The role of RNA helicases in neuromuscular development and diseases

RNA helicases are enzymes that bind or remodel RNA and RNA-protein complexes. They are involved in numerous cellular functions including RNA metabolism, transcription, translation, and mRNA decay. Defects in helicase function or disregulated expression, can cause diseases. DEAD-box (DDX) RNA helicases are highly conserved and are known to be involved in muscle development and disease, by interacting with muscle specific transcription factors and genes in humans. The Gupta Lab is currently studying zebrafish (an established and reliable model to study muscle diseases) with a mutation in ddx27. These fish have impaired motility behavior, skeletal muscle hypotrophy, and extensive central nucleation. They also exhibit disorganization of skeletal muscle, abnormalities in the brain, eyes, and heart. These phenotypes mimic the abnormalities seen in human myotonic dystrophy. It is known that ddx27 is necessary for regulation of rRNA maturation. Recent studies have pointed to it’s non-ribosomal roles of nucleolar genes. IGHMBP2, another RNA helicase, is known to result in spinal muscular atrophy (SMARD1) or Charcot-Marie Tooth disease when mutated. We used zebrafish and patient myoblast cells to determine the role of ddx27 in myogenesis and diseases. As a basis for future studies, the 43 known human DDX genes were outlined for their functions. Immunofluorescence studies in ddx27 mutant zebrafish showed drastic skeletal muscle and nucleolar assembly defects with large numbers of cells with transcriptionally active euchromatin, suggesting altered gene regulation. In addition, IF with Pax7 (a marker for satellite cells) and MF20 (a marker for myosin heavy chain antibodies) showed a significant increase in the number of Pax7 positive cells that suggest perturbed satellite cell regulation. Nucleolar defects were also seen in cells isolated from myotonic dystrophy patients. While the cause of these defects is not known, the results lead us to believe that ddx27 may be involved in cell cycle regulation or apoptosis events. Finally, while this study also attempted to develop a zebrafish model of IGHMBP2 deficiency in order to study and develop therapies for SMARD1, a consistent phenotype was not observed and further work is required to characterize this model. More than one million Americans suffer from neuromuscular disorders, however many of these conditions have no known treatments. By studying the molecular pathways involved we can attempt to develop therapies for these diseases

Knowledge-based Biomedical Data Science 2019

Knowledge-based biomedical data science (KBDS) involves the design and implementation of computer systems that act as if they knew about biomedicine. Such systems depend on formally represented knowledge in computer systems, often in the form of knowledge graphs. Here we survey the progress in the last year in systems that use formally represented knowledge to address data science problems in both clinical and biological domains, as well as on approaches for creating knowledge graphs. Major themes include the relationships between knowledge graphs and machine learning, the use of natural language processing, and the expansion of knowledge-based approaches to novel domains, such as Chinese Traditional Medicine and biodiversity.Comment: Manuscript 43 pages with 3 tables; Supplemental material 43 pages with 3 table

Evaluation, Validation & Implementation of a Computerized Diagnostic Decision Support System in Primary Practice

Background: Medical diagnosis may be the most complex task attempted by humans. Studies estimate that 95% of diagnoses in outpatient care are accurate, implying that the annual rate of inaccurate diagnoses is 12 million in the US alone, with the potential for patient harm in about half. A well-researched differential might reduce inaccurate diagnoses by offering alternatives matching the patient’s symptoms. This study searched the literature for articles evaluating the diagnostic performance of commercially available computerized diagnostic decision support systems. This search led to selecting Isabel Pro, developed by Isabel Healthcare, Ltd. of Haslemere, UK. Evaluation and Validation: A computerized diagnostic decision support system should respond adequately to four questions: What is the “diagnostic retrieval accuracy”? Does it perform as well as clinicians? When provided with the differential, do clinicians improve diagnostic accuracy? Is it easily incorporated into routine practice? The project validated the diagnostic retrieval accuracy of Isabel Pro using 46 cases with a previously confirmed diagnosis. The confirmed diagnosis appeared in Isabel Pro’s differential in 24 cases (52.2%), outperforming even internal medicine faculty (47%). Using those 24 cases and the differentials produced, the author conducted a diagnostic challenge that involved 120 McGovern Medical School residents. The residents produced 406 diagnoses, of which 105 (25.9%) were correct without the differentials, and 37 were correct post-consultation, a 9.1% absolute improvement. In responses, 75.1% of the participants agreed the differentials would be helpful in routine practice, and 64.1% agreed they would consult the differentials if available. Implementation: The project successfully proposed Isabel Pro as a solution to UT practice leadership on September 16, 2021, and incorporated the system into the Epic EHR as a menu line link on November 30, 2021. This system-wide integration also included a QR code for downloading Isabel Pro to a mobile device. Usage of Isabel Pro in the practices of UTPhysicians began on December 8, 2021. Results: The project concluded data collection after 86 days on March 4, 2022, with usage showing a steady increase in the final three weeks. The project produced 73 unique users (37 faculty and 36 residents). The user survey responses showed 83.3% agreeing they would consult the differential generated by Isabel Pro if available at every patient encounter (+19.2% compared to the challenge survey) and 77.8% agreeing that the suggestions would be helpful in routine practice (+2.7% compared to the challenge survey). More than one-third (36.8%) responded that they changed their diagnosis in response to the differential. Limitations: Only usage statistics were analyzed; the system records no reason for the clinician discontinuing a diagnostic session. Only 20 participants responded out of 73 (27.4%), so even though the respondents represented a spread of experience levels, the results may not represent the total number of potential users. The project covered a limited period of 86 days. Conclusions: Diagnostic inaccuracy is a significant patient safety concern. Studies show that computerized diagnostic decision support systems improve diagnostic accuracy, but they are not wide implementation lags despite these findings. This project demonstrated the feasibility of implementing such a well-known system in academic medical practice. The responses to the surveys demonstrate favorable opinions about the system’s perceived usefulness. Active communication and dissemination programs may be essential to improve and sustain use

Cognitive aspects of chronic fatigue syndrome

Recent interest in cognitive behavioural therapy techniques for treatment of Chronic Fatigue Syndrome (CFS) has highlighted the contribution of psychological approaches to alleviating the debilitating symptoms of this illness. In previous research sufferers from CFS have been compared with depressed patients and patients with neuromuscular disease, as they share similar symptoms, but not diagnosis. This study attempts to compare four groups including a normal working group. A new measures was developed and piloted, designed to measure interpretations of symptoms in CFS. In addition standard instruments were used to focus on the measurement of high personal standards, perfectionism, emotional control and conscientiousness and levels of autonomy. Results showed the CFS group were similar to the normal working group on all standard scales and scored low on autonomous personality traits. Reasons for this result, and the clinical implications for treating such a heterogeneous patient group are discussed. Measures on the symptom interpretation scale show CFS patients are less likely to give an emotional explanation for their symptoms than the other participant groups. This has implications for communication between physician and patient, and the treatment of CFS with a psychological model

Understanding the diagnostic process in a rare, genetic disease: a mixed methods study of schwannomatosis

Diagnostic errors are relatively common in medicine and can cause significant patient harm. We adapted the National Academy of Medicine’s model of the diagnostic process to examine diagnostic errors in schwannomatosis, a rare, genetic syndrome in which patients commonly develop multiple nerve sheath tumors and chronic pain. We specifically assessed how well the schwannomatosis diagnostic process currently functions; identified specific failures in the diagnostic process and assessed their contribution to diagnostic error; and explored the impact of diagnostic errors on patients’ lives. In study one, we reviewed the medical records of 97 schwannomatosis patients seen in two tertiary care clinics to assess the extent of diagnostic error in this population. It took a median of 7.9 years from patients’ first sign/symptom for a diagnosis of schwannomatosis to be established and communicated to patients. One-fifth of patients had a clear missed opportunity for appropriate workup that could have led to an earlier diagnosis. About one-third of patients experienced a misdiagnosis of their pain etiology, tumor pathology, or underlying genetic diagnosis. In study two, we created narrative summaries detailing patients’ diagnostic journeys using the medical record data of 52 schwannomatosis patients included in study one. Directed content analysis of these summaries identified the specific diagnostic process failures patients experience. Almost all patients experienced at least one failure, which most commonly reflected deficiencies in diagnostic testing, the clinical history/interview, or follow-up. Two-thirds of failures significantly impacted patient outcomes, most often by delaying needed diagnostic workup and communication of a final diagnosis to the patient. In study three, we interviewed 18 people with schwannomatosis from across the United States and used thematic analysis to explore patients’ symptom appraisal and the personal impact of diagnostic errors. Participants and their healthcare providers often ascribed schwannomatosis symptoms to more common conditions, which could delay care-seeking and initial workup. Diagnostic delay and misdiagnosis could result in unnecessary surgery, delayed receipt of effective pain management, psychological distress, and stigmatization. Collectively, these studies give unique insight into the prevalence, causes and ramifications of diagnostic error in schwannomatosis, and highlight opportunities to improve the diagnostic process across rare, genetic diseases

Computer, MD

Thesis (S.M. in Science Writing)--Massachusetts Institute of Technology, Dept. of Humanities, Graduate Program in Science Writing, 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 43-46).Clinical decision support is an emerging type of healthcare information technology that aims to actively guide doctors' decision-making processes. In its various forms, it can help physicians design treatment regimens, regulate dosage, avoid potentially harmful drug interactions and allergies, order preventative screenings, and even establish a diagnosis. This project is a journalistic investigation of this new technology, its applications, and its effect on the medical profession. It examines two decision support systems, Partners Healthcare's clinical reminder system, and Logical Images' product VisualDx, in order to explore the potential for these technologies and how their use may change the practice of medicine. Through extensive interviews of experts in medicine, healthcare IT, and healthcare policy, it considers the major problems in implementing decision support, with emphasis on how the technology may affect doctors' autonomy, and how physicians' financial and professional incentives may influence how it is used.by Joshua Feblowitz.S.M.in Science Writin

Textbook of Patient Safety and Clinical Risk Management

Implementing safety practices in healthcare saves lives and improves the quality of care: it is therefore vital to apply good clinical practices, such as the WHO surgical checklist, to adopt the most appropriate measures for the prevention of assistance-related risks, and to identify the potential ones using tools such as reporting & learning systems. The culture of safety in the care environment and of human factors influencing it should be developed from the beginning of medical studies and in the first years of professional practice, in order to have the maximum impact on clinicians' and nurses' behavior. Medical errors tend to vary with the level of proficiency and experience, and this must be taken into account in adverse events prevention. Human factors assume a decisive importance in resilient organizations, and an understanding of risk control and containment is fundamental for all medical and surgical specialties. This open access book offers recommendations and examples of how to improve patient safety by changing practices, introducing organizational and technological innovations, and creating effective, patient-centered, timely, efficient, and equitable care systems, in order to spread the quality and patient safety culture among the new generation of healthcare professionals, and is intended for residents and young professionals in different clinical specialties

Department of Radiology-Annual Executive Summary Report-July 1, 2002 to June 30, 2003

94 page Department of Radiology Annual Executive Summary Report, July 1, 2002 to June 30, 2003, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, United States

District nursing in England and Wales c.1919-1979, in the context of the development of a Community Health Team

The thesis views the development of District Nursing as a sub-profession or specialty within the nursing profession together with the emergence and evolution of a team approach to community care during the middle sixty years of the twentieth century (1919-1979). This takes in the period immediately following the Nurses' Registration Act (1919), through the inter-wa,r period and Second World War, the introduction of the National Health Service, up to the reorganisation of Community Healthcare culminating with the Nurses, Midwives and Health Visitors Act of 1979. By the end-point of the thesis the district nurse can be seen to have become an established member of the primary health care team within the community. Contextualising this period of change within the development of a community health team enabled the thesis to consider the relative importance of intra- and inter- professional tensions to the development of a sub-profession - in this case, district nursing. The study has included under this remit the extended professional roles, social and political professional issues and changing power bases, and the conflict between desire for recognised autonomy and for membership of a health care team. In addition, it has been possible to address issues of gender central to a profession largely composed of women throughout the period working alongside a medical profession largely composed of men. The subject has lent itself to a consideration of the degree of influence of medically-related technologies and of developments in communications and transport on the changing role, image and work-experience of the district nurse. The geographical focus of the research has broadly encompassed England and Wales, within which three contrasting regions have been selected for more detailed study of their comparability. These were felt to provide a varied and demographically representative cross­ section of environments in England and Wales. Perhaps the most challenging, but also most innovative aspect of the thesis is the grass-roots view given of the district nurse obtained through employing the viewpoints of individual nurses based on oral history supplemented with personal communications and written, autobiographical accounts. A case study of one district nursing association in Lancashire has supplemented this 'bottom-up' view of the nurse's experience and changing role. And a study of imagery relating to district nursing, incorporating various forms of media and professional representations, examines changing cultural images and social stereotypes of district nurses. Underlying changes that were taking place in district nursing at micro and macro levels are here quantitatively illustrated, such as the shifting pattern of district nursing associations throughout the regions of England and Wales in the inter-war period, the changing numbers of district nurses of various grades employed, and their varying workloads. The thesis concludes with a brief forward look to consider how the changes that were to follow the 1979 reorganisation were to affect district nurses' professional relationships, roles and images in the decade to follow