Cardiac Cachexia in Left Ventricular Assist Device Recipients and the Implications of Weight Gain Early After Implantation.

Background Severe cardiac cachexia or malnutrition are commonly considered relative contraindications to left ventricular assist device (LVAD) implantation, but post-LVAD prognosis for patients with cachexia is uncertain. Methods and Results Intermacs (Interagency Registry for Mechanically Assisted Circulatory Support) 2006 to 2017 was queried for the preimplantation variable cachexia/malnutrition. Cox proportional hazards modeling examined the relationship between cachexia and LVAD outcomes. Of 20 332 primary LVAD recipients with available data, 516 (2.54%) were reported to have baseline cachexia and had higher risk baseline characteristics. Cachexia was associated with higher mortality during LVAD support (unadjusted hazard ratio [HR], 1.36 [95% CI, 1.18-1.56]; P<0.0001), persisting after adjustment for baseline characteristics (adjusted HR, 1.23 [95% CI, 1.0-1.42]; P=0.005). Mean weight change at 12 months was +3.9±9.4 kg. Across the cohort, weight gain ≥5% during the first 3 months of LVAD support was associated with lower mortality (unadjusted HR, 0.90 [95% CI, 0.84-0.98]; P=0.012; adjusted HR, 0.89 [95% CI, 0.82-0.97]; P=0.006). Conclusions The proportion of LVAD recipients recognized to have cachexia preimplantation was low at 2.5%. Recognized cachexia was independently associated with higher mortality during LVAD support. Early weight gain ≥5% was independently associated with lower mortality during subsequent LVAD support.

Association between postoperative hemodynamic metrics of pulmonary hypertension and right ventricular dysfunction and clinical outcomes after left ventricular assist device implantation.

BACKGROUND: While preoperative hemodynamic risk factors associated with early right heart failure (RHF) following left ventricular assist device (LVAD) surgery are well-established, the relationship between postoperative hemodynamic status and subsequent outcomes remains poorly defined. METHODS: We analyzed adult CF-LVAD patients from the STS-INTERMACS registry surviving at least 3 months without evidence of early RHF and with hemodynamic data available at 3 months after LVAD implant. The association between metrics of RV afterload and function and the subsequent risk of death, right heart failure (RHF), gastrointestinal bleeding (GIB), or stroke were assessed using multivariable Cox proportional hazards modeling. RESULTS: Among 1,050 patients with available 3-month hemodynamics, pulmonary hypertension was common, with 585 (55.7%) having mPAP ≥ 20 mm Hg and 164 (15.6%) having PVR ≥ 3 WU. Pulmonary artery pulsatility index (PAPi, HR 0.62 per log-increase for values < 3, 95% CI 0.43-0.89) and PVR (HR 1.19 per 1 WU-increase for values > 1.5 WU, 95% CI 1.03-1.38) were independently associated with the composite of death or RHF. Postoperative RAP (HR 1.18 per 5 mm Hg increase, 95% CI 1.04-1.33), RAP:PCWP (HR 1.46 per log-increase, 95% CI 1.12-1.91), and PAPi (HR 0.76 per log-increase, 95% CI 0.61-0.95) were each associated with GIB risk. Postoperative hemodynamics was not associated with stroke risk. CONCLUSIONS: Hemodynamic metrics of postoperative RV dysfunction and elevated RV afterload are independently associated with RHF, mortality and GIB. Whether strategies targeting postoperative optimization of RV function and afterload can reduce the burden of these adverse events requires prospective study.

Electrically controlled nicotine delivery through Carbon nanotube membranes via electrochemical oxidation and nanofluidically enhanced electroosmotic flow.

A promising tool for nicotine addiction treatment is a programmable nicotine delivery device coupled to smart phone-assisted behavioral therapies. Key metrics for such a device are delivery of adjustable nicotine doses tailored to individual needs, compact size and power efficiency. Reported here is a detailed optimization of carbon nanotube (CNT) membrane fabrication based on electrochemical oxidation, to improve its electrically driven performance for nicotine fluxes and switching ON (-1.5 V)-OFF (0 V) flux ratio. ON- state nicotine flux of ~ 6 µmoles/cm2/h at -1.5 V applied bias was achieved allowing ~ 6-folds decrease in the size of device (4 cm2) to attain flux equivalent to high dose nicotine gum (1.1 µmoles/cm2/h). Application of + 1.5 V bias in OFF state reduced diffusional background flux, giving an ON (-1.5 V)/OFF (+ 1.5 V) flux ratio of 68 that enabled device to deliver between the highest nicotine gum (1.1 µmoles/cm2/h) and lowest nicotine patch (0.08 µmoles/cm2/h) doses, as well as taper off nicotine doses for long term addiction treatment. The nicotine transport mechanism was studied as a function of pH and applied bias, using neutral tracer molecule, showing a mechanism of both electroosmosis and electrophoresis in the atomically smooth nanofluidic pores of CNTs. Optimal power consumption/flux efficiency of 111(µW/cm2)/µmoles/cm2/h was achieved allowing watch-battery lifetimes of 7-62 days for conventional treatment dosing regimens. Bluetooth-enabled, remotely controlled CNT membrane system has potential for treatments of nicotine, opioid and alcohol addictions that needs dose adjustment with precise temporal control.

Successful Urine Multiplex Bead Assay to Measure Lupus Nephritis Activity.

INTRODUCTION: Lupus nephritis (LN) confers a poor prognosis, mainly from lack of effective laboratory tests to diagnose and to evaluate therapies. We have previously shown that a set of 6 urinary biomarkers (NGAL, KIM-1, MCP-1, adiponectin, hemopexin, and ceruloplasmin) are highly sensitive and specific to identify adult and pediatric patients with active LN using renal biopsy as reference standard. Using these combinatorial urinary biomarkers, the Renal Activity Score for Lupus (RAIL) score was established, with biomarkers measured by enzyme-linked immunosorbent assay (ELISA). To enhance clinical utility of the biomarkers and RAIL, we tested the performance of RAIL with biomarkers measured by ELISA to that of biomarkers measured by the bead multiplex method, hypothesizing that the multiplex bead method would be comparable. METHODS: Spot urine samples (n = 341) of 46 patients aged 20 to 73 years with or without LN were used. Samples were assayed both by ELISA and multiplex using LUMINEX. RAIL scores and biomarker quantities were assessed for agreement with intraassay correlation coefficients and compared using Bland-Altman and regression. RESULTS: Biomarker measurement by LUMINEX was successful for NGAL, KIM-1, MCP-1, and adiponectin, but not for ceruloplasmin and hemopexin. There was good agreement of the RAIL obtained from these 4 biomarkers, irrespective of assay method (intraclass correlation coefficient [ICC] = 0.78, 95% confidence interval [CI] = 0.78-0.82). The RAIL scores from 4 biomarkers further correlated with those when considering all 6 biomarkers (ICC = 0.97, 95% CI = 0.96-0.98). CONCLUSION: The LUMINEX platform allows for the convenient and simultaneous measurement of 4 RAIL biomarkers. RAIL scores considering only these 4 biomarkers may be sufficient to accurately capture LN activity.

A preclinical evaluation of a programmable CNT membrane device for transdermal nicotine delivery in hairless Guinea pigs.

Nicotine replacement therapy in the form of transdermal nicotine patches and nicotine gums combined with behavioral counseling still has a low smoking cessation rate of 25%. A promising approach to smoking cessation is to remotely program variable transdermal nicotine delivery rates, with inputs from counselor and patient through a smartphone counseling application. A switchable carbon nanotube (CNT) membrane device has been developed for transdermal nicotine delivery that can be programmed to deliver variable doses matching those of nicotine patches (7, 14 and 21 mg/24 h) and nicotine gums (2 mg /4 mg). The performance of switchable devices was evaluated in vitro on flow-cell geometry and in vivo on the skin of hairless guinea pig (HGP). In vitro, CNT membrane devices successfully switched between therapeutically useful nicotine fluxes of 1.3-1.8 µmoles/cm2/h (ON, -1.5 V) and 0.17-0.23 µmoles/cm2/h (OFF, 0 V), corresponded to the higher doses of gum and nicotine patch fluxes. In vivo, a microdialysis membrane probe was implanted in skin of HGP to directly detect nicotine fluxes through the skin barriers into dialysate with high temporal resolution. The CNT membrane device on HGP skin resulted in an ON/OFF nicotine flux ratio 6.4 ±â€¯2.5 as detected in microdialysis membrane probe in skin. Compared to commercial nicotine patches, the device in ON state was approximately 2-2.4 times the commercial nicotine patch dose as measured by dialysate nicotine fluxes. These results enable smartphone-controlled, battery operated transdermal delivery devices that can be coupled to remote counseling apps for personalized smoking cessation therapy.

Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus.

OBJECTIVES: To delineate urine biomarkers that reflect kidney structural damage and predict renal functional decline in pediatric lupus nephritis (LN). METHODS: In this prospective study, we evaluated kidney biopsies and urine samples of 89 patients with pediatric LN. Urinary levels of 10 biomarkers [adiponectin, ceruloplasmin, kidney injury molecule-1, monocyte chemotactic protein-1, neutrophil gelatinase-associated lipocalin, osteopontin, transforming growth factor-ß (TGFß), vitamin-D binding protein, liver fatty acid binding protein (LFABP), and transferrin] were measured. Regression analysis was used to identify individual and combinations of biomarkers that determine LN damage status [NIH-chronicity index (NIH-CI) score ≤ 1 vs. ≥ 2] both individually and in combination, and biomarker levels were compared for patients with vs. without renal functional decline, i.e., a 20% reduction of the glomerular filtration rate (GFR) within 12 months of a kidney biopsy. RESULTS: Adiponectin, LFABP, and osteopontin levels differed significantly with select histological damage features considered in the NIH-CI. The GFR was associated with NIH-CI scores [Pearson correlation coefficient (r) = - 0.49; p < 0.0001] but not proteinuria (r = 0.20; p > 0.05). Similar to the GFR [area under the ROC curve (AUC) = 0.72; p < 0.01], combinations of osteopontin and adiponectin levels showed moderate accuracy [AUC = 0.75; p = 0.003] in discriminating patients by LN damage status. Renal functional decline occurred more commonly with continuously higher levels of the biomarkers, especially of TGFß, transferrin, and LFABP. CONCLUSION: In combination, urinary levels of adiponectin and osteopontin predict chronic LN damage with similar accuracy as the GFR. Ongoing LN activity as reflected by high levels of LN activity biomarkers heralds renal functional decline. KEY MESSAGES: • Levels of osteopontin and adiponectin measured at the time of kidney biopsy are good predictors of histological damage with lupus nephritis. • Only about 20% of children with substantial kidney damage from lupus nephritis will have an abnormally low urine creatinine clearance. • Continuously high levels of biomarkers reflecting lupus nephritis activity are risk factors of declining renal function.

Discovery of SERPINA3 as a candidate urinary biomarker of lupus nephritis activity.

Objectives: We used an unbiased proteomics approach to identify candidate urine biomarkers (CUBMs) predictive of LN chronicity and pursued their validation in a larger cohort. Methods: In this cross-sectional pilot study, we selected urine collected at kidney biopsy from 20 children with varying levels of LN damage (discovery cohort) and performed proteomic analysis using isobaric tags for relative and absolute quantification (iTRAQ). We identified differentially excreted proteins based on degree of LN chronicity and sought to distinguish markers exhibiting different relative expression patterns using hierarchically clustered log10-normalized relative abundance data with linked and distinct functions by biological network analyses. For each CUBM, we performed specific ELISAs on urine from a validation cohort (n = 41) and analysis of variance to detect differences between LN chronicity, with LN activity adjustment. We evaluated for CUBM expression in LN biopsies with immunohistochemistry. Results: iTRAQ detected 112 proteins in urine from the discovery cohort, 51 quantifiable in all replicates. Simple analysis of variance revealed four differentially expressed, chronicity-correlated proteins (P-values < 0.05). Further correlation and network analyses led to selection of seven CUBMs for LN chronicity. In the validation cohort, none of the CUBMs distinguished LN chronicity degree; however, urine SERPINA3 demonstrated a moderate positive correlation with LN histological activity. Immunohistochemistry further demonstrated SERPINA3 staining in proximal tubular epithelial and endothelial cells. Conclusion: We identified SERPINA3, a known inhibitor of neutrophil cathepsin G and angiotensin II production, as a potential urine biomarker to help quantify LN activity.

Smoking Cessation Potential of Smartphone-Assisted Behavioral Therapy Coupled to Programmable Carbon Nanotube Membrane Nicotine Delivery Device.

Smoking tobacco continues to be a worldwide major cause of premature death. Although combined behavioral and pharmacotherapy interventions can increase the smoking cessation rate to nearly 25%, the combined approach is generally economically unattainable, and the low success rate leaves large populations at risk. Reviewed are treatments following primarily the principles of cognitive behavioral therapy (CBT) and nicotine replacement therapy (NRT), based on an addiction disease model with reduced dopamine receptors. Particular emphasis is placed on technology-assisted (Internet and smartphone applications) behavioral therapy to reduce economic costs. For smartphone apps, the established clinical strategies of the "5 A's of intervention" and the "5 R's of motivation" should be used. Counseling generally identifies self-expansion behaviors to stimulate dopamine cascades in reward pathways, but success rates are generally low because these patients have fewer dopamine receptors. Timing pharmacological therapy to induce dopamine cascades during self-expansion therapy offers an important increase in CBT success rates. An ideal platform would be a smartphone app, using best CBT practices along with a carbon nanotube-based programmable nicotine delivery device. These devices release variable doses of nicotine to provide relief from sustained withdrawal symptoms and relapse events, and reinforcement of self-expansion behaviors.

Abnormalities in 3-Dimensional Left Ventricular Mechanics With Anthracycline Chemotherapy Are Associated With Systolic and Diastolic Dysfunction.

OBJECTIVES: The objective of this study was to evaluate the changes in three-dimensional (3D) speckle-tracking echocardiography-derived measures of mechanics and their associations with systolic and diastolic dysfunction after anthracyclines. BACKGROUND: An improved understanding of the changes in 3D cardiac mechanics with anthracyclines may provide important mechanistic insight and identify new metrics to detect cardiac dysfunction. METHODS: A total of 142 women with breast cancer receiving doxorubicin (240 mg/m2) with or without trastuzumab underwent 3D speckle-tracking echocardiography at standardized intervals prior to, during, and annually after chemotherapy. Left ventricular ejection fraction (LVEF), global circumferential strain (GCS), global longitudinal strain (GLS), principal strain, twist, and torsion were quantified. Linear regression analyses defined the associations between clinical factors and 3D parameters. Linear regression models with cluster robust variance estimators determined the associations between 3D measures and 2-dimensional (2D) LVEF and Doppler-derived E/e' over time. RESULTS: There were significant abnormalities in 3D LVEF, GCS, GLS, and principal strain post-doxorubicin compared with control subjects (p < 0.001). The 3D parameters worsened post-anthracyclines, and only partially recovered to baseline over a median of 2.1 years (interquartile range: 1 to 4 years). Higher blood pressure and body mass index were associated with worse post-anthracycline 3D GCS and GLS, respectively. All 3D measures were associated with 2D LVEF at the same visit; only 3D LVEF, GCS, GLS, and principal strain were associated with 2D LVEF at subsequent visits (p < 0.05). In exploratory analyses, 3D LVEF and GCS were associated with subsequent systolic function independent of their corresponding 2D measures. The 3D LVEF, GCS, principal strain, and twist were significantly associated with concurrent, but not subsequent, E/e'. CONCLUSIONS: Anthracyclines result in early and persistent abnormalities in 3D mechanics. The 3D LVEF and strain measures are associated with concurrent and subsequent systolic dysfunction, and concurrent diastolic dysfunction. Future research is needed to define the mechanisms and clinical relevance of abnormal 3D mechanics.

Translation of combination nanodrugs into nanomedicines: lessons learned and future outlook.

The concept of nanomedicine is not new. For instance, some nanocrystals and colloidal drug molecules are marketed that improve pharmacokinetic characteristics of single-agent therapeutics. For the past two decades, the number of research publications on single-agent nanoformulations has grown exponentially. However, formulations advancing to pre-clinical and clinical evaluations that lead to therapeutic products has been limited. Chronic diseases such as cancer and HIV/AIDS require drug combinations, not single agents, for durable therapeutic responses. Therefore, development and clinical translation of drug combination nanoformulations could play a significant role in improving human health. Successful translation of promising concepts into pre-clinical and clinical studies requires early considerations of the physical compatibility, pharmacological synergy, as well as pharmaceutical characteristics (e.g. stability, scalability and pharmacokinetics). With this approach and robust manufacturing processes in place, some drug-combination nanoparticles have progressed to non-human primate and human studies. In this article, we discuss the rationale and role of drug-combination nanoparticles, the pre-clinical and clinical research progress made to date and the key challenges for successful clinical translation. Finally, we offer insight to accelerate clinical translation through leveraging robust nanoplatform technologies to enable implementation of personalised and precision medicine.

Urine Biomarkers to Predict Response to Lupus Nephritis Therapy in Children and Young Adults.

OBJECTIVE: To delineate urine biomarkers that forecast response to therapy of lupus nephritis (LN). METHODS: Starting from the time of kidney biopsy, patients with childhood-onset systemic lupus erythematosus who were diagnosed with LN were studied serially. Levels of 15 biomarkers were measured in random spot urine samples, including adiponectin, α-1-acid glycoprotein (AGP), ceruloplasmin, hemopexin, hepcidin, kidney injury molecule 1, monocyte chemotactic protein-1, lipocalin-like prostaglandin D synthase (LPGDS), transforming growth factor-ß (TGF-ß), transferrin, and vitamin D binding protein (VDBP). RESULTS: Among 87 patients (mean age 15.6 yrs) with LN, there were 37 treatment responders and 50 nonresponders based on the American College of Rheumatology criteria. At the time of kidney biopsy, levels of TGF-ß (p < 0.0001) and ceruloplasmin (p = 0.006) were significantly lower among responders than nonresponders; less pronounced differences were present for AGP, hepcidin, LPGDS, transferrin, and VDBP (all p < 0.05). By Month 3, responders experienced marked decreases of adiponectin, AGP, transferrin, and VDBP (all p < 0.01) and mean levels of these biomarkers were all outstanding (area under the receiver-operating characteristic curve ≥ 0.9) for discriminating responders from nonresponders. Patient demographics and extrarenal disease did not influence differences in biomarker levels between response groups. CONCLUSION: Low urine levels of TGF-ß and ceruloplasmin at baseline and marked reduction of AGP, LPGDS, transferrin, or VDBP and combinations of other select biomarkers by Month 3 are outstanding predictors for achieving remission of LN. If confirmed, these results can be used to help personalize LN therapy.

Programmable carbon nanotube membrane-based transdermal nicotine delivery with microdialysis validation assay.

To evaluate the performance of switchable carbon nanotubes (CNT) membrane devices for transdermal nicotine delivery, we have developed an in-vitro microdialysis method that allow us to detect variable transdermal fluxes of nicotine through CNT devices and can be applied directly to in-vivo studies. Microdialysis membranes were placed beneath the porcine skin and its nicotine levels increased 6-8 times when the CNT membrane on skin was turned from OFF to ON state by application of bias. Fluxes in the ON state were approximately 3 times that of commercial nicotine patches and switching times were less than two hours, thus suggesting the improved therapeutic potential of our device. Blue tooth enabled CNT devices that can be programmed by smartphone and coupled with remote counseling application for enhanced smoking cessation treatments.

Ischemia/reperfusion-induced alterations of enzymatic and signaling functions of the rat cardiac Na+/K+-ATPase: protection by ouabain preconditioning.

Cardiac glycosides (CG) are traditionally known as positive cardiac inotropes that inhibit Na+/K+-ATPase-dependent ion transport. CG also trigger-specific signaling pathways through the cardiac Na+/K+-ATPase, with beneficial effects in ischemia/reperfusion (I/R) injury (e.g., ouabain preconditioning, known as OPC) and hypertrophy. Our current understanding of hypersensitivity to CG and subsequent toxicity in the ischemic heart is mostly based on specific I/R-induced alterations of the Na+/K+-ATPase enzymatic function and has remained incomplete. The primary goal of this study was to investigate and compare the impact of I/R on Na+/K+-ATPase enzymatic and signaling functions. Second, we assessed the impact of OPC on both functions. Langendorff-perfused rat hearts were exposed to 30 min of ischemia and 30 min of reperfusion. At the inotropic concentration of 50 µmol/L, ouabain increased ERK and Akt phosphorylation in control hearts. In I/R hearts, this concentration did not induced positive inotropy and failed to induce Akt or ERK phosphorylation. The inotropic response to dobutamine as well as insulin signaling persisted, suggesting specific alterations of Na+/K+-ATPase. Indeed, Na+/K+-ATPase protein expression was intact, but the enzyme activity was decreased by 60% and the enzymatic function of the isoform with high affinity for ouabain was abolished following I/R. Strikingly, OPC prevented all I/R-induced alterations of the receptor. Further studies are needed to reveal the respective roles of I/R-induced modulations of Na+/K+-ATPase enzymatic and signaling functions in cardiomyocyte death.

Bullous skin lesions in an adult male: a diagnostic dilemma.

BACKGROUND: Henoch-Schönlein Purpura (HSP) is an IgA small-vessel vasculitis that is primarily a disease of childhood. Its presentation in adulthood is rare and has a more severe disease course. We present a case with an atypical presentation of this disease that was a diagnostic challenge for multiple providers. CASE REPORT: A 42-year-old man noticed bullous lesions over his ankles that spread to his entire legs over a few weeks. They later became necrotic and ulcerated areas. His primary care physician and 2 dermatologists could not reach a definitive diagnosis. He then presented to our hospital with new abdominal pain, rectal bleeding, and a new elevation in liver enzymes. A biopsy of his skin lesions led to the diagnosis of HSP. CONCLUSIONS: We discuss this highly unusual initial presentation with bullous skin lesions and liver enzyme abnormalities and explore the medical literature to understand its pathogenesis. Clinicians need to be aware of this rare presentation to avoid a delay in diagnosis and management.

Cancer and cardiovascular disease: the use of novel echocardiography measures to predict subsequent cardiotoxicity in breast cancer treated with anthracyclines and trastuzumab.

As the population of breast cancer survivors grows, it has become evident that chemotherapy has significant cardiotoxic side effects. Echocardiography is a noninvasive, cost-effective, and widely available imaging tool that is well positioned to serve as a primary modality for monitoring chemotherapy-induced cardiotoxicity. Although left ventricular ejection fraction is a standard measurement by which to monitor chemotherapy-induced cardiotoxicity, its predictive value in identifying subsequent cardiotoxicity is limited. More sophisticated echocardiography modalities may offer improved sensitivity and specificity for detecting chemotherapy-induced cardiotoxicity. These include tissue Doppler imaging measures, newer techniques based upon two- and three-dimensional strain and torsion analysis, and three-dimensional measures of cardiac size. While these modalities are not all currently part of clinical practice, a body of data supporting their use is steadily building. More research remains to be performed, and noninvasively detecting cancer therapy-induced cardiac dysfunction at the earliest stages is of increasing interest.

A biochemically active MCM-like helicase in Bacillus cereus.

The mini-chromosome maintenance (MCM) proteins serve as the replicative helicases in archaea and eukaryotes. Interestingly, an MCM homolog was identified, by BLAST analysis, within a phage integrated in the bacterium Bacillus cereus (Bc). BcMCM is only related to the AAA region of MCM-helicases; the typical amino-terminus is missing and is replaced by a segment with weak homology to primases. We show that BcMCM displays 3'-->5' helicase and ssDNA-stimulated ATPase activity, properties that arise from its conserved AAA domain. Isolated BcMCM is a monomer in solution but likely forms the functional oligomer in vivo. We found that the BcMCM amino-terminus can bind ssDNA and harbors a zinc atom, both hallmarks of the typical MCM amino-terminus. No BcMCM-catalyzed primase activity could be detected. We propose that the divergent amino-terminus of BcMCM is a paralog of the corresponding region of MCM-helicases. A divergent amino terminus makes BcMCM a useful model for typical MCM-helicases since it accomplishes the same function using an apparently unrelated structure.