Coronary Hemodynamics in Patients With Severe Aortic Stenosis and Coronary Artery Disease Undergoing Transcatheter Aortic Valve Replacement: Implications for Clinical Indices of Coronary Stenosis Severity.

In this study, a systematic analysis was conducted of phasic intracoronary pressure and flow velocity in patients with severe aortic stenosis (AS) and coronary artery disease, undergoing transcatheter aortic valve replacement (TAVR), to determine how AS affects: 1) phasic coronary flow; 2) hyperemic coronary flow; and 3) the most common clinically used indices of coronary stenosis severity, instantaneous wave-free ratio and fractional flow reserve. A significant proportion of patients with severe aortic stenosis (AS) have concomitant coronary artery disease. The effect of the valve on coronary pressure, flow, and the established invasive clinical indices of stenosis severity have not been studied. Twenty-eight patients (30 lesions, 50.0% men, mean age 82.1 ± 6.5 years) with severe AS and coronary artery disease were included. Intracoronary pressure and flow assessments were performed at rest and during hyperemia immediately before and after TAVR. Flow during the wave-free period of diastole did not change post-TAVR (29.78 ± 14.9 cm/s vs. 30.81 ± 19.6 cm/s; p = 0.64). Whole-cycle hyperemic flow increased significantly post-TAVR (33.44 ± 13.4 cm/s pre-TAVR vs. 40.33 ± 17.4 cm/s post-TAVR; p = 0.006); this was secondary to significant increases in systolic hyperemic flow post-TAVR (27.67 ± 12.1 cm/s pre-TAVR vs. 34.15 ± 17.5 cm/s post-TAVR; p = 0.02). Instantaneous wave-free ratio values did not change post-TAVR (0.88 ± 0.09 pre-TAVR vs. 0.88 ± 0.09 post-TAVR; p = 0.73), whereas fractional flow reserve decreased significantly post-TAVR (0.87 ± 0.08 pre-TAVR vs. 0.85 ± 0.09 post-TAVR; p = 0.001). Systolic and hyperemic coronary flow increased significantly post-TAVR; consequently, hyperemic indices that include systole underestimated coronary stenosis severity in patients with severe AS. Flow during the wave-free period of diastole did not change post-TAVR, suggesting that indices calculated during this period are not vulnerable to the confounding effect of the stenotic aortic valve

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Master of two worlds: facilitating community reintegration of combat veterans

INTRODUCTION: Since September 11, 2001, over 2.5 million military service members have been deployed to combat zones to support operations in the War on Terror and over 250,000 service members transition out of the military every year (United States Department of Veterans Affairs, 2022). Evidence-based research suggests that this cohort of post-9/11 combat veterans can struggle with community reintegration and associated functional difficulties in the areas of disruption of identity, challenged beliefs about self and others due to trauma and moral injury, occupational disengagement, and limitations with social and role participation. OBJECTIVES: Many combat veterans find themselves returning home by a different way, struggling to find their place in the civilian world while maintaining their identity as a warrior. Occupational therapy can bridge the functional divide between these two worlds by helping modern-day warriors rebuild and reclaim their roles, occupations, and purpose. Master of Two Worlds is an interactive multimedia workbook designed to facilitate posttraumatic growth and community reintegration for post-9/11 combat veterans in the VA system with or without a mental health diagnosis. METHOD/APPROACH: The workbook uses Campbell’s (2008) Hero’s Journey framework to help veterans form a cohesive life narrative, determine new goals, and acquire civilian occupational skills. Readers will be able to access interactive multimedia videos and activities with their cell phones through QR codes in the workbook. Practical hands-on workbook activities focus on self-care, habit and routine formation, spirituality, and social and leisure participation, as well as integrating roles and identity to empower mastery of the military and civilian worlds. A mixed-methods pilot study will be conducted at the VA Long Beach Healthcare System (VALBHS). Quantitative data will be collected pre- and post-intervention using the following standardized outcome measures: Military to Civilian Questionnaire (M2C-Q), the PTSD Checklist for DSM-5 (PCL-5), and the Posttraumatic Growth Inventory – Expanded version (PTGI-X). Qualitative data will be collected via one-on-one interviews. ANTICIPATED OUTCOMES: Successful community reintegration of post-9/11 combat veterans through forming a new civilian occupational identity that integrates the warrior experiences as expressed through establishing healthy habits and routines, developing new priorities, goals, and possibilities for the future, redefining personal moral code to heal from moral injury, establishing a close social support network, and finding a sense of personal strength. Results and or Practice Implications: It is hypothesized that results will demonstrate statistically significant score changes on the outcome measures. Dissemination of the workbook will take place through an interdisciplinary community of practice on the national VA level and through key VA staff at strategic clinics within the system. CONCLUSION: Combat is a form of trauma. Posttraumatic growth and community reintegration are the ultimate successful outcomes of war trauma. It is incumbent on practitioners in occupational therapy to facilitate these outcomes for the betterment of those who have served and for society

Challenges and learning from the transcatheter aortic valve implantation team during the COVID-19 pandemic: a nurse's perspective

The COVID-19 pandemic has had a major impact on NHS resources, causing disruption to all elective procedures and affecting each stage of the patient journey. For patients with severe symptomatic aortic stenosis, there is a significant risk of clinical deterioration if left untreated. The risk of delay needs to be weighed against the risk of acquiring COVID-19 during an admission for a procedure. This has presented many challenges for the transcatheter aortic valve implantation team. When offering any procedures during 2020, NHS trusts had a responsibility to protect patients from exposure to COVID-19 through infection control measures and adapting to COVID-19 secure pathways. The aim was to prevent the spread of COVID-19, while performing planned care to high-risk patients where possible, to prevent clinical harm caused by delays. The authors' practice needed to set realistic targets for the care that could be safely delivered at each phase of the pandemic. Therefore, new considerations and methods needed to be applied at every stage of the patient journey, from the patient referrals on the waiting list to post-procedure discharge planning. This required a team-based approach throughout. Transcatheter aortic valve implantation clinical nurse specialists have played a fundamental role in the coordination of the ever-changing situation, implementing the new pathways and monitoring the patients on the waiting list. Nurses in this role are also often the first point of contact for patients and family. This experience presented an opportunity for innovation and learning from change. This article will discuss the challenges faced by the transcatheter aortic valve implantation team, the strategies used during the pandemic and the lessons that can be applied to future practice from the authors' experiences in one centre in London. </jats:p

Adjustments to pharmacologic therapies for hemophagocytic lymphohistiocytosis while on extracorporeal support

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysregulatory syndrome characterized by severe inflammation and end‐organ damage. Due to significant organ dysfunction, patients often require extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). In this report, we describe consideration for adjusting treatment in the context of extracorporeal organ support. We describe agents commonly used and dosing adjustments made in light of extracorporeal organ support. We report six cases that illustrate the feasibility of initiating standard HLH therapies in patients requiring these modalities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167484/1/pbc29007.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167484/2/pbc29007_am.pd

Adjustments to pharmacologic therapies for hemophagocytic lymphohistiocytosis while on extracorporeal support

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysregulatory syndrome characterized by severe inflammation and end‐organ damage. Due to significant organ dysfunction, patients often require extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). In this report, we describe consideration for adjusting treatment in the context of extracorporeal organ support. We describe agents commonly used and dosing adjustments made in light of extracorporeal organ support. We report six cases that illustrate the feasibility of initiating standard HLH therapies in patients requiring these modalities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167484/1/pbc29007.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167484/2/pbc29007_am.pd