Balancing Blood, Balancing Books: Medicine, Commerce, and the Royal Court in Seventeenth-Century England

This dissertation argues that the Williams Harvey's novel conceptualization of the circulation developed from a set of concerns and sensitivities that Harvey shared with merchants and courtiers, and that it emerged at the courts of King James and King Charles, alongside a new conceptualizations of commercial circulation. As a brother to merchants and a physician to kings during the commercial crises of the 1620s, Harvey was exposed to ways of thinking about circulation that he used to make sense of the disparate observations he made about the motion of the heart and blood. Harvey's famous quantitative argument, the thought experiment at the center of his conceptualization of the blood, was an exercise in accounting. Through a process of "reckoning," and "by laying of account," Harvey balanced blood like a merchant balances books, conceptualizing arterial and venous blood as fungible. Harvey showed that there was a recirculation of blood through the heart. Over time, these aspects of Harvey's circulation became easier to overlook; the Great Fire of 1666 destroyed the most tangible artifacts of Harvey's mercantile sociability, such as his fine Persian rugs or the collection of marvels contained in the library and museum that Harvey established at the College of Physicians of London. By situating Harvey among courtiers and royal patrons who were concerned with the circulation of cloths, dyestuffs, coin, and bullion, this dissertation aims to add to the burgeoning literature on the scientific revolution that posits a multitude of different scientific practitioners with diverse philosophical commitments and varied connections to other facets of early modern life, while stressing key conceptual changes in Harvey's thought

Neural differentiation potential of human bone marrow-derived mesenchymal stromal cells: misleading marker gene expression

Background: In contrast to pluripotent embryonic stem cells, adult stem cells have been considered to be multipotent, being somewhat more restricted in their differentiation capacity and only giving rise to cell types related to their tissue of origin. Several studies, however, have reported that bone marrow-derived mesenchymal stromal cells (MSCs) are capable of transdifferentiating to neural cell types, effectively crossing normal lineage restriction boundaries. Such reports have been based on the detection of neural-related proteins by the differentiated MSCs. In order to assess the potential of human adult MSCs to undergo true differentiation to a neural lineage and to determine the degree of homogeneity between donor samples, we have used RT-PCR and immunocytochemistry to investigate the basal expression of a range of neural related mRNAs and proteins in populations of non-differentiated MSCs obtained from 4 donors. Results: The expression analysis revealed that several of the commonly used marker genes from other studies like nestin, Enolase2 and microtubule associated protein 1b (MAP1b) are already expressed by undifferentiated human MSCs. Furthermore, mRNA for some of the neural-related transcription factors, e.g. Engrailed-1 and Nurr1 were also strongly expressed. However, several other neural-related mRNAs (e.g. DRD2, enolase2, NFL and MBP) could be identified, but not in all donor samples. Similarly, synaptic vesicle-related mRNA, STX1A could only be detected in 2 of the 4 undifferentiated donor hMSC samples. More significantly, each donor sample revealed a unique expression pattern, demonstrating a significant variation of marker expression. Conclusion: The present study highlights the existence of an inter-donor variability of expression of neuralrelated markers in human MSC samples that has not previously been described. This donor-related heterogeneity might influence the reproducibility of transdifferentiation protocols as well as contributing to the ongoing controversy about differentiation capacities of MSCs. Therefore, further studies need to consider the differences between donor samples prior to any treatment as well as the possibility of harvesting donor cells that may be inappropriate for transplantation strategies

Direct Flow Medical vs. Edwards Sapien 3 Prosthesis: A Propensity Matched Comparison on Intermediate Safety and Mortality

Aims: To compare intermediate performance and mortality rates in patients, who underwent transcatheter aortic valve implantation (TAVI) with two different types of prostheses: Edwards Sapien 3 (ES3) and Direct Flow Medical (DFM).Methods and Results: 42 consecutive patients implanted with a DFM prosthesis for severe aortic stenosis were matched 1:1 with an equal number of patients, who received an ES3 during the same period. Primary endpoint was mortality. MACE, as a composite of all-cause death, stroke, and re-do-procedure (valve-in-valve), was defined as secondary endpoint. Moreover, we compared NYHA class, NT-proBNP-levels and the extent of restenosis. Patients were followed for 2 years. DFM patients showed echocardiographic elevated mean pressure gradients compared to ES3 patients before discharge (11.2 mmHg ± 5.3 vs. 3.5 mmHg ± 2.7; p < 0.001) and upon 6-months follow-up (20.3 mmHg ± 8.8 vs. 12.3 mmHg ± 4.4; p < 0.001). ES3 candidates showed superior NYHA class at follow-up (p = 0.001). Kaplan-Meier analysis revealed significantly worse survival in patients receiving a DFM prosthesis compared to ES3 (Breslow p = 0.020). MACE occurred more often in DFM patients compared to ES3 (Breslow p = 0.006).Conclusions: Patients receiving DFM valve prostheses showed worse survival and higher rates in MACE compared to ES3. Prosthesis performance regarding mean pressure gradients and patients' NYHA class also favored ES3

Mapping cardiac remodeling in chronic kidney disease

Patients with advanced chronic kidney disease (CKD) mostly die from sudden cardiac death and recurrent heart failure. The mechanisms of cardiac remodeling are largely unclear. To dissect molecular and cellular mechanisms of cardiac remodeling in CKD in an unbiased fashion, we performed left ventricular single-nuclear RNA sequencing in two mouse models of CKD. Our data showed a hypertrophic response trajectory of cardiomyocytes with stress signaling and metabolic changes driven by soluble uremia-related factors. We mapped fibroblast to myofibroblast differentiation in this process and identified notable changes in the cardiac vasculature, suggesting inflammation and dysfunction. An integrated analysis of cardiac cellular responses to uremic toxins pointed toward endothelin-1 and methylglyoxal being involved in capillary dysfunction and TNFα driving cardiomyocyte hypertrophy in CKD, which was validated in vitro and in vivo. TNFα inhibition in vivo ameliorated the cardiac phenotype in CKD. Thus, interventional approaches directed against uremic toxins, such as TNFα, hold promise to ameliorate cardiac remodeling in CKD.</p

Performance Measures Based on How Adults With Cancer Feel and Function: Stakeholder Recommendations and Feasibility Testing in Six Cancer Centers

PURPOSE Patient-reported outcome measures (PROMs) that assess how patients feel and function have potential for evaluating quality of care. Stakeholder recommendations for PRO-based performance measures (PMs) were elicited, and feasibility testing was conducted at six cancer centers. METHODS Interviews were conducted with 124 stakeholders to determine priority symptoms and risk adjustment variables for PRO-PMs and perceived acceptability. Stakeholders included patients and advocates, caregivers, clinicians, administrators, and thought leaders. Feasibility testing was conducted in six cancer centers. Patients completed PROMs at home 5-15 days into a chemotherapy cycle. Feasibility was operationalized as $75$ 75% patient acceptability. RESULTS Stakeholder priority PRO-PMs for systemic therapy were GI symptoms (diarrhea, constipation, nausea, vomiting), depression/anxiety, pain, insomnia, fatigue, dyspnea, physical function, and neuropathy. Recommended risk adjusters included demographics, insurance type, cancer type, comorbidities, emetic risk, and difficulty paying bills. In feasibility testing, 653 patients enrolled (approximately 110 per site), and 607 (93%) completed PROMs, which indicated high feasibility for home collection. The majority of patients (470 of 607; 77%) completed PROMs without a reminder call, and 137 (23%) of 607 completed them after a reminder call. Most patients (72%) completed PROMs through web, 17% paper, or 2% interactive voice response (automated call that verbally asked patient questions). For acceptability, . 95% of patients found PROM items to be easy to understand and complete. CONCLUSION Clinicians, patients, and other stakeholders agree that PMs that are based on how patients feel and function would be an important addition to quality measurement. This study also shows that PRO-PMs can be feasibly captured at home during systemic therapy and are acceptable to patients. PRO-PMs may add value to the portfolio of PMs as oncology transitions from fee-for-service payment models to performance-based care that emphasizes outcome measures