable to that of TEM. We applied this technology to analyze the synaptogenesis of labeled adult-generated granule cells (GCs) in mice. 3D reconstruction of dendritic spines in GCs aged 3-4 and 8-9 weeks revealed two different stages of dendritic spine development and unexpected features of synapse formation, including vacant and branched dendritic spines and presynaptic terminals establishing synapses with up to 10 dendritic spines. Given the reliability, efficiency, and high resolution of FIB/SEM technology and the wide use of DAB in conventional EM, we consider FIB/SEM fundamental for the detailed characterization of identified synaptic contacts in neurons in a high-throughput manner.