Feasibility of a Composite Measure of Pulmonary Vascular Impedance and Application to Patients with Chronic RV Failure Post LVAD Implant.

Pulmonary vascular impedance (PVZ) describes RV afterload in the frequency domain and has not been studied extensively in LVAD patients. We sought to determine (1) feasibility of calculating a composite (c)PVZ using standard of care (SoC), asynchronous, pulmonary artery pressure (PAP) and flow (PAQ) waveforms; and (2) if chronic right ventricular failure (RVF) post-LVAD implant was associated with changes in perioperative cPVZ.PAP and PAQ were obtained via SoC procedures at three landmarks: T(1), Retrospectively, pre-operative with patient conscious; and T(2) and T(3), prospectively with patient anesthetized, and either pre-sternotomy or chest open with LVAD, respectively. Additional PAP's were taken at T(4), following chest closure; and T(5), 4-24 h post chest closure. Harmonics (z) were calculated by Fast Fourier Transform (FFT) with cPVZ(z) = FFT(PAP)/FFT(PAQ). Total pulmonary resistance Z(0); characteristic impedance Zc, mean of cPVZ(2-4); and vascular stiffness PVS, sum of cPVZ(1,2), were compared at T(1,2,3) between +/-RVF groups.Out of 51 patients, nine experienced RVF. Standard hemodynamics and changes in cPVZ-derived parameters were not significant between groups at any T.In conclusion, cPVZ calculated from SoC measures is possible. Although data that could be obtained were limited it suggests no difference in RV afterload for RVF patients post-implant. If confirmed in larger studies, focus should be placed on cardiac function in these subjects.

Cardiac amyloidosis worsens prognosis in patients with heart failure: findings from the PREVAMIC study.

BACKGROUND AND OBJECTIVES: Cardiac amyloidosis (CA) is a common pathology in elderly patients that usually presents as heart failure (HF). However, it is not clear whether CA associated with HF has a worse prognosis compared with HF due to other etiologies. MATERIAL AND METHODS: Prospective, observational cohort study that recruited patients ≥65 years of age with HF in 30 Spanish centers. The cohort was divided according to whether the patients had AC or not. Patients were followed for 1 year. RESULTS: A total of 484 patients were included in the analysis. The population was elderly (median 86 years) and 49% were women CA was present in 23.8 % of the included patients. In the CA group, there was a lower prevalence of diabetes mellitus and valvular disease. At one year of follow-up, mortality was significantly more frequent in patients with CA compared to those without (33.0 vs.14.9%, p < 0.001). However, there were no differences between both groups in visits to the emergency room or readmissions. In the multivariate analysis, the variables that were shown to predict all-cause mortality at one year of follow-up were chronic kidney disease (HR 1.75 (1.01-3.05) p 0.045), NT-proBNP levels (HR 2.51 (1.46-4.30) p < 0.001), confusion (HR 2.05 (1.01-4.17), p 0.048), and the presence of CA (HR 1.77 (1.11-2.84), p 0.017). CONCLUSION: The presence of CA in elderly patients with HF is related to a worse prognosis at one year of follow-up. Early diagnosis of the pathology and multidisciplinary management can help improve patient outcomes.

Longitudinal outcomes of obeticholic acid therapy in ursodiol-nonresponsive primary biliary cholangitis: Stratifying the impact of add-on fibrates in real-world practice.

BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.

Pneumocystis carinii causes a distinctive interstitial pneumonia in immunocompetent laboratory rats that had been attributed to "rat respiratory virus".

A prevalent and distinctive infectious interstitial pneumonia (IIP) of immunocompetent laboratory rats was suspected to be caused by a putative virus, termed rat respiratory virus, but this was never substantiated. To study this disease, 2 isolators were independently populated with rats from colonies with endemic disease, which was perpetuated by the regular addition of naive rats. After Pneumocystis was demonstrated by histopathology and polymerase chain reaction (PCR) in the lungs of rats from both isolators and an earlier bedding transmission study, the relationship between Pneumocystis and IIP was explored further by analyzing specimens from 3 contact transmission experiments, diagnostic submissions, and barrier room breeding colonies, including 1 with and 49 without IIP. Quantitative (q) PCR and immunofluorescence assay only detected Pneumocystis infection and serum antibodies in rats from experiments or colonies in which IIP was diagnosed by histopathology. In immunocompetent hosts, the Pneumocystis concentration in lungs corresponded to the severity and prevalence of IIP; seroconversion occurred when IIP developed and was followed by the concurrent clearance of Pneumocystis from lungs and resolution of disease. Experimentally infected immunodeficient RNU rats, by contrast, did not seroconvert to Pneumocystis or recover from infection. qPCR found Pneumocystis at significantly higher concentrations and much more often in lungs than in bronchial and nasal washes and failed to detect Pneumocystis in oral swabs. The sequences of a mitochondrial ribosomal large-subunit gene region for Pneumocystis from 11 distinct IIP sources were all identical to that of P. carinii. These data provide substantial evidence that P. carinii causes IIP in immunocompetent rats.

Prevalence and impact on prognosis of right-bundle branch block in patients with acute heart failure: Findings from the RICA registry.

OBJECTIVES: This work aims to determine the prevalence, characteristics, and impact on prognosis of right bundle branch block (RBBB) in a cohort of acute heart failure (AHF) patients. METHODS: We prospectively analyzed 3,638 AHF patients included in the RICA registry (National Heart Failure Registry of the Spanish Internal Medicine Society). We independently analyzed the relationship between baseline and clinical characteristics and the presence of RBBB as well as the potential impact of RBBB on 1-year all-cause mortality and a composite endpoint of 90-day post-discharge hospitalization or death. RESULTS: The prevalence of RBBB was 10.9%. Patients with RBBB were older, a higher proportion were male, had more pulmonary comorbidities, had higher left ventricular ejection fraction values, and had worse functional status. There were no differences in risk for patients with RBBB, with an adjusted hazard ratio (95% confidence interval) for 1-year mortality of 1.05 (0.83-1.32), and for the composite endpoint of 90-day post-discharge hospitalization or death of 0.97 (0.74-1.25). These results were consistent on the sensitivity analyses. CONCLUSIONS: Few patients with AHF present with RBBB, which is consistently associated with advanced age, male sex, pulmonary comorbidities, preserved left ventricular ejection fraction, and worse functional status. Nonetheless, after considering these factors, RBBB in AHF patients is not associated with worse outcomes.

Feline leukemia virus outbreak in the critically endangered Iberian lynx (Lynx pardinus): high-throughput sequencing of envelope variable region A and experimental transmission.

The Iberian lynx is the most endangered felid species. During winter/spring 2006/7, a feline leukemia virus (FeLV) outbreak of unexpected virulence killed about 2/3 of the infected Iberian lynxes. All FeLV-positive animals were co-infected with feline hemoplasmas. To further characterize the Iberian lynx FeLV strain and evaluate its potential virulence, the FeLV envelope gene variable region A (VRA) mutant spectrum was analyzed using the Roche 454 sequencing technology, and an in vivo transmission study of lynx blood to specified-pathogen-free cats was performed. VRA mutations indicated weak apolipoprotein B mRNA editing enzyme and catalytic polypeptide-like cytidine deaminase (APOBEC) restriction of FeLV replication, and variants characteristic of aggressive FeLV strains, such as FeLV-C or FeLV-A/61C, were not detected. Cats exposed to FeLV/Candidatus Mycoplasma haemominutum-positive lynx blood did not show a particularly severe outcome of infection. The results underscore the special susceptibility of Iberian lynxes to infectious diseases.

Elder abuse and mortality: the role of psychological and social wellbeing.

BACKGROUND: Elder abuse is a pervasive human right and public health issue. OBJECTIVES: We aimed to examine the mortality associated with elder abuse across levels of psychological and social factors. METHODS: The Chicago Health and Aging Project (CHAP) is a prospective population-based cohort study that began in 1993. A subset of these participants enrolled between 1993 and 2005 had elder abuse reported to social services agencies (n = 113). Mortality was ascertained during follow-up and with the National Death Index. Psychosocial factors (depression, social network and social engagement) were assessed during the CHAP interview. Cox proportional hazard models were used to assess the mortality of elder abuse across levels of psychosocial factors using time-varying covariate analyses. RESULTS: The median follow-up time for the cohort (n = 7,841) was 7.6 years (interquartile range 3.8-12.4 years). In multivariate analyses, those with highest (hazard ratio (HR) 2.60, 95% CI 1.58-4.28) and middle levels (HR 2.18, 95% CI 1.19-3.99) of depressive symptoms had an increased mortality risk associated with elder abuse. For social network, those with lowest (HR 2.50, 95% CI 1.62-3.87) and middle levels (HR 2.65, 95% CI 1.52-4.60) of social network had increased mortality risk associated with elder abuse. For social engagement, those with lowest (HR 2.32, 95% CI 1.47-3.68) and middle levels (HR 2.59, 95% CI 1.65-5.45) of social engagement had increased mortality risk associated with elder abuse. Among those with lowest levels of depressive symptoms, highest levels of social network and social engagement, there was no significant effect of reported or confirmed elder abuse on mortality risk. CONCLUSION: Mortality risk associated with elder abuse was most prominent among those with higher levels of depressive symptoms and lower levels of social network and social engagement.

Patients' preferences for treatment with the new direct acting antiviral therapies for chronic hepatitis C virus infection.

OBJECTIVES: The efficacy of new direct-acting antivirals (DAAs) in treating hepatitis C infection can depend on treatment adherence, which may be influenced by the patient's current lack of awareness of the disease. This study set out to understand the treatment naïve chronic hepatitis C patients' preferences for new DAAs (attributes) and to compile information about the diagnosis process. MATERIAL AND METHOD: Spanish quantitative market research study conducted between November 2018 and January 2019 to assess the posology preferences of treatment-naïve patients with chronic hepatitis C before starting treatment (seen by hepatologists and infectious diseases specialists). A telephone interview was carried out to collect demographic, diagnostic and treatment preference data, consisting of two dosing OPTIONS: 1) three tablets/day (single dose), at the same time, with food (8 weeks). 2) single tablet/day, at any time with/without food (12 weeks). A descriptive analysis of pooled results was performed. RESULTS: 104 patients (mean age: 49 years) with hepatitis C diagnosed 7.3±9.7 years ago (average), mainly in primary care (PC) (42%). The most common reasons for not having started treatment were health problems/comorbidities (31%). Fifty-eight percent of patients were not informed about the available treatments. Seventy-two percent of patients preferred a simple tablet/day, at any time, with/without food (12 weeks), and considered compatibility with other treatments, side effects, ease of administration, treatment duration and the number of tablets to be very important. DISCUSSION: Patient preferences are mainly driven by dosing flexibility and simplicity, including freedom to take the medication with/without food. The role of PC in the diagnosis should be taken into account. There are still patients who are untreated after diagnosis.

Unusual presentation of intussusception: Gallstone ileus.

Gallstone ileus is a rare pathology, occurring in an estimated 0.5% of cases, which preferentially affect females and the elderly population. This rare pathology is the result of a fistulous connection between the bowel and gallbladder. This connection allows gallstones to pass into the bowel leading to mechanical obstruction. On rare occasions the enteric gallstone can act as a lead point causing intussusception. We present a rare case of intussusception secondary to gallstone ileus in a young, relatively asymptomatic patient. CT played a critical role in diagnosis and appropriate management of our patient.

Heat rectification with a minimal model of two harmonic oscillators.

We study heat rectification in a minimalistic model composed of two unequal atoms subjected to linear forces and in contact with effective Langevin baths induced by Doppler lasers. Analytic expressions of the heat currents in the steady state are spelled out. Asymmetric heat transport is found in this linear system if both the bath temperatures and the temperature-dependent bath-system couplings are exchanged. The model can be realized with two ions in either common or individual traps. This physical setting allows for a natural temperature dependence of the coupling to the baths. We also explore the parameter space of the model to optimize asymmetric heat current and find conditions for maximal rectification. High rectification corresponds to a good match of the power spectra of the ions for forward temperature bias and mismatch for reverse bias, which may be understood by the behavior of dissipative normal modes.

Early regeneration of thymic progenitors in rhesus macaques infected with simian immunodeficiency virus.

The thymus plays a critical role in the maturation and production of T lymphocytes and is a target of infection by human immunodeficiency virus (HIV) and the related simian immunodeficiency virus (SIV). Using the SIV/macaque model of AIDS, we examined the early effects of SIV on the thymus. We found that thymic infection by SIV resulted in increased apoptosis 7-14 d after infection, followed by depletion of thymocyte progenitors by day 21. A marked rebound in thymocyte progenitors occurred by day 50 and was accompanied by increased levels of cell proliferation in the thymus. Our results demonstrate a marked increase in thymic progenitor activity very early in the course of SIV infection, long before marked declines in peripheral CD4(+) T cell counts.

Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes.

Clinical evidence suggests that cellular immunity is involved in controlling human immunodeficiency virus-1 (HIV-1) replication. An animal model of acquired immune deficiency syndrome (AIDS), the simian immunodeficiency virus (SIV)-infected rhesus monkey, was used to show that virus replication is not controlled in monkeys depleted of CD8+ lymphocytes during primary SIV infection. Eliminating CD8+ lymphocytes from monkeys during chronic SIV infection resulted in a rapid and marked increase in viremia that was again suppressed coincident with the reappearance of SIV-specific CD8+ T cells. These results confirm the importance of cell-mediated immunity in controlling HIV-1 infection and support the exploration of vaccination approaches for preventing infection that will elicit these immune responses.

Variation in ecosystem function in Appalachian streams along an acidity gradient.

Acidification is a widespread phenomenon that damages aquatic systems, and it has been the focus of intensive management efforts. While most management has focused on community structure as an endpoint, ecosystem function is also sensitive to acidification and important in stream health. We examined how a key ecosystem function in streams, leaf breakdown, varied along a gradient of pH resulting from acid deposition, natural conditions, and liming. We also measured how invertebrate and microbial assemblage structure and microbial function were related to altered leaf breakdown rates. Leaf breakdown rates declined more than threefold along a gradient of stream acidity from pH 6.8 to 4.9. The diversity of leaf-shredding invertebrates, bacteria, and fungi showed little response to variation in pH. The abundance of one acid-sensitive caddisfly, Lepidostoma, declined with acidification, and Lepidostoma abundance explained 37% of the variation in leaf breakdown rates among sites. Microbial respiration was suppressed along the acidity gradient, although the pattern was weaker than that for breakdown rate. In short-term laboratory incubations, microbes at acidic and circumneutral sites demonstrated adaptation to ambient pH. The activity of microbial extracellular enzymes was strongly influenced by pH. In particular, the pattern of activity of phosphatase indicated increasing P limitation of microbes with increasing acidification. Our results show that leaf breakdown is a sensitive tool for examining the response of stream function to acidification and also for defining the mechanisms that drive functional response. Future management efforts should focus on key taxa that are particularly sensitive and effective at shredding leaves and also the role of shifting acidity in mediating the availability of phosphorus to microbial films that are important for stream function.

Histopathology of naturally transmitted "rat respiratory virus": progression of lesions and proposed diagnostic criteria.

Rat respiratory virus (RRV) is the working name for a novel respiratory pathogen of laboratory rats in North America, Europe, and Asia. Although the agent has not been definitively identified, evidence supports a viral etiology. Because no serologic or molecular assays for RRV are available, diagnosis depends on histopathologic evaluation of the lung. We introduced 104 Wistar Han rats, free of known pathogens and of RRV-associated lesions, into a rat production colony positive for RRV-type lesions, but free of other histologic, serologic, or microbiologic evidence of infectious disease. Lungs of 8 of the naïve rats were examined grossly and microscopically each week, weeks 0-13. Irregular gray-white lesions suggestive of interstitial pneumonia were grossly evident from weeks 6 through 13. Primary histopathologic evaluation of all lungs by one pathologist found multifocal, lymphohistiocytic interstitial pneumonia or prominent perivascular lymphoid cuffing from weeks 5 through 13. Based on results of the initial evaluation, diagnostic criteria for RRV infection (i.e., changes seen only after exposure to the RRV-positive colony) were tentatively selected and used by 2 other pathologists to classify each lung as RRV positive, RRV equivocal, or RRV negative. The secondary evaluation found 95% concordance in RRV diagnosis between pathologists, and correlated well with the initial evaluation, thus confirming the consistency of the criteria. These data show that RRV-naïve rats introduced into an RRV-endemic colony develop equivocal microscopic lesions of RRV by 5 weeks of exposure, and positive diagnostic lesions by 7 weeks. Interstitial pneumonia becomes grossly evident after 6 weeks of exposure.

Cardiac hemodynamic profiles and pro-B-type natriuretic Peptide in cirrhotic patients undergoing liver transplantation.

BACKGROUND: The aim of our study was to determine concentrations of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with cirrhosis, thereby describing the hemodynamic and cardiac profiles to verify the existence of cirrhotic cardiomyopathy. METHODS: Clinical data, NT-proBNP levels, echocardiography, and right heart hemodynamic measurements were performed on all patients undergoing liver transplantation for cirrhosis. RESULTS: Our patients showed a hyperdynamic circulation with elevated left-sided pressures despite high cardiac outputs. This observation suggested abnormalities in left ventricular diastolic compliance. We verified these results, because our cohort showed a significant left ventricular mass index and, consequently, diastolic dysfunction. Mean NT-proBNP levels were high. The great expansion of central volume may explain these results and the later development of left ventricular hypertrophy. CONCLUSION: We concluded that elevated concentrations of NT-proBNP indicated the presence of hyperdynamic syndrome and cardiac dysfunction.

N-terminal brain natriuretic peptide as a diagnostic test in cirrhotic patients with pulmonary arterial hypertension.

BACKGROUND: The aim of this study was to assessed the correlation of N-terminal natriuretic peptide type B (NT-proBNP) with echocardiographic and hemodynamic indexes of right ventricular (RV) function and to evaluate the sensitivity and specificity of Doppler echocardiography in the diagnosis of portopulmonary hypertension. METHODS: All patients underwent liver transplantation for cirrhosis. We obtained clinical data, NT-proBNP levels, echocardiography, and right heart hemodynamic measurements before transplantation. RESULTS: Patients with pulmonary hypertension displayed significantly higher levels of NT-proBNP. They also showed higher model for End-stage Liver Disease scores and higher indices of RV overload on cardiac hemodynamics. The negative predictive value of echocardiography to identify pulmonary hypertension was 83%. A correlation was not observed between systolic pulmonary artery pressures measured by the two methods; however, NTproBNP showed a trend toward a significant correlation with mean pulmonary pressure as determined by hemodynamics (r = .3; P < .01). CONCLUSION: We concluded that NT-proBNP values showed significant correlations with pulmonary hypertension that could assist in a noninvasive diagnoseis for this group of patients.

Asymmetric heat transport in ion crystals.

We numerically demonstrate heat rectification for linear chains of ions in trap lattices with graded trapping frequencies, in contact with thermal baths implemented by optical molasses. To calculate the local temperatures and heat currents we find the stationary state by solving a system of algebraic equations. This approach is much faster than the usual method that integrates the dynamical equations of the system and averages over noise realizations.

Hemoconcentration as a prognostic factor after hospital discharge in acute heart failure in the RICA registry. / Hemoconcentración como predictor de supervivencia al año de ingreso por insuficiencia cardiaca aguda en el registro RICA.

OBJECTIVE: Several studies have reported that a higher degree of hemoconcentration in patients admitted for the treatment of acute heart failure (HF) constitutes a favorable prognostic factor in the year following the index episode. The objective of this study was to evaluate whether the highest degree of hemoconcentration at 3 months after admission for HF is also a prognostic factor for mortality and/or readmission in the 12 months after admission. PATIENTS AND METHOD: The hemoconcentration group was the upper quartile of the sample distributed according to hemoglobin increase at month 3 after discharge with respect to hemoglobin at the time of admission for HF in a multicenter prospective cohort of 1,659 subjects with HF. RESULTS: The mean follow-up until the first event was 294 days, and a total of 487 deaths and 1,125 readmissions were recorded. The hemoconcentration group had a lower risk of mortality or readmission for any cause (RR=0.75, 95% CI: 0.51-1.09 and RR=0.86, 95% CI: 0.70-1.05), although statistical significance was lost after multivariate analysis, while it was retained for other factors with recognized negative impact on the prognosis of patients with HF, such as age and functional class. CONCLUSIONS: The degree of hemoconcentration at 3 months after admission for HF is not prognostic of readmission or death in the subsequent year.

Disabled is a putative adaptor protein that functions during signaling by the sevenless receptor tyrosine kinase.

DRK, the Drosophila homolog of the SH2-SH3 domain adaptor protein Grb2, is required during signaling by the sevenless receptor tyrosine kinase (SEV). One role of DRK is to provide a link between activated SEV and the Ras1 activator SOS. We have investigated the possibility that DRK performs other functions by identifying additional DRK-binding proteins. We show that the phosphotyrosine-binding (PTB) domain-containing protein Disabled (DAB) binds to the DRK SH3 domains. DAB is expressed in the ommatidial clusters, and loss of DAB function disrupts ommatidial development. Moreover, reduction of DAB function attenuates signaling by a constitutively activated SEV. Our biochemical analysis suggests that DAB binds SEV directly via its PTB domain, becomes tyrosine phosphorylated upon SEV activation, and then serves as an adaptor protein for SH2 domain-containing proteins. Taken together, these results indicate that DAB is a novel component of the SEV signaling pathway.