Annalisa De Silvestri

A meta-analysis of remote monitoring of heart failure patients

OBJECTIVES The purpose of this study was to assess the effect of remote patient monitoring (RPM) on the outcome of chronic heart failure (HF) patients. BACKGROUND RPM via regularly scheduled structured telephone contact between patients and health care providers or electronic transfer of physiological data using remote access technology via remote external, wearable, or implantable electronic devices is a growing modality to manage patients with chronic HF. METHODS After a review of the literature published between January 2000 and October 2008 on a multidisciplinary heart failure approach by either usual care (in-person visit) or RPM, 96 full-text articles were retrieved: 20 articles reporting randomized controlled trials (RCTs) and 12 reporting cohort studies qualified for a meta-analysis. RESULTS Respectively, 6,258 patients and 2,354 patients were included in RCTs and cohort studies. Median follow-up duration was 6 months for RCTs and 12 months for cohort studies. Both RCTs and cohort studies showed that RPM was associated with a significantly lower number of deaths (RCTs: relative risk [RR]: 0.83, 95% confidence interval [CI]: 0.73 to 0.95, p = 0.006; cohort studies: RR: 0.53, 95% CI: 0.29 to 0.96, p < 0.001) and hospitalizations (RCTs: RR: 0.93, 95% CI: 0.87 to 0.99, p = 0.030; cohort studies: RR: 0.52, 95% CI: 0.28 to 0.96, p < 0.001). The decrease in events was greater in cohort studies than in RCTs. CONCLUSIONS RPM confers a significant protective clinical effect in patients with chronic HF compared with usual care.

Circulating Endothelial Progenitor Cells in Preterm Infants with Bronchopulmonary Dysplasia

RATIONALE The new form of bronchopulmonary dysplasia (BPD) is characterized by lung immaturity with disrupted alveolar and capillary development after extremely premature birth, but the mechanism of impaired lung vascular formation is still not completely understood. OBJECTIVES We tested the hypothesis that reduced numbers of circulating endothelial progenitor cells at birth are associated with the development of BPD. METHODS We studied ninety-eight preterm infants with gestational age of less than 32 weeks or a birth weight less than 1,500 g. Endothelial colony-forming cells (ECFCs) were assessed by clonogenic analysis in infants for whom cord blood was available. The proportion of circulating endothelial and hematopoietic cells was measured by flow cytometry at birth, at 48 hours, and at 7 days of life. MEASUREMENTS AND MAIN RESULTS ECFCs in cord blood were lower in infants who later developed BPD (median [range]: 0.00 [0.00-0.48] vs. 2.00 [0.00-21.87]; P = 0.002). ECFCs decreased with decreasing gestational age (r = 0.41; P = 0.02), but even at extremely low gestational ages, infants with higher numbers of ECFCs were protected from BPD. The endothelial and hematopoietic cell subsets studied by flow cytometry were comparable in infants with and without BPD and rapidly decreased after birth. CONCLUSIONS ECFCs are low at extremely low gestational ages and increase during gestation; extremely preterm infants who display lower numbers at birth have an increased risk of developing BPD. Our findings suggest that decreased ECFCs following extremely preterm birth may be associated with the risk for developing lung vascular immaturity characteristic of new BPD.

Economic impact of remote patient monitoring: an integrated economic model derived from a meta-analysis of randomized controlled trials in heart failure.

To assess the cost‐effectiveness and the cost utility of remote patient monitoring (RPM) when compared with the usual care approach based upon differences in the number of hospitalizations, estimated from a meta‐analysis of randomized clinical trials (RCTs).

CYP ENZYME POLYMORPHISMS AND SUSCEPTIBILITY TO HCV-RELATED CHRONIC LIVER DISEASE AND LIVER CANCER

Cancer risk can be influenced by the exposure to endogenous or environmental toxins. Polymorphic enzymes involved in the metabolic activation/detoxification of carcinogens may account for individual variations of risk. We studied the polymorphisms of five enzymes of the P450 superfamily, CYP1A1, CYP1A2, CYP2D6, CYP2E1 and CY3A4, as risk factors for liver disease progression and cancer in hepatitis C virus‐infected patients. CYP genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism or allele‐specific PCR. Different stages of disease were considered, as follows: 90 asymptomatic carriers and 87 chronic hepatitis, 92 cirrhosis and 91 hepatocellular carcinoma (HCC) cases. Reference allele frequencies were obtained from 99 blood donors. Allele distributions among categories were compared using the χ2 test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to express relative risks. Independent associations were modeled by correspondence analysis and logistic regression. Frequencies of the CYP1A1 highly inducible alleles, MspI m2 and Val, were increased in liver disease patients compared with carriers; no specific association with HCC was found. The high‐activity CYP2E1 c2 allele was underrepresented among HCC patients with respect to other HCV categories, including cirrhosis. CYP2D6 poor metabolizer (PM) genotypes were significantly more frequent in healthy subjects (7.1%) and carriers (11.1%) than in hepatitis/cirrhosis (4.6%) and HCC (1.2%) patients. This was confirmed by multivariable analysis. PM genotypes protected against progressive disease as ORs reduced proportionally to stage. The age at diagnosis for HCC was anticipated in non‐PM individuals. No differences were seen for CYP1A2 and CYP3A4 genes. Polymorphic variants of CYP genes may contribute to the progression of liver disease and HCC risk in HCV‐infected subjects.

In Vitro Megakaryocyte Differentiation and Proplatelet Formation in Ph-Negative Classical Myeloproliferative Neoplasms: Distinct Patterns in the Different Clinical Phenotypes

Background Ph-negative myeloproliferative neoplasms (MPNs) are clonal disorders that include primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET). Although the pathogenesis of MPNs is still incompletely understood, an involvement of the megakaryocyte lineage is a distinctive feature. Methodology/Principal Findings We analyzed the in vitro megakaryocyte differentiation and proplatelet formation in 30 PMF, 8 ET, 8 PV patients, and 17 healthy controls (CTRL). Megakaryocytes were differentiated from peripheral blood CD34+ or CD45+ cells in the presence of thrombopoietin. Megakaryocyte output was higher in MPN patients than in CTRL with no correlation with the JAK2 V617F mutation. PMF-derived megakaryocytes displayed nuclei with a bulbous appearance, were smaller than ET- or PV-derived megakaryocytes and formed proplatelets that presented several structural alterations. In contrast, ET- and PV-derived megakaryocytes produced more proplatelets with a striking increase in bifurcations and tips compared to both control and PMF. Proplatelets formation was correlated with platelet counts in patient peripheral blood. Patients with pre-fibrotic PMF had a pattern of megakaryocyte proliferation and proplatelet formation that was similar to that of fibrotic PMF and different from that of ET. Conclusions/Significance In conclusion, MPNs are associated with high megakaryocyte proliferative potential. Profound differences in megakaryocyte morphology and proplatelet formation distinguish PMF, both fibrotic and prefibrotic, from ET and PV.

Emerging mutations at virological failure of HAART combinations containing tenofovir and lamivudine or emtricitabine.

Objective:To compare the emergence of drug-resistant HIV variants at failure of lamivudine (3TC)/tenofovir (TDF)-containing or emtricitabine (FTC)/TDF-containing HAART as a consequence of the different 3TC and FTC intracellular half-lives. Design:Retrospective evaluation of 859 patients selected from an Italian HIV resistance database (Antiretroviral Resistance Cohort Analysis). Methods:Patients were selected for analysis if treated with a HAART whose nucleoside/nucleotide reverse transcriptase inhibitor backbone was either 3TC/TDF or FTC/TDF; if they experienced a virological failure after at least 6 months of plasma HIV-RNA undetectability; and if HIV genotypes before treatment and at failure were available. Univariate and multivariate logistic regression analyses were done to detect predictors of resistance mutations emerging at failure. Results:Of 714 patients failing with 3TC/TDF and 145 with FTC/TDF, 35.8 and 21.1% were in Centers for Disease Control and Prevention stage C, and 8.8 and 15.2% were on first-line HAART, respectively. At multivariate analysis, the emergence of K70R (P = 0.002), M184V (P = 0.031), T215F (P = 0.020) and Y181C (P = 0.005) was significantly more common in 3TC-treated than in FTC-treated patients, with an odds ratio of 4, 1.56, 1.89 and 3.84, respectively. Conclusion:Despite their close structural similarity, 3TC and FTC are associated with a significantly different rate of drug resistance at treatment failure when combined with TDF in HAART regimens independently of the third drug used.

A Systematic Review and Meta-Analysis of Ginkgo biloba in Neuropsychiatric Disorders: From Ancient Tradition to Modern-Day Medicine

Ginkgo biloba (Gb) has demonstrated antioxidant and vasoactive properties as well as clinical benefits in several conditions such as ischemia, epilepsy, and peripheral nerve damage. Additionally, Gb is supposed to act as potential cognitive enhancer in dementia. So far, several trials have been conducted to investigate the potential effectiveness of Gb in neuropsychiatric conditions. However, the results of these studies remain controversial. We conducted a systematic review and a meta-analysis of three randomised controlled trials in patients with schizophrenia and eight randomised controlled trials in patients with dementia. Gb treatment reduced positive symptoms in patients with schizophrenia and improved cognitive function and activities of daily living in patients with dementia. No effect of Gb on negative symptoms in schizophrenic patients was found. The general lack of evidence prevents drawing conclusions regarding Gb effectiveness in other neuropsychiatric conditions (i.e., autism, depression, anxiety, attention-deficit hyperactivity disorder, and addiction). Our data support the use of Gb in patients with dementia and as an adjunctive therapy in schizophrenic patients.

Influence of HLA-DQ2 and DQ8 on severity in celiac Disease.

Background HLA-DQB1*02 homozygosity was shown to be more common in patients with complicated rather than uncomplicated celiac disease (CD). Goals To study HLA-DQA1 and DQB1 profile in adult patients with different forms of CD, including patients with complicated and potential CD, the most affected and the most preserved histologic end of the pathologic celiac spectrum. Study HLA-DQA1 and DQB1 molecular typing was performed in 218 adult CD patients (169 with uncomplicated CD, 27 with complicated CD, and 22 with potential CD) and 224 healthy stem cell donors. HLA-DQA1 and DQB1 gene polymorphism was analyzed using polymerase chain reaction sequence-specific primers and/or reverse polymerase chain reaction sequence-specific oligonucleotides techniques. Results As expected, the frequency of HLA-DQB1*02 allele, DQB1*02 homozygosity, and DQB1*0302 gene were statistically different in the 4 groups. However, multivariate analysis demonstrated that patients with potential CD have a higher frequency of both HLA-DQB1*0302 and HLA-DQB1*0603 alleles and a reduced frequency of DQB1*02 homozygosity compared with patients with uncomplicated and complicated CD. Conclusions The increased frequency of DQB1*0302 and the reduced frequency of DQB1*02 homozygosity in potential CD is consistent with the idea that different clinical/pathologic evolutions might be related to different immunogeneses. This could be clinically relevant in the future.

Kinetics of T-Lymphocyte Subsets and Posttransplant Opportunistic Infections in Heart and Kidney Transplant Recipients

Background. The potential use of T-lymphocyte measurements as infection risk markers after solid organ transplant has not been fully investigated. We analyzed the kinetics of T-lymphocyte subsets within the first 8 months posttransplant and their correlation with opportunistic infections (OIs) in solid organ transplant recipients. Methods. Serial measurement of CD4 and CD8 T cells was performed retrospectively in 48 heart transplant recipients (HTR) and 42 kidney transplant recipients (KTR). Generalized estimating equation models were used to analyze longitudinal data separately for HTR and KTR. Results. An initial CD4 T-cell drop (at months 1 and 2, in HTR and KTR, respectively) coincided with the peak of OIs. HTR with a low nadir CD4 T-cell count (≤200/&mgr;L) showed poor CD4 T-cell recovery (175±277 cells/&mgr;L at baseline vs 242±99 cells/&mgr;L at month 8) and their CD8 T cells increased from 153±194 cells/&mgr;L at baseline to 601±399 cells/&mgr;L at month 8. KTR with a low nadir CD4 T-cell count (≤200/&mgr;L) showed a modest CD4 T-cell recovery (138±46 cells/&mgr;L at baseline vs. 440±448 cells/&mgr;L at month 8), and their CD8 T cells increased from 90±41 cells/&mgr;L at baseline to 450±242 cells/&mgr;L at month 8. HTR developing OIs had lower CD4 (P<0.001) and CD8 T cells (P=0.001) than those without infections, whereas in KTR the risk for OIs seemed restricted to patients with low CD8 T cells. HTR with OIs had a low CD4/CD8 T-cell ratio, whereas KTR had a high CD4/CD8 T-cell ratio. Conclusions. Determination of T-lymphocyte subsets is a simple and effective parameter to identify patients at risk of developing OIs.

Efficacy of low-dose rituximab for the treatment of mixed cryoglobulinemia vasculitis: Phase II clinical trial and systematic review

OBJECTIVE To evaluate whether rituximab at a low dose of 250 mg/m(2) × 2 may be as effective as at higher dosages, most commonly 375 mg/m(2)×4, used in previous studies on the treatment of patients with refractory mixed cryoglobulinemia (MC) vasculitis associated with hepatitis C virus (HCV) infection. METHODS We conducted a phase 2, single-arm two-stage trial (EUDRACT n. 2008-000086-38) of low-dose rituximab in 52 patients with HCV-associated MC who were ineligible/intolerant or non-responder to antiviral therapy. The primary outcomes were response of vasculitis evaluated by the Birmingham Vasculitis Activity Score (BVAS) at months 3, 6 and 12, rate of relapses and time to relapse, and rate of adverse events. Our data were compared with those reported in 19 published studies selected among 291 reviewed in a literature search. RESULTS The cumulative response rate (complete and partial) at month 3 was 81% in our patients, and 86% in 208 patients from studies using high-dose rituximab. The relapse rate and median time to relapse were, respectively, 41% and 6 months in our study, and 32% and 7 months in high-dose studies. Treatment-related adverse events were 11.5% in our study and 19.9% in high-dose studies. None of these differences was statistically significant. CONCLUSION Rituximab at a low dosage of 250 mg/m(2) × 2 is as effective as at higher dosages for treating MC vasculitis. This low-dose regimen may improve the cost/benefit profile of rituximab therapy for MC.