Impact of Mechanical Circulatory Support on Exercise Capacity in Patients With Advanced Heart Failure.

Approximately 6 million individuals have heart failure in the United States alone and 15 million in Europe. Left ventricular assist devices (LVAD) improve survival in these patients, but functional capacity may not fully improve. This article examines the hypothesis that patients supported by LVAD experience persistent reductions in functional capacity and explores mechanisms accounting for abnormalities in exercise tolerance.

Undergraduate support for university smoke-free and vape-free campus policies and student engagement: a quasi-experimental intervention.

BackgroundCollege campuses have policies restricting smoking/vaping on campus. Previous studies involving mostly European-American students showed smoking prevalence declines following implementation of such policies.ObjectiveTo evaluate a social media campaign promotive of stronger campus support for an existing campus no-smoking/no-vaping policy where most (∼75%) of the undergraduates were non-European-American. A demographically comparable university served as a no-intervention control.ParticipantsTarget was 200 random intercept surveys at each university during fall 2016, spring 2017. Of 800 respondents, 681 were undergraduates.MethodsBaseline and post-intervention surveys assessed awareness of and support for campus-wide smoke-free/vape-free policies. Staged smoke-free/vape-free policy violations assessed students' propensity to intervene in support of the policy.ResultsRespondent support for the no-smoking/no-vaping policy did not change.ConclusionsThe social media campaign and Policy Ambassadors program did not increase support for the campus no-smoking/no-vaping policy. Most (∼90%) respondents agreed that the campus no-smoking/no-vaping policy was important for public health.

Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is an acute, febrile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated syndrome, often with cardiohemodynamic dysfunction. Insight into mechanism of disease is still incomplete. OBJECTIVE: Our objective was to analyze immunologic features of MIS-C patients compared to febrile controls (FC). METHODS: MIS-C patients were defined by narrow criteria, including having evidence of cardiohemodynamic involvement and no macrophage activation syndrome. Samples were collected from 8 completely treatment-naive patients with MIS-C (SARS-CoV-2 serology positive), 3 patients with unclassified MIS-C-like disease (serology negative), 14 FC, and 5 MIS-C recovery (RCV). Three healthy controls (HCs) were used for comparisons of normal range. Using spectral flow cytometry, we assessed 36 parameters in antigen-presenting cells (APCs) and 29 in T cells. We used biaxial analysis and uniform manifold approximation and projection (UMAP). RESULTS: Significant elevations in cytokines including CXCL9, M-CSF, and IL-27 were found in MIS-C compared to FC. Classic monocytes and type 2 dendritic cells (DCs) were downregulated (decreased CD86, HLA-DR) versus HCs; however, type 1 DCs (CD11c+CD141+CLEC9A+) were highly activated in MIS-C patients versus FC, expressing higher levels of CD86, CD275, and atypical conventional DC markers such as CD64, CD115, and CX3CR1. CD169 and CD38 were upregulated in multiple monocyte subtypes. CD56dim/CD57-/KLRGhi/CD161+/CD38- natural killer (NK) cells were a unique subset in MIS-C versus FC without macrophage activation syndrome. CONCLUSION: Orchestrated by complex cytokine signaling, type 1 DC activation and NK dysregulation are key features in the pathophysiology of MIS-C. NK cell findings may suggest a relationship with macrophage activation syndrome, while type 1 DC upregulation implies a role for antigen cross-presentation.

An Electronically Delivered Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure With Reduced Ejection Fraction: The EPIC-HF Trial.

BACKGROUND: Major gaps exist in the routine initiation and dose up-titration of guideline-directed medical therapies (GDMT) for patients with heart failure with reduced ejection fraction. Without novel approaches to improve prescribing, the cumulative benefits of heart failure with reduced ejection fraction treatment will be largely unrealized. Direct-to-consumer marketing and shared decision making reflect a culture where patients are increasingly involved in treatment choices, creating opportunities for prescribing interventions that engage patients. METHODS: The EPIC-HF (Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction) trial randomized patients with heart failure with reduced ejection fraction from a diverse health system to usual care versus patient activation tools-a 3-minute video and 1-page checklist-delivered electronically 1 week before, 3 days before, and 24 hours before a cardiology clinic visit. The tools encouraged patients to work collaboratively with their clinicians to "make one positive change" in heart failure with reduced ejection fraction prescribing. The primary endpoint was the percentage of patients with GDMT medication initiations and dose intensifications from immediately preceding the cardiology clinic visit to 30 days after, compared with usual care during the same period. RESULTS: EPIC-HF enrolled 306 patients, 290 of whom attended a clinic visit during the study period: 145 were sent the patient activation tools and 145 were controls. The median age of patients was 65 years; 29% were female, 11% were Black, 7% were Hispanic, and the median ejection fraction was 32%. Preclinic data revealed significant GDMT opportunities, with no patients on target doses of ß-blocker, sacubitril/valsartan, and mineralocorticoid receptor antagonists. From immediately preceding the cardiology clinic visit to 30 days after, 49.0% in the intervention and 29.7% in the control experienced an initiation or intensification of their GDMT (P=0.001). The majority of these changes were made at the clinician encounter itself and involved dose uptitrations. There were no deaths and no significant differences in hospitalization or emergency department visits at 30 days between groups. CONCLUSIONS: A patient activation tool delivered electronically before a cardiology clinic visit improved clinician intensification of GDMT. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03334188.

An Electronically delivered, Patient-activation tool for Intensification of medications for Chronic Heart Failure with reduced ejection fraction: Rationale and design of the EPIC-HF trial.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) benefits from initiation and intensification of multiple pharmacotherapies. Unfortunately, there are major gaps in the routine use of these drugs. Without novel approaches to improve prescribing, the cumulative benefits of HFrEF treatment will be largely unrealized. Direct-to-consumer marketing and shared decision making reflect a culture where patients are increasingly involved in treatment choices, creating opportunities for prescribing interventions that engage patients. HYPOTHESIS: Encouraging patients to engage providers in HFrEF prescribing decisions will improve the use of guideline-directed medical therapies. DESIGN: The Electronically delivered, Patient-activation tool for Intensification of Chronic medications for Heart Failure with reduced ejection fraction (EPIC-HF) trial randomizes patients with HFrEF to usual care versus patient-activation tools-a 3-minute video and 1-page checklist-delivered prior to cardiology clinic visits that encourage patients to work collaboratively with their clinicians to intensify HFrEF prescribing. The study assesses the effectiveness of the EPIC-HF intervention to improve guideline-directed medical therapy in the month after its delivery while using an implementation design to also understand the reach, adoption, implementation, and maintenance of this approach within the context of real-world care delivery. Study enrollment was completed in January 2020, with a total 305 patients. Baseline data revealed significant opportunities, with <1% of patients on optimal HFrEF medical therapy. SUMMARY: The EPIC-HF trial assesses the implementation, effectiveness, and safety of patient engagement in HFrEF prescribing decisions. If successful, the tool can be easily disseminated and may inform similar interventions for other chronic conditions.

Military Service Member Perspectives About Occupational Therapy Treatment in a Military Concussion Clinic.

The purpose of this study is to describe important features of occupational therapy practice for treatment of military service members with chronic symptoms and a history of mild traumatic brain injury (mTBI) in a military concussion care clinic from service members' perspectives with support from occupational therapy practitioners. Two series of focus groups were conducted with service members with chronic mTBI-related symptoms (n = 6) and practitioners (n = 5). Data were analyzed concurrently with collection. We identified five main themes: therapeutic relationship, consistent inclusion of family members, combat versus noncombat injuries, loss of military identity, and assessment against population norms. The findings of this study suggest that service members' evaluations of occupational therapy are based on the overall experience of the encounter, centered by the therapeutic relationship, rather than specific intervention strategies or technology.

Effects of radiofrequency energy delivered through partially insulated metallic catheter tips on myocardial tissue heating and ablation lesion characteristics.

BACKGROUND: Cardiac radiofrequency (RF) ablation is typically achieved using symmetric catheter tips, which may result in unintended heating adjacent to targeted tissue. Partial insulation may alter lesion geometry and prevent collateral heating. OBJECTIVE: The purpose of this study was to assess partially insulated focused ablation (PIFA). METHODS: Partial insulation using thermally conductive materials was applied to a 4-mm or 8-mm nonirrigated catheter and a 3.5-mm open-irrigated catheter. These PIFA tips, or their noninsulated counterparts, were applied to ex vivo viable bovine myocardium. Ablations were delivered at various powers and under temperature control. Potential clinical applicability was evaluated in vivo by targeting porcine epicardium with irrigated PIFA and assessing its protective effects on the pericardium. RESULTS: PIFA catheters exhibited different properties and produced asymmetric lesions compared with corresponding standard ablation catheters. Temperatures at 3- and 5-mm depths were higher for PIFA catheters, with a temperature increase measured at the catheter tip-tissue interface; however, in temperature control ablation, tip-tissue temperature increases did not limit power delivery. Furthermore, temperatures were lower on the insulated surface and were significantly higher on the noninsulated PIFA side. Impedance changes were significantly larger; more steam pops were observed with PIFA but were mitigated by external irrigation, a larger tip electrode, and use of more thermally conductive insulation. In contrast to standard ablation, open-irrigated PIFA created larger asymmetric lesions in vivo over porcine epicardium, without evidence of pericardial injury. CONCLUSION: PIFA ablation has different characteristics compared with symmetrically conductive ablation. Further research is needed to assess the clinical implications of insulated catheter ablation.

Contemporary infrapopliteal intervention for limb salvage and wound healing: harmonization of revascularization and wound management.

Infrapopliteal arterial disease is a significant cause of critical limb ischemia (CLI), whether single-segment or multisegment disease. The collaboration between the tremendous advancements in endovascular technology and the refinement of endovascular techniques has renewed the classic infrapopliteal interventions during the past decade. With this paradigm shift in the treatment of CLI, the role of a comprehensive approach of different disciplines for tissue loss is becoming greater. Given the increasing global burden of CLI, we review the cutting-edge diagnostic and endovascular approaches to infrapopliteal artery disease, and the importance of wound management in optimizing clinical outcomes.

Contemporary Infrapopliteal Intervention for Limb Salvage and Wound Healing.

Infrapopliteal arterial disease is a significant cause of critical limb ischemia (CLI), whether single-segment or multisegment disease. The collaboration between the tremendous advancements in endovascular technology and the refinement of endovascular techniques has renewed the classic infrapopliteal interventions during the past decade. With this paradigm shift in the treatment of CLI, the role of a comprehensive approach of different disciplines for tissue loss is becoming greater. Given the increasing global burden of CLI, we review the cutting-edge diagnostic and endovascular approaches to infrapopliteal artery disease, and the importance of wound management in optimizing clinical outcomes.

Impaired contractile recovery after low-flow myocardial ischemia in a porcine model of metabolic syndrome.

Clinical metabolic syndrome conveys a poor prognosis in patients with acute coronary syndrome, not fully accounted for by the extent of coronary atherosclerosis. To explain this observation, we determined whether postischemic myocardial contractile and metabolic function are impaired in a porcine dietary model of metabolic syndrome without atherosclerosis. Micropigs (n = 28) were assigned to a control diet (low fat, no added sugars) or an intervention diet (high saturated fat and simple sugars, no added cholesterol) for 7 mo. The intervention diet produced obesity, hypertension, dyslipidemia, and impaired glucose tolerance, but not atherosclerosis. Under open-chest, anesthetized conditions, pigs underwent 45 min of low-flow myocardial ischemia and 120 min of reperfusion. In both diet groups, contractile function was similar at baseline and declined similarly during ischemia. However, after 120 min of reperfusion, regional work recovered to 21 ± 12% of baseline in metabolic syndrome pigs compared with 61 ± 13% in control pigs (P = 0.01). Ischemia-reperfusion caused a progressive decline in mechanical/metabolic efficiency (regional work/O2 consumption) in metabolic syndrome hearts, but not in control hearts. Metabolic syndrome hearts demonstrated altered fatty acyl composition of cardiolipin and increased Akt phosphorylation in both ischemic and nonischemic regions, suggesting tonic activation. Metabolic syndrome hearts used more fatty acid than control hearts (P = 0.03). When fatty acid availability was restricted by prior insulin exposure, differences between groups in postischemic contractile recovery and mechanical/metabolic efficiency were eliminated. In conclusion, pigs with characteristics of metabolic syndrome demonstrate impaired contractile and metabolic recovery after low-flow myocardial ischemia. Contributory mechanisms may include remodeling of cardiolipin, abnormal activation of Akt, and excessive utilization of fatty acid substrates.

PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty.

Peroxisome proliferator-activated receptor γ (PPAR-γ) is a key regulator of fatty acid metabolism, promoting its storage in adipose tissue and reducing circulating concentrations of free fatty acids. Activation of PPAR-γ has favorable effects on measures of adipocyte function, insulin sensitivity, lipoprotein metabolism, and vascular structure and function. Despite these effects, clinical trials of thiazolidinedione PPAR-γ activators have not provided conclusive evidence that they reduce cardiovascular morbidity and mortality. The apparent disparity between effects on laboratory measurements and clinical outcomes may be related to limitations of clinical trials, adverse effects of PPAR-γ activation, or off-target effects of thiazolidinedione agents. This review addresses these issues from a clinician's perspective and highlights several ongoing clinical trials that may help to clarify the therapeutic role of PPAR-γ activators in cardiovascular disease.

Genetic variations in the C epsilon mX domain of human membrane-bound IgE.

The epsilon chain of membrane-bound IgE (mIgE) is expressed predominantly as a "long" isoform, containing an extra segment of 52 amino acid (a.a.) residues, referred to as C epsilon mX, between the CH4 domain and the C-terminal membrane-anchoring transmembrane peptide. C epsilon mX results from an alternative splicing of the epsilon RNA transcript at 156-bp upstream of the splicing acceptor site used by the "short" isoform. Here, based on an analysis of the C epsilon mX genomic DNA sequences of 320 subjects residing in Taiwan, we report that single-nucleotide polymorphisms have been found at two positions, namely, G/T at #46 and A/G at #93 (along the 156 bp of C epsilon mX), with the former creating an amino acid change from Val to Leu at #16 (along the 52 a.a. of C epsilon mX) and the latter resulting in no change (Gly). Among the 640 C epsilon mX sequences identified, the previously known 46G93A allelic form appeared 293 times, the newly discovered 46T93A allelic form (GeneBank accession no. GU208817) 26 times, and the 46G93G allelic form (GU208818) 321 times. No 46T93G allelic form was found. Serum IgE measurements showed that the polymorphisms did not correlate with the levels of serum IgE. The anti-C epsilon mX monoclonal antibody, 4B12, could bind equally well to mIgE.Fc(L)(16V) and mIgE.Fc(L)(16L). While genetic variation of C epsilon mX of broader populations should also be investigated, these newly discovered genetic variants of C epsilon mX in the Taiwanese population do not seem to affect the feasibility of using an anti-C epsilon mX mAb, such as 4B12, to target mIgE-expressing B cells.

Prescription-filling rates for key medications in Veterans Affairs patients after coronary artery bypass grafting.

PURPOSE: The six-month prescription-filling rates for key secondary-prevention drugs in Department of Veterans Affairs (VA) patients who had undergone coronary artery bypass grafting (CABG) were studied. METHODS: Patient records for elective CABG from April 2000 through March 2002 (divided into four six-month periods) were analyzed. The study population included 8925 CABG-only patients surviving to hospital discharge. For each six-month period and in aggregate, the primary study endpoint was the six-month prescription-filling rate. RESULTS: Across the four six-month periods, prescription-filling rates increased for all categories of medications studied. There were modest progressive increases for lipid-lowering agents, statins, -blockers, angiotensin-converting-enzyme Inhibitors, and angiotensin-receptor blockers. The antithrombotic-filling rate averaged 88.5%. Filling rates for aspirin were much higher than for aspirin alternatives. CONCLUSION: Prescription-filling rates for post-CABG medications in VA facilities were generally high and suggested compliance with guidelines for the prevention of cardiovascular events.

An investigation of the cytotoxicity and histocompatibility of in situ forming lactic acid based orthopedic biomaterials.

The cytotoxicity and biocompatibility of polymer networks prefabricated from multifunctional lactic acid based oligomers that are being developed for orthopedic applications were assessed through in vitro cytotoxicity analysis and subcutaneous implantation. After 7 and 14 days, no significant difference was observed in the relative viability or alkaline phosphatase activity of primary rat calvarial osteoblasts cultured in the presence or absence of degrading polymer networks, indicating that the degradation products had no detrimental effect on the function or activity of the cultured cells. The tissue response to preformed lactic acid networks implanted in rats consisted of a mild inflammatory response with an increase in fibrous capsule thickness and inflammation correlating with faster degrading polymer compositions. This relatively neutral response is indicative of a biocompatible, degradable polymer that has potential medical applications. Finally, porous scaffolds were implanted subcutaneously in rats, and vascularized fibrous tissue infiltration was highly dependent on the scaffold porosity and architecture. This finding indicates that an in situ forming porous scaffold of this composition may support the infiltration of surrounding vascularized tissue, and thus be applicable to orthopedic treatments of large bone defects.

Monoclonal antibodies against the C(epsilon)mX domain of human membrane-bound IgE and their potential use for targeting IgE-expressing B cells.

BACKGROUND: IgE mediates immediate-type hypersensitivity reactions responsible for various allergic symptoms. It is secreted by IgE-producing plasma cells, which differentiate from B cells expressing membrane-bound IgE (mIgE) on their surface. The epsilon-chain of human mIgE contains a membrane-anchoring peptide and an extra 52-amino-acid (a.a.)-long domain (referred to as C(epsilon)mX) between the membrane anchor and the CH4 domain. OBJECTIVE: The study was designed to evaluate the effects of C(epsilon)mX-specific monoclonal antibodies (mAbs) to target IgE-expressing B cells and decrease IgE production. METHODS: A C(epsilon)mX-containing IgG1.Fc fusion protein was produced in CHO cells and used to immunize mice; five hybridoma clones secreting C(epsilon)mX-specific mAbs were obtained. RESULTS: Characterization of the mAbs using ELISA, immunoprecipitation, and immunoblotting methods showed that they could bind to both native and denatured forms of C(epsilon)mX. The mAbs exhibited mutual inhibition of binding to mIgE. Epitope mapping using synthetic peptides revealed that all five mAbs recognize the same epitope, RADWPGPP, located near the C-terminus of C(epsilon)mX. Binding of one of the mAbs to mIgE on SKO-007 cells induced the cross-linking of mIgE molecules on the cell surface, resulting in their patching and capping. In vitro functional analysis revealed that mAbs are able to cause complement-mediated cytotoxicity on transfectants expressing the Fc portion of mIgE. CONCLUSION: We have prepared several human mIgE-specific mAbs. The potential of the mAbs on targeting mIgE+ B cells was demonstrated by CDC analysis.

Inducing specific reactivity against B cells in mice by immunizing with an Fc fusion protein containing self-Igbeta.

A recombinant chimeric fusion protein, muIgbeta-hugamma4.Fc, composed of the extracellular domain of mouse Igbeta (CD79b) and the CH2-CH3 domains of human IgGgamma4.Fc (hugamma4.Fc), linked via an immunologically inert flexible peptide, was prepared. The fusion protein was evaluated for its ability to induce specific auto-reactive immune response against Igbeta and to modulate B cell activity in Balb/c mice. Upon immunization with muIgbeta-hugamma4.Fc, mice developed immunoglobulin (IgG) against self-Igbeta, which could bind to the cells of a mouse B cell line expressing Igbeta on the cell surface. The proportion of B cells in mononuclear cells in the peripheral blood (PBMC) of treated mice decreased as compared to that of mice immunized with hugamma4.Fc without the Igbeta component. Furthermore, mice immunized against muIgbeta-hugamma4.Fc displayed a reduced antibody response against an irrelevant antigen. The implications of employing the present approach in developing a therapeutic strategy for regulating B cell activity has been discussed.

Down regulation of B cells by immunization with a fusion protein of a self CD20 peptide and a foreign IgG.Fc fragment.

In vivo studies of mice were performed to investigate whether auto-reactive antibodies specific for self CD20 antigen on B cells could be induced by immunizing with a CD20 peptide linked to a foreign, human IgG.Fc fragment through a T cell immunologically inert linker peptide and how such an auto-reactivity, if generated, would affect the levels of B cells. The dimeric Fc fusion protein containing the extracellular 44-amino acid portion of CD20, and the CH2-CH3 domains of human gamma 1 immunoglobulin were prepared. After several subcutaneous immunizations with this CD20-Fc protein, mice produced anti-CD20 antibodies that can bind to native CD20 on normal B cells and B-lymphoma cells. In mice immunized with the CD20-Fc protein, the fraction of B cells in total peripheral blood lymphocytes decreased to about 40%, significantly lower than that of mice immunized with human IgG. In addition, antibody response towards an irrelevant bystander antigen, chicken ovalbumin, was weakened compared with that of mice immunized with human IgG. These results show that auto-reactive antibodies specific for CD20 can be induced by immunizing with an autologous CD20 peptide fused with a foreign IgG.Fc and that the auto-antibodies can partially reduce the levels of B cells and their response to other antigens.