Applicability and performance of heart failure prognostic scores in dilated cardiomyopathy: the real-world experience of an Italian referral center for cardiomyopathies.

BACKGROUND: The performance of heart failure (HF) risk models is validated in the general population with HF but in specific aetiological settings, and specifically in dilated cardiomyopathy (DCM), has scarcely been explored. We tested eight of the main prognostic scores used in HF in a large real-world population of patients with DCM. METHODS: We included 784 consecutive DCM patients enrolled, both inpatients and outpatients, enrolled between January 2000 and December 2017. The risk of 1 and/or 3-year all-cause mortality/heart transplantation/durable left ventricular assist device (LVAD) implantation (D/HTx/LVAD) was estimated in our cohort according to the following risk scores SHFM, 3-CHF, CHARM, MAGGIC, GISSI-HF, MECKI, Barcelona Bio-HF, Krakow score and their accuracy calculated through the receiver operator characteristic (ROC) curve analysis. RESULTS: During a median follow-up of 5.8 years (Interquartile Range 3.2-7.6 years), 191 patients (20%) died or underwent HTx/LVAD (158 deaths, 30 heart transplantations, and 3 LVAD implantations). The high missing rate allowed to calculated only four prognostic models (MAGGIC, CHARM, 3-CHF and SHFM). All the scores overestimated the rate of D/HTx/LVAD. The prognostic accuracy was suboptimal for MAGGIC (AUC 0.754) and CHARM (AUC 0.720) scores and only modest for 3-CHF (AUC 0.677) and SHFM (AUC 0.667). CONCLUSIONS: Main prognostic scores for the risk stratification of HF are only partially applicable to real-world patients with DCM. MAGGIC and CHARM scores showed the best accuracy, despite the overestimation of risk. Our findings corroborate the need of specific risk scores for the prognostic stratification of DCM. CLINICAL PERSPECTIVE: What is new? The present study is the largest analysis in literature which investigate how the main existing heart failure prognostic risk scores performed in a real-world of dilated cardiomyopathy population, both in- and outpatients. What are the clinical implications? DCM is a stand-alone model of heart failure, where the performance of multiple heart failure prognostic scores for the risk stratification is quite limited. The need for contemporary, dedicated prognostic scores in this disease is increasingly evident.

The hypothalamic-pituitary-adrenal and -thyroid axes activation lasting one year after an earthquake swarm: results from a big data analysis.

PURPOSE: To cope physical and/or psychological threats, the human body activates multiple processes, mediated by a close interconnection among brain, endocrine and inflammatory systems. The aim of the study was to assess the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes involvement after an acute stressful event (Emilia Romagna earthquake swarm) with a big data approach. METHODS: A retrospective, observational trial was performed, collecting all biochemical examinations regarding HPA and HPT axes performed in the same laboratory the year before and the year after the earthquake swarm (20-29 May 2012). RESULTS: Comparing 2576 pre-earthquake to 3021 post-earthquake measurements, a cortisol serum level increase was observed (p < 0.001). Similar increase was evident for urinary free cortisol (p = 0.016), but not for adrenocorticotropic hormone (p = 0.222). The biochemical hypercortisolism incidence increased from 7.6 to 10.3% after earthquakes (p = 0.001). Comparing 68,456 pre-earthquake to 116,521 post-earthquake measurements, a reduction in thyroid-stimulating hormone (TSH) levels was evident (p = 0.018), together with an increase in free triiodothyronine and free thyroxine levels (p < 0.001 and p < 0.001). Moreover, a significant increase in altered TSH after earthquakes was registered considering the epicenter-nearest measurements (p < 0.001). No clinically relevant alterations were observed considering thyroid-specific autoantibodies. CONCLUSION: A long-term HPA axis activation in the inhabitants of the earthquake-affected areas was highlighted for the first time. Moreover, an increased incidence of biochemical hypercortisolism emerged after earthquakes. We confirmed a recruitment of HPT axis after stressful events, together with increased incidence of altered TSH in the. Our big data study allowed to increase knowledge about the connection between external stressors and endocrine regulation.

Detection of influenza A(H1N1)pdm09 virus in a patient travelling from Shanghai to Italy in July 2018: an uncommon clinical presentation in a non-seasonal period.

Influenza is one of the most common infectious diseases in travellers, especially in those returning from subtropical and tropical regions. In late June 2018 an influenza A(H1N1)pdm09 virus infection was diagnosed in a 36-years-old man, returned from a travel in Shanghai and hospitalized at the Ospedale Policlinico San Martino, Genoa, Italy, with a diagnosis of fever and an uncommon clinical presentation characterised by a persistent leukopenia. Phylogenetic analysis revealed a closeness with influenza A(H1N1)pdm09 strains circulating in the US in May-June 2018. Prompt recognition of influenza infection led to a proper case management, demonstrating the crucial role of the continuous influenza surveillance programme.

Quality of life in an Italian cohort of people living with HIV in the era of combined antiretroviral therapy (Evidence from I.A.N.U.A. study-investigation on antiretroviral therapy).

The aims of this study were to assess the Health Related Quality of Life (HRQoL) of People Living with HIV/AIDS (PLWHA) who attend outpatient services in Genoa, Italy, and to evaluate the relationship between HRQoL and clinical factors, primarily: CD4+ cell count, viral load and HIV-Hepatitis C Virus (HCV) coinfection. A cross-sectional study was performed involving a sample of 943 consecutive patients. Firstly the EuroQol-Five Dimensions-Three Level (EQ-5D-3L) self-reported questionnaire was used to evaluate HRQoL, while socio-demographic information was collected using a separate self-administered questionnaire. Descriptive statistical analysis was then used to show the socio-demographic and clinical characteristics of the sample. Having characterized the sample, Pearson's correlation technique was used to assess the relationship between HRQoL and socio-demographic and clinical characteristics. Finally, multivariable linear regression was used to determine factors associated with HRQOL. The median EQ-Visual analogue scale (EQ-VAS) score was 75.4 (SD 18.4). We found statistically significant associations between the EQ-VAS score and age, coinfection with HCV+, education, other drugs taken over cART, hospitalization due to HIV and a CD4+ cell count <200 mm3 compared with CD4+ cell count >500 mm3. Factors independently associated with lower HRQoL were: older age, coinfection with HCV+, other drugs used in addition to cART, hospitalization due to HIV and CD4+ cell count <200 mm3 compared with CD4+ cell count >500 mm3.

Rs12979860 and rs8099917 single nucleotide polymorphisms of interleukin-28B gene: simultaneous genotyping in caucasian patients infected with hepatitis C virus.

INTRODUCTION: Recent studies have demonstrated the role of the interleukin 28B (IL28B) polymorphisms in predicting treatment induced and spontaneous clearance from Hepatitis C virus (HCV) infection, suggesting the possibility of tailored therapy in HCV infected patients. Genome-wide association studies have shown that single nucleotide polymorphisms (SNPs) near IL 28B gene on chromosome 19 are strong predictors of sustained virologic response (SVR) to pegylated interferon and ribavirin. This study was aimed at analyzing the co-prevalence of two common and clinically significant SNPs in a cohort of Ligurian patients. METHODS: Two SNPs (rs12979860, rs8099917) were genotyped in the IL28B locus from 175 DNA samples collected from HCV-infected consecutive patients in a Laboratory of Liguria Region, northern Italy. A real-time polymerase chain reaction in a Corbett Research Termocycler (Rotor Gene 3000A) by fluorescent probes (Fast Set IL 28B, Arrow Diagnostics) was used for the detection, according to the manufacturer's instructions. RESULTS: Carriers of rs12979860CT genotype predominated (87/175, 50%), homozygotes for allele C were 68/175 (39%) and the remaining were homozygotes for IFN-resistant allele T (11%). As for the rs8099917 SNP, genotypes were thus distributed: 96/175 (55%) carried the rs8099917 TT genotype, whereas 70/175 (40%) and 9/175 (5%), were heterozygotes or homozygotes for the G allele. The variants rs12979860CC and rs8099917TT were found in 39% and 54% of overall patients with HCV genotype 1, respectively. The combined assessment of examined SNPs resulted in three most prevalent genotypes (rs12979860CC/rs8099917TT, rs12979860CT/rs8099917TG and rs12979860CT/rs8099917TT) with a frequency of 35%, 31% and 18%, respectively. DISCUSSION: Recent findings demonstrated that in carriers of rs12979860CT the determination of additional genotype of rs8099917 SNP could significantly improve the prediction of SVR. In our study cohort carriers of rs12979860CT represented 50% of all patients, who could take advantage with respect to SVR prediction by further determination of the rs8099917 SNP. The simultaneous genotyping of two IL28B SNPs should thus be recommended in HCV infected patients prior to treatment initiation.

Relevance of CD38 expression on CD8 T cells to evaluate antiretroviral therapy response in HIV-1-infected youths.

Surrogate markers for monitoring immuno-virological discordant responders, in addition to plasma viral load and CD4 cells, are still lacking. We assessed the diagnostic utility of CD38 expression on CD8 T cell assay, alone or in association with lymphocyte proliferation to mycotic antigens, in evaluating antiretroviral response. 28 vertically HIV-infected youths, 21 HAART- and seven 2 nucleotide reverse transcriptase inhibitors-treated, were enrolled in a retrospective study. Responders (57.1%) and non-responders (42.9%) to stable antiretroviral therapy for a minimum of 6 months, on the basis of viral load and CD4 T cells, comprehensively evaluated by CD38 expression on CD8 T lymphocytes [measured as CD38 antibody bound per CD8 T cell (CD38 ABC) and %CD38+ of total CD8 T cells (%CD38/CD8)] and lymphocyte proliferation to P. jiroveci, C. albicans, C. neoformans, A. fumigatus at a single time point after treatment, were selected. CD38 expression > or =2401 CD38 ABC and > or =85% CD38/CD8 cut-off points, accurately discriminates responders versus non-responders, both measures resulting in 75.0% (CI 42.8-94.5) sensitivity (identification of non-responder) and 93.8% (CI 69.8-99.8) specificity (identification of responder), when considered as single assays. The association '> or =2401 CD38 ABC or > or =85% CD38/CD8' improved sensitivity to 83.3% (CI 51.6-97.9), while the association '<2401 CD38ABC (or <85% CD38/CD8) and lymphoproliferative response positive to > or =2 tested organisms' improved specificity to 100% (CI 79.4-100). In conclusions, CD38 expression and mycotic antigen-specific T-cell proliferation may be used as additional parameters to existing criteria to evaluate antiretroviral response in immuno-virological discordant patients.

Prevalence of transmitted HIV-1 drug resistance in HIV-1-infected patients in Italy: evolution over 12 years and predictors.

OBJECTIVES: Transmitted HIV-1 drug resistance (TDR) can reduce the efficacy of first-line antiretroviral therapy. PATIENTS AND METHODS: A retrospective analysis was performed to assess the prevalence and correlates of TDR in Italy over time. TDR was defined as the presence of at least one of the mutations present in the surveillance drug resistance mutation (SDRM) list. RESULTS: Among 1690 antiretroviral therapy-naive patients, the most frequent HIV subtypes were B (78.8%), CRF02_AG (5.6%) and C (3.6%). Overall, TDR was 15%. TDR was 17.3% in subtype B and 7.0% in non-B carriers (P < 0.001). TDR showed a slight, although not significant, decline (from 16.3% in 1996-2001 to 13.4% in 2006-07, P = 0.15); TDR declined for nucleoside reverse transcriptase inhibitors (from 13.1% to 8.2%, P = 0.003) but remained stable for protease inhibitors (from 3.7% to 2.5%, P = 0.12) and non-nucleoside reverse transcriptase inhibitors (from 3.7% to 5.8%). TDR to any drug was stable in B subtype and showed a decline trend in non-B. In multivariable analysis, F1 subtype or any non-B subtype, compared with B subtype, and higher HIV RNA were independent predictors of reduced odds of TDR. CONCLUSIONS: Prevalence of TDR to nucleoside reverse transcriptase inhibitors seems to have declined in Italy over time. Increased prevalence of non-B subtypes partially justifies this phenomenon.

Hypoadiponectinemia in lipodystrophic HIV individuals: a metabolic marker of subclinical cardiac damage.

BACKGROUND AND AIM: To evaluate cardiovascular abnormalities in highly active antiretroviral therapy (HAART) treated HIV patients with no signs or symptoms of cardiovascular impairment, and to assess the relative role of multiple concomitant risk factors. METHODS AND RESULTS: Forty-four consecutive HIV subjects (mean age 41+/-6 yrs) were enrolled. Inclusion criteria were HIV infection, CD4+cell count>150/ml, HAART treatment for at least 4 years. Metabolic serum levels, morphological and functional echocardiographic parameters were assessed in all subjects. Sixteen healthy age and sex matched subjects with no cardiovascular risk factors were recruited as controls. HIV patients showed increased left ventricular mass index with reduced mid-wall fractional shortening (mFS) when compared to controls (50.2+/-10.5 vs. 38.6+/-14.4, p=0.05 and 18.3+/-0.6 vs. 21.9+/-0.7, p<0.05, respectively). Twenty-nine patients were lipodystrophic (LD) and showed a longer HAART period (p=0.0004) and greater use of protease inhibitors (PI) (p=0.001). Coronary flow reserve (CFR) was significantly reduced in HIV patients as compared to controls (p<0.0001), as it was in LD subjects when compared to non-lipodystrophic ones (NLD) (p<0.001). Adiponectin concentrations were found to be significantly lower in LD subjects than in NLD ones (7.8+/-0.8 vs. 13.8+/-1.2 microg/ml, p=0.01), and showed a direct correlation with CFR. In multiple regression analysis, insulin, HDL and adiponectin accounted for 63% of CFR variations. CONCLUSIONS: Left ventricular hypertrophy, depressed mFS and reduced CFR represent the main signs of subclinical cardiac damage in HIV subjects treated with HAART. Hypoadiponectinemia in these subjects seems to be a metabolic risk factor of cardiovascular impairment.

Non-antigen-specific CD8(+) T suppressor lymphocytes in diseases characterized by chronic immune responses and inflammation.

Recent studies on regulatory lymphocytes demonstrate that CD8(+) T suppressor (Ts) cells may have great relevance in controlling immune system homeostasis and avoiding development of chronic inflammatory diseases. Among the three subpopulations of CD8(+) Ts cells so far recognized in humans, the type 2 (non-antigen-specific) cell is characterized by the capacity to inhibit both T cell proliferation and cytotoxic T lymphocyte activity through secretion of soluble factors. Previous work has shown the impairment of in vitro generation of type 2 CD8(+) Ts cells from the peripheral blood of relapsed patients with multiple sclerosis, systemic lupus erythematosus, or systemic sclerosis. Here, similar findings are demonstrated for patients with human immunodeficiency virus or chronic hepatitis C virus infection. Furthermore, the presence of type 2 CD8(+) Ts cells infiltrating diseased tissues in patients with autoimmune thyroiditis or cancer is shown. Collectively, these findings suggest that type 2 CD8(+) Ts cells may be involved in the control of pathologic chronic immune responses, contributing in some cases to the pathogenesis of the disease.

Blunted coronary flow reserve in systemic sclerosis.

OBJECTIVES: We investigated whether the non-invasive determination of coronary flow reserve (CFR), as evaluated by transthoracic Doppler echocardiography, might be a potential method to detect early dysfunction of cardiovascular system in patients affected by systemic sclerosis (SSc) without clinical signs or symptoms of cardiac impairment. The possible correlations between the CFR values and the duration of the disease, specific autoantibodies and cutaneous involvement subsets were investigated. METHODS: Forty-four consecutive patients affected by SSc were analysed. The CFR was detected in the distal left anterior descending coronary artery by contrast-enhanced transthoracic second harmonic Doppler in all SSc patients and in 16 healthy controls. CFR was assessed at rest and during hyperaemia induced by administration of adenosine at 0.14 mg/kg/min over 5 min. The CFR was calculated as the ratio between hyperaemic (peak adenosine infusion) and resting peak diastolic velocity (PdvCFR) and resting velocity time integral (VtiCFR). Past medical history was carefully investigated. RESULTS: Both PdvCFR and VtiCFR were significantly reduced in SSc patients when compared with controls (P<0.0001). In particular, both PdvCFR and VtiCFR were significantly lower in patients with dSSc when compared with patients affected by lSSc (P<0.02 and P<0.04 respectively). No statistically significant correlation was found between CFR values and history of smoking, serum levels of cholesterol or triglycerides, blood pressure, age of patients, duration of SSc and serum autoantibody positivity for ANA, ACA and Scl70. CONCLUSIONS: CFR is often reduced in SSc patients. CFR was lower in patients with dSSc than in those affected by lSSc. A reduced CFR value should be considered an indirect sign of heart involvement in scleroderma, but its clinical and prognostic implications need to be clarified.

Modifications of immunological and neuro-endocrine parameters induced by antiorthostatic bed-rest in human healthy volunteers.

AIM: Space flight has profound effects on immunological and neuroendocrine parameters. Microgravity plays a major role in the induction of these changes. The aim of the present study was the evaluation on ground of the effects induced by antigravitary posture on immune and neuroendocrine functions. METHODS: Eight healthy male volunteers (mean age 24+/-1 years) were maintained in antigravitary posture (-10 degrees) for 72 hours. Four of them were also maintained in supine posture for 72 hours as controls. The following immunological and neuroendocrine parameters have been analysed: peripheral white blood cells count, CD11b integrin expression and H(2)O(2) production by neutrophils, lymphocyte and monocyte phenotype, intracytoplasmic cytokine (IFN-gamma, TNF-alpha and IL-4) pattern, lymphocyte proliferation to mitogens and antigens, cortisol, ACTH, catecholamines, GH, LH, prolactin and testosterone plasma levels. RESULTS: In subjects maintained in antigravitary posture, norepinephrine, dopamine, cortisol, ACTH, GH and prolactin plasma levels increased whereas H(2)O(2) production by neutrophils, lymphocyte proliferation, NK cells number and intracytoplasmic IFN-g expression decreased. No significant modifications were observed in subjects maintained in supine posture. CONCLUSION: The results of this study indicate that several neuroendocrine and immunological parameters are modulated by a prolonged antigravitary posture on ground and may negatively affect astronauts defenses against pathogens during space flights.

Reverse transcriptase mutations in HIV-1 infected patients treated with two nucleoside analogues: the SMART study.

Resistance to nucleoside reverse transcriptase inhibitors (NRTIs) was studied in 527 HIV-1-infected patients, 342 responder and 185 non-responder to two NRTIs. Responders were followed for one year to assess the incidence of clinical failure. The prevalence of the 215Y/F substitution was higher among non-responder, compared to responder patients (33.7&#x0025 vs. 17&#x0025, P = 0.0005), whereas the prevalence of the 184V and of the 70R mutations was comparable between these two groups. The 74V substitution was never observed and the 75T mutation was detected in only two subjects non-responder to a stavudine including regimen. Reduced susceptibility to didanosine or stavudine was infrequent. Reduced susceptibility to zidovudine was observed in 25&#x0025 of individuals failing a zidovudine including regimen, whereas reduced susceptibility to lamivudine was detected in all subjects failing a lamivudine including regimen. In the prospective analysis, patients with undetectable viral load at enrollment had a lower incidence of failure rate over one year compared to those with detectable HIV-RNA at entry (P &#x003C 0.0001). A detectable viral load at enrollment was the only independent variable that predicted clinical failure over one year (P &#x003C 0.0001).

In vitro immunosuppressive activity of soluble HLA class I and Fas ligand molecules: do they play a role in autologous blood transfusion?

BACKGROUND: The immunomodulatory effects of allogeneic blood transfusion may contribute to a poor prognosis in patients with cancer who are undergoing surgery, and clinical trials have been carried out to investigate whether these patients would benefit from autologous blood donation. As the immunomodulatory effects of allogeneic blood transfusion have been related to soluble molecules released from residual WBCs during storage, the in vitro immunomodulatory activity of soluble molecules detected in supernatants from stored autologous blood was evaluated. STUDY DESIGN AND METHODS: Blood was donated by four healthy volunteers. Packed WBC-reduced RBCs were obtained and stored for 30 days, and supernatants were collected. FFP and serum were also obtained. The concentration of soluble molecules was determined by immunoenzymatic assays. The in vitro immunomodulatory activity of undiluted blood component supernatant was assessed by antigen-specific cytotoxic T-cell activity and mixed lymphocyte reactions in autologous combinations and by apoptosis induction in Fas+ cells. RESULTS: The concentrations of soluble Fas-ligand and HLA class I molecules were higher in packed RBCs than in WBC-reduced RBCs, FFP, and serum. Undiluted supernatants of packed RBCs strongly inhibited functional assays and induced apoptosis in Fas+ cells. The immunomodulatory effects were correlated with the amount of soluble Fas ligand and HLA class I molecules. CONCLUSION: The results of the present study are comparable with those already reported in allogeneic blood components, and they indicate that undiluted supernatants of autologous blood components may exert immunosuppressive effects in vitro.

Identification of key mutations in HIV reverse transcriptase gene can influence the clinical outcome of HAART.

Therapeutic failures due to in vivo loss of drug sensitivity are still a major problem in AIDS care. Currently, the role of and methods for detecting resistant mutant strains in patients before therapeutic choices are still under debate. To investigate the relevance of screening for key mutations alone the commercial INNO-LiPA HIV-1 RT method was applied retrospectively to analyzing several HIV codons correlated with resistance to RTI (reverse-transcriptase inhibitors) in sera from 62 patients before starting HAART protocols, selected on the basis of clinical parameters. INNO-LiPA detected several resistant mutant strains, which were strictly consistent with previous selective pressure in the patients. A significant correlation between genotype pattern and response to HAART was found. The presence of key mutations associated with resistance to one or two RTI included in the protocol correlated with a decrease in treatment benefits, whereas patients with wild-type or non-resistant viral strains exhibited better response to HAART. Even if this information had been available when treatment was started, 45 of the patients would not have received different treatment. When compared with the total number of patients, the subgroup receiving a treatment that was considered retrospectively as consistent with the key mutation pattern exhibited a significantly better outcome. Although the interpretation of resistance-related key mutations needs improvement, this surrogate LiPA method seems to maintain a predictive role in the management of HIV infection, and is less expensive.

Impairment of CD8+ T suppressor cell function in patients with active systemic lupus erythematosus.

Alteration of T cell suppression function has been recognized in patients with systemic lupus erythematosus (SLE). Recently, CD8(+) T suppressor lymphocytes (CD8(+) Ts) have been generated in vitro by incubating purified CD8(+) T cells with IL-2 and GM-CSF. Using this method, we generated CD8(+) Ts from patients affected by SLE. No major differences were found in the CD8(+) Ts phenotype between SLE patients and healthy subjects. CD8(+) Ts from SLE patients with active disease did not inhibit the anti-CD3 mAb-induced proliferation of autologous PBMC, whereas CD8(+) Ts from SLE patients in remission exerted an inhibitory activity comparable to normal subjects. The inhibitory effect of CD8(+) Ts cells was neither mediated by cytotoxic activity nor by apoptosis induction. Two cytokines, IFN-gamma and IL-6, were found to be responsible for the function of CD8(+) TS: In fact, counteraction of CD8(+) Ts suppression activity was obtained by blocking IFN-gamma with a specific Ab or by inhibiting CD8(+) Ts-mediated IL-6 secretion by an antisense oligonucleotide. Interestingly, CD8(+) Ts from SLE patients showed a peculiar cytokine pattern characterized by an impaired secretion of IL-6 and an increased secretion of IL-12. Thus, it appears that an altered balance between inhibitory (IL-6) and stimulatory (IL-12) cytokines might be responsible for the functional impairment of CD8(+) Ts in SLE patients.