Cambridge, MA, United States

Founded in 1970, the Harvard–MIT Division of Health science and Technology, or HST, is one of the oldest and largest biomedical engineering and physician-scientist training programs in the United States and the longest-standing functional collaboration between Harvard University and the Massachusetts Institute of Technology .HST's unique interdisciplinary educational program brings engineering as well as the physical and biological science from the scientist's bench to the patient's bedside. Conversely, it brings clinical insight from the patient's bedside to the laboratory bench. In this way, HST students are trained to have deep understanding of engineering, physical science, and the biological science, complemented with hands-on experience in the clinic or in industry; and they become conversant with the underlying quantitative and molecular aspects of medicine and biomedical science. Within the division, more than 400 graduate students work with eminent faculty and affiliated faculty members from throughout the MIT and Harvard communities. HST is also the home of the Laboratory of Computational Physiology which hosts the MIMIC II database and PhysioNet.In addition to its outstanding record of accomplishment for research in human health care, HST educational programs are distinguished by three key elements: A strong quantitative orientation Required hands-on experience in a clinical or industry setting A focused interdisciplinary research project↑ Wikipedia.


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Bourgeois F.T.,Childrens Hospital Boston | Murthy S.,University of Toronto | Mandl K.D.,Harvard-MIT Division of Health Sciences and Technology
Annals of Internal Medicine | Year: 2010

Background: Clinical trial registries are in widespread use to promote transparency around trials and their results. Objective: To describe characteristics of drug trials listed in ClinicalTrials. gov and examine whether the funding source of these trials is associated with favorable published outcomes. Design: An observational study of safety and efficacy trials for anticholesteremics, antidepressants, antipsychotics, proton-pump inhibitors, and vasodilators conducted between 2000 and 2006. Setting: ClinicalTrials.gov, a Web-based registry of clinical trials launched in 1999. Measurements: Publications resulting from the trials for the 5 drug categories of interest were identified, and data were abstracted on the trial record and publication, including timing of registration, elements of the study design, funding source, publication date, and study outcomes. Assessments were based on the primary funding categories of industry, government agencies, and nonprofit or nonfederal organizations. Results: Among 546 drug trials, 346 (63%) were primarily funded by industry, 74 (14%) by government sources, and 126 (23%) by nonprofit or nonfederal organizations. Trials funded by industry were more likely to be phase 3 or 4 trials (88.7%; P < 0.001 across groups), to use an active comparator in controlled trials (36.8%; P = 0.010 across groups), to be multicenter (89.0%; P < 0.001 across groups), and to enroll more participants (median sample size, 306 participants; P < 0.001 across groups). Overall, 362 (66.3%) trials had published results. Industry-funded trials reported positive outcomes in 85.4% of publications, compared with 50.0% for government-funded trials and 71.9% for nonprofit or nonfederal organization-funded trials (P < 0.001). Trials funded by nonprofit or nonfederal sources with industry contributions were also more likely to report positive outcomes than those without industry funding (85.0% vs. 61.2%; P = 0.013). Rates of trial publication within 24 months of study completion ranged from 32.4% among industry-funded trials to 56.2% among nonprofit or nonfederal organization-funded trials without industry contributions (P = 0.005 across groups). Limitations: The publication status of a trial could not always be confirmed, which could result in misclassification. Additional information on study protocols and comprehensive trial results were not available to further explore underlying factors for the association between funding source and outcome reporting. Conclusion: In this sample of registered drug trials, those funded by industry were less likely to be published within 2 years of study completion and were more likely to report positive outcomes than were trials funded by other sources. Primary Funding Source: National Library of Medicine and National Institute of Child Health and Human Development, National Institutes of Health. © 2010 American College of Physicians.


Greenberg S.A.,Harvard-MIT Division of Health Sciences and Technology
Muscle and Nerve | Year: 2014

Introduction: Recent studies have identified circulating immunoglobulin (Ig) G autoantibodies against cytoplasmic 5′-nucleotidase 1A (cN1A; NT5C1A) in patients with inclusion body myositis (IBM), whose detection provides for an IBM blood diagnostic test. Whether or not anti-cN1A autoantibody isotypes other than IgG are present in IBM has not previously been reported. Methods: Plasma and serum samples from 205 patients (50 with and155 without IBM) were studied for the presence of IgM and IgA, in addition to IgG, anti-cN1A autoantibodies using immunoblots and enzyme-linked immunoassays (ELISAs). Results: IgM, IgA, and IgG anti-cN1A autoantibodies were detected by ELISA with similar sensitivities (49-53%) and specificities (94-96%), but with differing patterns of autoantibody isotype presence. Combination assays of all 3 autoantibody levels improved diagnostic sensitivity to 76%. Conclusions: In addition to previously recognized IgG anti-cN1A autoantibodies, IBM patients have circulating IgM and IgA anti-cN1A autoantibodies. Differing patterns of these isotypes may be present and useful for diagnosis. © 2014 Wiley Periodicals, Inc.


Mirny L.A.,Harvard-MIT Division of Health Sciences and Technology
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Cooperative binding of transcription factors (TFs) to promoters and other regulatory regions is essential for precise gene expression. The classical model of cooperativity requires direct interactions between TFs, thus constraining the arrangement of TF sites in regulatory regions. Recent genomic and functional studies, however, demonstrate a great deal of flexibility in such arrangements with variable distances, numbers of sites, and identities of TF sites located in cis-regulatory regions. Such flexibility is inconsistent with cooperativity by direct interactions between TFs. Here, we demonstrate that strong cooperativity among noninteracting TFs can be achieved by their competition with nucleosomes. We find that the mechanism of nucleosome-mediated cooperativity is analogous to cooperativity in another multimolecular complex: hemoglobin. This surprising analogy provides deep insights, with parallels between the heterotropic regulation of hemoglobin (e.g., the Bohr effect) and the roles of nucleosome-positioning sequences and chromatin modifications in gene expression. Nucleosome-mediated cooperativity is consistent with several experimental studies, is equally applicable to repressors and activators, allows substantial flexibility in and modularity of regulatory regions, and provides a rationale for a broad range of genomic and evolutionary observations. Striking parallels between cooperativity in hemoglobin and in transcriptional regulation point to a general mechanism that can be used in various biological systems.


Moody B.E.,Harvard-MIT Division of Health Sciences and Technology
Computing in Cardiology | Year: 2011

It is possible, using a smart phone or similar device, to collect ECGs from patients in remote locations, storing the results to be analyzed later. In this situation, however, the person collecting the ECG may not have the time or the necessary training to evaluate the quality of the recording at the time it is collected. It is useful for the device itself to analyze the recorded signals and provide feedback to the user about their quality. This paper explores a number of heuristic rules that can be used to detect the most common problems in ECG recordings. These rules are designed to be simple enough that they can easily be tested in real time on a mobile phone. A combination of several of these rules is able to correctly detect a majority of poor-quality ECGs, as demonstrated using the PhysioNet/CinC 2011 Challenge database. © 2011 CCAL.


Qi H.,Harvard-MIT Division of Health Sciences and Technology
Nature communications | Year: 2013

Using DNA as programmable, sequence-specific 'glues', shape-controlled hydrogel units are self-assembled into prescribed structures. Here we report that aggregates are produced using hydrogel cubes with edge lengths ranging from 30 μm to 1 mm, demonstrating assembly across scales. In a simple one-pot agitation reaction, 25 dimers are constructed in parallel from 50 distinct hydrogel cube species, demonstrating highly multiplexed assembly. Using hydrogel cuboids displaying face-specific DNA glues, diverse structures are achieved in aqueous and in interfacial agitation systems. These include dimers, extended chains and open network structures in an aqueous system, and dimers, chains of fixed length, T-junctions and square shapes in the interfacial system, demonstrating the versatility of the assembly system.


Moody G.B.,Harvard-MIT Division of Health Sciences and Technology
Computing in Cardiology | Year: 2010

Participants in the 11th annual PhysioNet/CinC Challenge were asked to reconstruct, using any combination of available prior and concurrent information, 30-second segments of ECG, continuous blood pressure waveforms, respiration, and other signals that had been removed from recordings of patients in intensive care units. Fifteen of the 53 participants provided reconstructions for the entire test set of 100 ten-minute recordings. The mean correlation between the segments that had been removed (the "target signals") and the reconstructions produced using the two most successful methods is 0.9, and the sum of the squared residual errors in these reconstructions is less than 20% of the energy of the target signals. Sources for the most successful methods developed for this challenge have been made available by their authors to support research on robust estimation of parameters derived from unreliable signals, detection of changes in patient state, and recognition of signal corruption.


Mirny L.A.,Harvard-MIT Division of Health Sciences and Technology
Chromosome Research | Year: 2011

The fractal globule is a compact polymer state that emerges during polymer condensation as a result of topological constraints which prevent one region of the chain from passing across another one. This long-lived intermediate state was introduced in 1988 (Grosberg et al. 1988) and has not been observed in experiments or simulations until recently (Lieberman-Aiden et al. 2009). Recent characterization of human chromatin using a novel chromosome conformational capture technique brought the fractal globule into the spotlight as a structural model of human chromosome on the scale of up to 10 Mb (Lieberman-Aiden et al. 2009). Here, we present the concept of the fractal globule, comparing it to other states of a polymer and focusing on its properties relevant for the biophysics of chromatin. We then discuss properties of the fractal globule that make it an attractive model for chromatin organization inside a cell. Next, we connect the fractal globule to recent studies that emphasize topological constraints as a primary factor driving formation of chromosomal territories. We discuss how theoretical predictions, made on the basis of the fractal globule model, can be tested experimentally. Finally, we discuss whether fractal globule architecture can be relevant for chromatin packing in other organisms such as yeast and bacteria. © 2011 The Author(s).


Oliva N.,Harvard-MIT Division of Health Sciences and Technology
Nature Materials | Year: 2015

The therapeutic potential of miRNA (miR) in cancer is limited by the lack of efficient delivery vehicles. Here, we show that a self-assembled dual-colour RNA-triple-helix structure comprising two miRNAs—a miR mimic (tumour suppressor miRNA) and an antagomiR (oncomiR inhibitor)—provides outstanding capability to synergistically abrogate tumours. Conjugation of RNA triple helices to dendrimers allows the formation of stable triplex nanoparticles, which form an RNA-triple-helix adhesive scaffold upon interaction with dextran aldehyde, the latter able to chemically interact and adhere to natural tissue amines in the tumour. We also show that the self-assembled RNA-triple-helix conjugates remain functional in vitro and in vivo, and that they lead to nearly 90% levels of tumour shrinkage two weeks post-gel implantation in a triple-negative breast cancer mouse model. Our findings suggest that the RNA-triple-helix hydrogels can be used as an efficient anticancer platform to locally modulate the expression of endogenous miRs in cancer. © 2015 Nature Publishing Group


Li L.,Harvard-MIT Division of Health Sciences and Technology
Lab on a chip | Year: 2012

In the stomach, a layer of gastric mucus protects the epithelial cells of the stomach wall against damage by the acidic digestive juices in the gastric lumen. Despite considerable research, the biophysical mechanisms for this acid barrier are not understood. We present an in vitro microfluidic tool to characterize the stomach acid barrier, in which purified mucin polymers are "secreted" against an acidic zone on chip, mimicking the in vivo secretion of gastric mucus into an acidic stomach lumen. This device reconstitutes both the H(+) concentration gradient and outward flow environment of the mucus layer in vivo. Our experiments demonstrate that a continuously secreted mucin layer hinders acid diffusion, suggesting novel insights into the barrier role of mucins. More broadly, our system may serve as a platform tool for studying the barrier functions provided by mucus layers in the body and for studying mucus drug interactions.


Ghaffari R.,Harvard-MIT Division of Health Sciences and Technology
Nature communications | Year: 2010

Remarkable sensitivity and exquisite frequency selectivity are hallmarks of mammalian hearing, but their underlying mechanisms remain unclear. Cochlear insults and hearing disorders that decrease sensitivity also tend to broaden tuning, suggesting that these properties are linked. However, a recently developed mouse model of genetically altered hearing (Tectb(-/-)) shows decreased sensitivity and sharper frequency selectivity. In this paper, we show that the Tectb mutation reduces the spatial extent and propagation velocity of tectorial membrane (TM) travelling waves and that these changes in wave propagation are likely to account for all of the hearing abnormalities associated with the mutation. By reducing the spatial extent of TM waves, the Tectb mutation decreases the spread of excitation and thereby increases frequency selectivity. Furthermore, the change in TM wave velocity reduces the number of hair cells that effectively couple energy to the basilar membrane, which reduces sensitivity. These results highlight the importance of TM waves in hearing.

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