David D. McManus

Burden of Psychosocial and Cognitive Impairment in Patients With Atrial Fibrillation

Background: Impairments in psychosocial status and cognition relate to poor clinical outcomes in patients with atrial fibrillation (AF). However, how often these conditions co-occur and associations between burden of psychosocial and cognitive impairment and quality of life (QoL) have not been systematically examined in patients with AF. Methods: A total of 218 patients with symptomatic AF were enrolled in a prospective study of AF and psychosocial factors between May 2013 and October 2014 at the University of Massachusetts Medical Center. Cognitive function, depression, and anxiety were assessed at baseline and AF-specific QoL was assessed 6 months after enrollment using validated instruments. Demographic and clinical information were obtained from a structured interview and medical record review. Results: The mean age of the study participants was 63.5u2009±u200910.2 years, 35% were male, and 81% had paroxysmal AF. Prevalences of impairment in 1, 2, and 3 psychosocial/cognitive domains (eg, depression, anxiety, or cognition) were 75 (34.4%), 51 (23.4%), and 16 (7.3%), respectively. Patients with co-occurring psychosocial/cognitive impairments (eg, >1 domain) were older, more likely to smoke, had less education, and were more likely to have heart failure (all P < 0.05). Compared with participants with no psychosocial/cognitive impairments, AF-specific QoL at 6 months was significantly poorer among participants with baseline impairment in 2 (B = −13.6, 95% CI: −21.7 to −5.4) or 3 (B = −15.1, 95% CI: −28.0 to −2.2) psychosocial/cognitive domains. Conclusion: Depression, anxiety, and impaired cognition were common in our cohort of patients with symptomatic AF and often co-occurred. Higher burden of psychosocial/cognitive impairment was associated with poorer AF-specific QoL.

Role of microRNAs in atrial fibrillation

M myeloma (MM) is the second most common hematological malignancy and represents approximately 20% of deaths from hematological malignancies. Despite the success of numerous contemporary therapies to eradicate MM in vitro and in animal models, more than 90% of MM patients develop resistance to therapy and relapse. The discrepancy between drug efficacy in laboratory settings and the dissatisfactory clinical outcomes can be attributed to limitations of the classic drug development models, including the neglect of the interaction of tumor cells with other components of the bone marrow (BM) microenvironment; lack of tri-dimensional (3D) aspects of the BM niche (hypoxia and drug-gradient); and relying on a limited number of cell lines and do not reflect the enormous heterogeneity between individual patients. In our study, we produced a 3D-tissue engineered in vitro model of BM (3DTEBM) in MM, including MM cells, stromal cells, endothelial cells and extracellular matrix. All cells used for one 3DTEBM are isolated from a BM aspirate from individual MM patient. The 3D scaffold to accommodate the cells was produced by biological cross-linking of the BM supernatant of the same individual MM patient. We found that, in the 3DTEBM, MM cells proliferated more and showed significantly more drug resistance compared to classic tissue cultures. This 3DTEBM is currently investigated to predict the drug-response in MM patients, in which, we develop 3DTEBM for individual patients to test their response to therapy in vitro and correlate our findings with clinical response; to develop personalized therapeutic strategies for each individual MM patients.S critical size defects can occur due to tumor resections, infections or trauma. Autologous bone grafts are still the gold standard for the reconstruction of skeletal defects, having an excellent combination of osteoconduction, osteoinduction and osteogenesis properties. However, the use of autologous bone grafts has certain limitations, since their use requires surgical procedure for harvest, the amount and size is limited and is associated with donor site morbidities. Because every skeletal defect has a unique form, any implant that is created to fill the defect has to be patient specific. Rapid manufacturing methods are a favorable possibility to overcome this problem. In our study we combined the principles of rapid manufacturing with a degradable implant material having good mechanical properties. Recently the production of magnesium structure using Selective Laser Melting (SLM) could be established. This material has the potential to create a patient specific, absorbable implant that meets physiological requirements. Especially in critical size defects an early and fast vascularization of implants is of great importance. Porous scaffolds enable vessel in growth and thus support bone ingrowth. Using SLM technique interconnected pores of the implant can be produced. To control the degradation of absorbable magnesium implants we examined different polymer coatings.Introduction: Many different factors contribute to the onset and progression of osteoarthritis (OA). The bone morphogenetic proteins (BMPs), that are subsets of the transforming growth factor (TGFß) superfamily, have a known protective role on cartilage. They are lately gaining attention for their questionable role in osteophyte synthesis and osteoarthritis pathogenesis. Aim of the work: The aim of this study was to investigate the role of plasma BMP-2 in primary knee osteoarthritis and its relation to disease severity. Methodology: The study included 30 patients with primary knee O.A and ten apparently healthy matched individuals as a control group. Pain intensity as well as, assessment of functional status using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), plasma levels of BMP-2, and radiological severity of the disease, were done. Results: • Plasma levels of BMP-2 were significantly higher in patients than in control group. • Patients with palpable osteophytes had the highest BMP-2 levels. • A strong positive correlation was found between plasma levels of BMP-2 and each of: radiological severity, disease duration and WOMAC score. Conclusion: BMP-2 levels correlate with radiographic severity of O.A. which make such biomarker measurement may not only act as a substitute marker for the disease, but also as an indicator of the disease severity and a potential future tool to assess the processes underlying the pathogenesis of O.A.H genome sequence differs among individuals and differences known as non-synonymous single nucleotide polymorphisms (nsSNPs) can be responsible for many human diseases or cause the natural differences among the individuals by affecting the structure, function, interactions and other properties of expressed proteins. From computational standpoint the mono-genetic diseases resulting from missense mutations which affect the wild type characteristics of a specific protein are of specific interest. Using various cases of disorders, it is demonstrated that almost always the mutations do not directly affect the functional properties of the corresponding protein, but rather indirectly alter its wild type characteristics. In addition, it is indicated that disease causing mutations do not necessary destabilize protein stability or protein-protein interactions, but can be stabilizing and still be harmful. Overall, a detailed computational analysis combined with an analysis of the corresponding biological function is needed to make reasonable prediction of the disease association of missense mutations. Once the molecular mechanism of disease is revealed, the disease-causing effect can be targeted with small molecule binding.Background: A general method to create adjusted recursive partitioning (tree-based) model on survival outcomes is developed. Prognostic survival trees have historically been used to automatically uncover complicated GxG and GxE interactions. However scientists often want to uncover this structure while adjusting for confounding factors that are not of direct interest. Interaction survival trees can automatically identify the best treatment choice for patients and are a promising model to enable personalized medicine, but simulations to assess their performance on the high dimensional data found in personalized medicine have not been conducted.D of tissue microarchitectures represents an early step of epithelial tumorigenesis and the degree of which has been widely used for the histopathological grading of glandular cancers. Molecular portraits of structural differentiation may identify key regulatory pathways and improve outcome prediction in human glandular cancers. To translate this concept to clinics and to facilitate patient-tailored cancer treatment decision, we performed comparative genomic analysis of glandular microarchitectures generated in a three-dimensional organotypic culture system which recapitulated the differentiated morphology and exocrine functions of human glandular epithelial tissues to identify differentiation and microarchitecturespecific gene signatures. This knowledge-based and model-informed biomarker strategy allows us to develop a highly accurate and robust 6-gene molecular diagnosis which can reflect tumor differentiation and cancer stem cell activity, thereby enabling a rationalized classification and prognostic prediction of pancreatic cancer patients. Similarly, we developed a 6-gene microarchitecture-specific signature which can prognostically classify prostate cancer patients with a remarkable accuracy. Thus, by exploiting the genomic program associated with glandular microarchitecture formation, we can identify differentiation-specific molecular subtypes and related prognostic markers that significantly enhance prognostic prediction of human glandular cancers. This strategy is now being used to develop differentiation-specific biomarkers in other types of glandular cancers that have high pathogenetic significance and clinical utility.