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Transthoracic echocardiography (TTE) is routinely required during pre-participation screening in the presence of symptoms, family history of sudden cardiac death or cardiomyopathies <40-year-old, murmurs, abnormal ECG findings or in the follow-up of athletes with a history of cardiovascular disease (CVD). TTE is a cost-effective first-line imaging modality to evaluate the cardiac remodeling due to long-term, intense training, previously known as the athlete's heart, and to rule out the presence of conditions at risk of sudden cardiac death, including cardiomyopathies, coronary artery anomalies, congenital, aortic and heart valve diseases. Moreover, TTE is useful for distinguishing physiological cardiac adaptations during intense exercise from pathological behavior due to an underlying CVD. In this expert opinion statement endorsed by the Italian Society of Sports Cardiology, we discussed common clinical scenarios where a TTE is required and conditions falling in the grey zone between the athlete's heart and underlying cardiomyopathies or other CVD. In addition, we propose a minimum dataset that should be included in the report for the most common indications of TTE in sports cardiology clinical practice., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest. All authors have seen and approved the manuscript being submitted, have contributed significantly to the work, attest to the validity and legitimacy of the data and its interpretation, and agree to its submission to the International Journal of Cardiology., (Copyright © 2024. Published by Elsevier B.V.)

Background: In patients with Hypertrophic Cardiomyopathy (HCM) S-ICD is usually the preferred option as pacing is generally not indicated. However, limited data are available on its current practice adoption and long-term follow-up., Methods: Consecutive HCM patients with S-ICD implanted between 2013 and 2021 in 3 international centers were enrolled in this observational study. Baseline, procedural and follow-up data were regularly collected. Efficacy and safety were compared with a cohort of HCM patients implanted with a tv-ICD., Results: Seventy patients (64% males) were implanted with S-ICD at 41 ± 15 years, whereas 168 patients with tv-ICD at 49 ± 16 years. For S-ICD patients, mean ESC SCD risk score was 4,5 ± 1.9%: 25 (40%) at low-risk, 17 (27%) at intermediate and 20 (33%) at high-risk. Patients were followed-up for 5.1 ± 2.3 years. Two patients (0.6 per 100-person-years, vs 0.4 per 100 person-years with tv-ICD, p = 0.45) received an appropriate shock on VF, 17 (24%) were diagnosed with de-novo AF. Inappropriate shocks occurred in 4 patients (1.2 per 100-person-years, vs 0.9 per 100 person-years with tv-ICD, p = 0.74), all before Smart-Pass algorithm implementation. Four patients experienced device-related adverse events (1.2 per 100-person-years, vs 1 per 100 person-years with tv-ICD, p = 0.35%)., Conclusions: S-ICDs were often implanted in patients with an overall low-intermediate ESC SCD risk, reflecting both the inclusion of additional risk markers and a lower decision threshold. S-ICDs in HCM patients followed for over 5 years showed to be effective in conversion of VF and safe. Greater scrutiny may be required to avoid overtreatment in patients with milder risk profiles., Competing Interests: Conflict of interest The authors report no conflict of interest regarding the topic discussed in the present manuscript. The study was supported by an educational grant from Boston Scientific, USA. Disclosures: Dr. I. Olivotto has received grants from Brystol Myers Squibb, Cytokinetics, Amicus, Genzyme, Shire, Bayer, Boston Scientific, Menarini International, and fees (honoraria or consulting) from Bristol Myers Squibb, Cytokinetics, Amicus, Genzyme, Shire, Boston Scientific, and served or currently serving as PI on EXPLORER-HCM, MAVA-LTE, REDWOOD-HCM, REDWOOD-OLE, and SEQUOIA-HCM trial. Dr. F. Cecchi received consultancy fees from Pfizer and Bristol Myers Squibb. Dr. L. Crotti and Dr. N. Maurizi received consultancy fees from Bristol Myers Squibb., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Within the continuum of consciousness, patients in a Minimally Conscious State (MCS) may exhibit high-level behavioral responses (MCS+) or may not (MCS-). The evaluation of residual consciousness and related classification is crucial to propose tailored rehabilitation and pharmacological treatments, considering the inherent differences among groups in diagnosis and prognosis. Currently, differential diagnosis relies on behavioral assessments posing a relevant risk of misdiagnosis. In this context, EEG offers a non-invasive approach to model the brain as a complex network. The search for discriminating features could reveal whether behavioral responses in post-comatose patients have a defined physiological background. Additionally, it is essential to determine whether the standard behavioral assessment for quantifying responsiveness holds physiological significance., Methods: In this prospective observational study, we investigated whether low-density EEG-based graph metrics could discriminate MCS+/- patients by enrolling 57 MCS patients (MCS-: 30; males: 28). At admission to intensive rehabilitation, 30 min resting-state closed-eyes EEG recordings were performed together with consciousness diagnosis following international guidelines. After EEG preprocessing, graphs' metrics were estimated using different connectivity measures, at multiple connection densities and frequency bands (α,θ,δ). Metrics were also provided to cross-validated Machine Learning (ML) models with outcome MCS+/-., Results: A lower level of brain activity integration was found in the MCS- group in the α band. Instead, in the δ band MCS- group presented an higher level of clustering (weighted clustering coefficient) respect to MCS+. The best-performing solution in discriminating MCS+/- through the use of ML was an Elastic-Net regularized logistic regression with a cross-validation accuracy of 79% (sensitivity and specificity of 74% and 85% respectively)., Conclusion: Despite tackling the MCS+/- differential diagnosis is highly challenging, a daily-routine low-density EEG might allow to differentiate across these differently responsive brain networks., Significance: Graph-theoretical features are shown to discriminate between these two neurophysiologically similar conditions, and may thus support the clinical diagnosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: There is emerging confidence that quantitative EEG (qEEG) has the potential to inform clinical decision-making and guide individualized rehabilitation after stroke, but consensus on the best EEG biomarkers is needed for translation to clinical practice. This study investigates the spatial qEEG spectral and symmetry distribution in patients with a left/right hemispheric stroke, to evaluate their side-specific prognostic power in post-acute rehabilitation outcome., Methods: Resting-state 19-channel EEG recordings were collected with clinical information on admission to intensive inpatient rehabilitation (within 30 days post stroke), and six months post stroke. After preprocessing, spectral (Delta-to-Alpha Ratio, DAR) and symmetry (pairwise and hemispheric Brain Symmetry Index) features were extracted. Patients were divided into Affected Right and Left (AR/AL) groups, according to the location of their lesion. Within each group, DAR was compared between homologous electrode pairs and the pairwise difference between pairs was compared across pairs in the scalp. Then, the prognostic power of qEEG admission metrics was evaluated by performing correlations between admission metrics and discharge mBI values., Results: Fifty-two patients with hemorrhagic or ischemic stroke (20 females, 38.5 %, median age 76 years [IQR = 22]) were included in the study. DAR was significantly higher in the affected hemisphere for both AR and AL groups, and, a higher frontal (to posterior) asymmetry was found independent of the side of the lesion. DAR was found to be a prognostic marker of 6-months modified Barthel Index (mBI) only for the AL group, while hemispheric asymmetry did not correlate with follow-up outcomes in either group., Discussion: While the presence of EEG abnormalities in the affected hemisphere of a stroke is well recognized, we have shown that the extent of DAR abnormalities seen correlates with disability at 6 months post stroke, but only for left hemispheric lesions. Routine prognostic evaluation, in addition to motor and functional scales, can add information concerning neuro-prognostication and reveal neurophysiological abnormalities to be assessed during rehabilitation., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interests., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Competing Interests: Declaration of Competing Interest CG has received grants from Italian Ministry of Health and BMS and Honoraria for presentations or lectures from AstraZeneca, BMS, Lilly, MSD, Roche, Sanofi, Takeda, Thermo Fisher; ML has received personal fees (advisory role and/or speaker honoraria) from Roche, Takeda, Sandoz, Eli Lilly, Pfizer, AstraZeneca, Novartis Exact Sciences and Ipsen; LDM has reported consulting fees from Roche, Novartis, MSD, Pfizer, Ipsen, AstraZeneca, Genomic Health, Eli Lilly, Seattle Genetics, Eisai, Pierre Fabre, and Daiichi Sankyo, speaker Honoraria from Roche, Novartis, Eli Lilly and MSD, travel grants from Roche, Pfizer and Celgene; FS has reported Honoraria for presentations or lectures from Sanofi Genzyme, Roche, BMS, Novartis, Merk, Sun Pharma, MSD, Pierre Fabre and for advisory board for Novartis, Philogen, SunPharma, MSD.

Consciousness can be defined as a phenomenological experience continuously evolving. Current research showed how conscious mental activity can be subdivided into a series of atomic brain states converging to a discrete spatiotemporal pattern of global neuronal firing. Using the high temporal resolution of EEG recordings in patients with a severe Acquired Brain Injury (sABI) admitted to an Intensive Rehabilitation Unit (IRU), we detected a novel endotype of consciousness from the spatiotemporal brain dynamics identified via microstate analysis. Also, we investigated whether microstate features were associated with common neurophysiological alterations. Finally, the prognostic information comprised in such descriptors was analysed in a sub-cohort of patients with prolonged Disorder of Consciousness (pDoC). Occurrence of frontally-oriented microstates (C microstate), likelihood of maintaining such brain state or transitioning to the C topography and complexity were found to be indicators of consciousness presence and levels. Features of left-right asymmetric microstates and transitions toward them were found to be negatively correlated with antero-posterior brain reorganization and EEG symmetry. Substantial differences in microstates' sequence complexity and presence of C topography were found between groups of patients with alpha dominant background, cortical reactivity and antero-posterior gradient. Also, transitioning from left-right to antero-posterior microstates was found to be an independent predictor of consciousness recovery, stronger than consciousness levels at IRU's admission. In conclusions, global brain dynamics measured with scale-free estimators can be considered an indicator of consciousness presence and a candidate marker of short-term recovery in patients with a pDoC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Clinical responsiveness of patients with a Disorder of Consciousness (DoC) correlates to sympathetic/parasympathetic homeostatic balance. Heart Rate Variability (HRV) metrics result in non-invasive proxies of modulation capabilities of visceral states. In this work, our aim was to evaluate whether HRV measures could improve the differential diagnosis between Unresponsive Wakefulness Syndrome (UWS) and Minimally Conscious State (MCS) with respect to multivariate models based on standard clinical electroencephalography (EEG) labeling only in a rehabilitation setting., Methods: A prospective observational study was performed consecutively enrolling 82 DoC patients. Polygraphic recordings were performed. HRV-metrics and EEG descriptors derived from the American Clinical Neurophysiology Society's Standardized Critical Care terminology were included. Descriptors entered univariate and then multivariate logistic regressions with the target set to the UWS/MCS diagnosis., Results: HRV measures resulted significantly different between UWS and MCS patients, with higher values being associated with better consciousness levels. Specifically, adding HRV-related metrics to ACNS EEG descriptors increased the Nagelkerke R 2 from 0.350 (only EEG descriptors) to 0.565 (HRV-EEG combination) with the outcome set to the consciousness diagnosis., Conclusions: HRV changes across the lowest states of consciousness. Rapid changes in heart rate, occurring in better consciousness levels, confirm the mutual correlation between visceral state functioning patterns and consciousness alterations., Significance: Quantitative analysis of heart rate in patients with a DoC paves the way for the implementation of low-cost pipelines supporting medical decisions within multimodal consciousness assessments., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Pre-partecipation ECG screening of large populations has a significant socioeconomic impact. Technological progress now allows for high-tech-low-cost ECG screening using validated smartphone-based devices capable of guiding to the correct performance of a 12‑lead ECG by layman with no medical background., Methods: We enrolled 728 (364, 52% males) individuals, aged 12-13 years who underwent ECG screening with a smartphone 12‑lead ECG during school hours by layman volunteers. Correct electrodes placement was provided by a validated image-processing algorithm by the smartphone camera in the App. ECG interpretation was via a telecardiology platform and alterations classified following current standards., Results: A total of 741 ECGs were recorded, of which 13(2%) were technically not interpretable. Mean PR, QRS and QTc were: 145 ± 22, 85 ± 19 and 387 ± 57 msec. No QTc prolongation was observed. Mean QRS axis was 15°; 26 (4%) patients presented an iRBB. T-wave inversion from V1-V3 was present in 145 (21%) subjects. Twenty-one(3%) patients were referred to second level examination: deep Q-waves in inferior leads in 12(1.6%), ventricular ectopics in 5(0.7%), anterior T-waves inversions V1-V4 in 3(0.4%); extreme right axis deviation in 1(0.3%). Second line investigations did not provide any definitive diagnosis. Total project costs (material equipment and human cost) was 14.460€, 19.51€ per individual. The potential net saving with respect to current pre-participation screening cost was 19%., Conclusions: Layman 12‑lead Smartphone-ECG population screening proved feasible and effective, with a rate of non-interpretable ECG of <5%. Potential cost-saving in ECG screening and recording was 19%, providing an appealing opportunity when large campaigns should be addressed also in developing countries., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Syncopal events in patients with hypertrophic cardiomyopathy (HCM) are of concern as they are a vital consideration in algorithms for risk stratification for sudden cardiac death (SCD) and ICD implantation. However, the cause of syncope is often under-investigated and/or unexplained. Current syncope guidelines do not provide a detailed definition of unexplained syncope. To address this important gap, an international panel of experts in the field of both syncope and HCM wrote a consensus document with the aim of providing practical guidance for the diagnosis and management of syncope in patients with HCM., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: To describe the proportion of patients with syncope among those affected by hypertrophic cardiomyopathy (HCM) and the relevance of syncope as risk factor for sudden cardiac death and life-threatening arrhythmic events., Method and Results: Systematic review of original articles that assessed syncope in HCM patients. Literature search of PubMed including all English publications from 1973 to 2021.We found 57 articles for a total of 21.791 patients; of these, 14 studies reported on arrhythmic events in the follow-up. Syncope was reported in 15.8% (3.452 of 21.791) patients. It was considered unexplained in 91% of cases. Life-threatening arrhythmic events occurred in 3.6% of non-syncopal patients and in 7.7% of syncopal patients during a mean follow-up of 5.6 years. A relative risk of 1.99 (95%CI 1.39 to 2.86) was estimated for syncope patients by the random effect model using Haldane continuity correction for 0 events., Conclusions: In the current practice, the cause of syncope remained unexplained in most patients affected by HCM. The management of patients seems mainly driven by risk stratification rather than identification of the aetiology of syncope. There is a need of precise instructions how to apply the recommendations of current guidelines to this disease, which tests are indicated and how to interpret their findings. The protocol was registered in Prospero (ID: 275963)., (Copyright © 2022. Published by Elsevier B.V.)

Patients with hypertrophic cardiomyopathy (HCM) exhibit a variable phenotype with ventricular hypertrophy as the cardinal manifestation and left ventricular (LV) outflow tract obstruction (LVOTO) as a key pathophysiologic determinant. Patients with severe LVOTO usually present with exertional dyspnea, exertional syncope, and heart failure symptoms, while successful relief of LVOTO by pharmacological or invasive interventions leads to a dramatic improvement in clinical status. Proper management of obstructive HCM remains challenging and poses numerous clinical dilemmas. Since the development of surgical myectomy over half a century ago, progress in the management of LVOTO in HCM has paralleled technological advances in genetic testing, cardiac imaging, arrhythmic prophylaxis, cardiac surgery and interventional cardiology. These changes have been incorporated in dedicated scientific guidelines on both sides of the Atlantic. However, either the 2011 American guidelines or the 2014 European guidelines remain largely based on expert consensus for lack of recommendations with level of evidence A regarding any of the treatment options commonly employed in HCM. Consequently, management of obstructive HCM patients remains largely subjective and dependent on clinical judgment, local expertise, and patient preference. Following the trend that has emerged for other cardiac diseases amenable to invasive interventions, adequate evaluation and management of obstruction in HCM today requires a multidisciplinary team capable of optimizing referral, choosing the best available options, minimizing complications and ensuring state-of-the-art results. The concept of an HCM Heart Team is coming of age. This review aims to provide an update of available pharmacologic and invasive options for the management of LVOTO in HCM, either in adulthood or in childhood, highlighting areas for multidisciplinary integration and future development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This paper reports the presence of various species of filarial nematodes in dogs in an area of central Italy at the border between two regions (Tuscany-Latium), which had previously been free of infection and for which there are no epidemiological data in the literature. Blood and serum samples from a total of 363 adult dogs were collected during in 2016/17 and 2018/19 in the provinces of Grosseto (Tuscany) and Viterbo (Latium). The dogs were of different breeds or mixed breeds, randomly selected, and living in public kennels or privately owned. Of the 363 samples tested, 55 dogs were positive to Knott's test for microfilariae (prevalence 15.1%; 95% confidence interval: 11.5-18.8%). Dirofilaria immitis was found in 25 cases (prevalence 6.9%; 95% CI 4.3-9.5%), D. repens in 27 (7.4%, 95% CI 4.7-10.1%) and Acanthocheilonema reconditum in 3 (0.8%, 95% CI 0.1-1.7%). Out of 55 dogs, only four were infested with both D. immitis and D. repens (1.1%, 95% CI 0.001-2.2%)., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Early motor development is characterized by progressive changes in general movements paralleled by a gradual organization of the four limbs' repertoire towards the midline, as shown by computerised movement analysis., Aims: Our aim was to test the performance of quantitative computerised kinematic indexes as predictors of post-term age in an independent cohort of typically developing subjects at fidgety age, tested cross-sectionally., Subjects: We selected twelve low risk term infants, who were video recorded between 9 and 20 weeks (fidgety age) during one spontaneous movements session., Study Design: We correlated post-term age with I)indexes of coordination including interlimb correlation of velocity and position, II)indexes of distance, including interlimb and limb-to- ground, both expressed as linear distance and as probability of midline limbs position III)indexes of global movement quality by calculating Hjorth's activity, mobility and complexity parameters. All indexes were calculated for both upper and lower limbs., Results: Significant positive correlations were found between post-term age and indexes of distance, and probability of occurrence of upper-limb antigravity patterns, and with both indexes of global movement quality. By combining linear and non-linear parameters related to the upper limb kinematics, we determined individual post-term age with a mean error of <1 week (5.2 days). No correlations were found between age and indexes of coordination., Conclusions: Quantitative computerised analysis of upper-limb movements is a promising predictor of post-term age in typically developing subjects at fidgety age., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2019. Published by Elsevier B.V.)

Background: Differential diagnosis of genetic causes of left ventricular hypertrophy (LVH) is crucial for disease-specific therapy. We aim to describe the prevalence of Cardiac Amyloidosis (CA) among patients ≥40 years with an initial diagnosis of HCM referred for second opinion to national cardiomyopathy centres., Methods: Consecutive patients aged ≥40 years referred with a tentative HCM diagnosis in the period 2014-2017 underwent clinical evaluation and genetic testing for HCM (including trans-thyretin-TTR). Patients with at least one red flag for CA underwent blood/urine tests, abdominal fat biopsy and/or bone-scintigraphy tracing and eventually ApoAI sequencing., Results: Out of 343 patients (age 60 ± 13 years), 251 (73%) carried a likely/pathogenic gene variant, including 12 (3.5%) in the CA-associated genes TTR (n = 11) and ApoAI (n = 1). Furthermore, 6 (2%) patients had a mutation in GLA. Among the remaining, mutation-negative patients, 26 with ≥1 CA red-flag were investigated further: 3 AL-CA and 17 wild-type-TTR-CA were identified. Ultimately, 32(9%) patients were diagnosed with CA. Prevalence of CA increased with age: 1/75 (1%) at age 40-49, 2/86 (2%) at age 50-59, 8/84 (9%) at age 60-69, 13/61 (21%) at age 70-79, 8/31 (26%) at age ≥80 (p for trend <0.01)., Conclusions: Among patients referred with and initial diagnosis of HCM, CA was the most common unrecognized mimic (9% prevalence) and increased with age (from 1% at ages 40-49 years to 26% >80 years). Age at diagnosis should be considered one of the most relevant red flags for CA in patients with HCM phenotypes; however, there is no clear age cut-off mandating scintigraphy and other second level investigations in the absence of other features suggestive of CA., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Although imaging techniques have demonstrated the existence of microvascular abnormalities in hypertrophic cardiomyopathy (HCM), a detailed histopathological assessment is lacking as well as a comparison between different phases of the disease. We aimed to compare microvasculopathy and myocardial fibrosis in hypertrophic obstructive cardiomyopathy (HOCM) versus end-stage (ES) HCM., Methods: 27 myectomy specimens of HOCM patients and 30 ES-HCM explanted hearts were analyzed. Myocardial fibrosis was quantitatively determined with dedicated software and qualitatively classified as scar-like or interstitial. Intramural coronary arteries were evaluated separately according to lumen diameter: 100-500 μ versus <100 μ. Microvasculopathy assessment included the description of medial and intimal abnormalities and stenosis grading. The two subgroups were compared considering only the anterobasal septum of ES explanted hearts., Results: Median value of fibrosis in the anterobasal septum of explanted hearts was 34.6% as opposed to 10.3% of myectomy specimens (p < 0.001). Scar-like fibrosis was widely found in ES hearts while interstitial fibrosis was distinctive of HOCM (p < 0.001). All slides showed 100-500 μ microvasculopathy without any differences between subgroups in terms of lumen narrowing, extent of the disease and type of parietal involvement. Among ES hearts these lesions were associated with scar-like fibrosis (p = 0.034). <100-μ microvasculopathy was also frequent with no differences between subgroups., Conclusions: Microvasculopathy is an intrinsic feature of HCM with similar characteristics across the natural phases of the disease. Conversely, myocardial fibrosis changes over time with ES hearts showing a three-fold greater amount, mainly scar-like. ES showed a closer association between microvasculopathy and replacement fibrosis., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Genetic testing in hypertrophic cardiomyopathy (HCM) has long relied on Sanger sequencing of sarcomeric genes. The advent of next-generation sequencing (NGS) has catalyzed routine testing of additional genes of dubious HCM-causing potential. We used 19 years of genetic testing results to define a reliable set of genes implicated in Mendelian HCM and assess the value of expanded NGS panels., Methods: We dissected genetic testing results from 1,198 single-center HCM probands and devised a widely applicable score to identify which genes yield effective results in the diagnostic setting., Results: Compared with early panels targeting only fully validated sarcomeric HCM genes, expanded NGS panels allow the prompt recognition of probands with HCM-mimicking diseases. Scoring by "diagnostic effectiveness" highlighted that PLN should also be routinely screened besides historically validated genes for HCM and its mimics., Conclusion: The additive value of expanded panels in HCM genetic testing lies in the systematic screening of genes associated with HCM mimics, requiring different patient management. Only variants in a limited set of genes are highly actionable and interpretable in the clinic, suggesting that larger panels offer limited additional sensitivity. A score estimating the relative effectiveness of a given gene's inclusion in diagnostic panels is proposed.

Background: Whether early vs. delayed referral to septal reduction therapies (SRT, alcohol septal ablation or surgical myectomy) bears prognostic relevance in hypertrophic obstructive cardiomyopathy (HOCM) is unresolved. We analyzed the impact of SRT timing on the outcome of HOCM patients., Methods: We followed 126 patients for 5 ± 4 years after SRT (mean age 53 ± 15 years; 55 post-ASA and 71 post-SM). Based on time-to-treatment (TTT; from HOCM diagnosis to SRT), patients were divided into three groups: "<3" years, N = 50; "3-5" years, N = 25; ">5" years, N = 51., Results: Patients with TTT > 5 years were younger at diagnosis and more often had atrial fibrillation (AF). Left ventricular outflow tract (LVOT) gradients were comparable in the 3 TTT groups. Two patients died peri-operatively, all with TTT > 5. Long-term, 8 patients died (3 suddenly and 5 due to heart failure). Mortality increased progressively with TTT (2% vs. 4% vs. 12% for TTT "<3", "3-5", and ">5" years, p for trend = 0.039). Independent predictors of disease progression (new-onset AF, worsening to NYHA III/IV symptoms, re-intervention or death) were TTT ("3-5" vs. "<3" years: HR: 4.988, 95%CI: 1.394-17.843; ">5" vs. "<3" years: HR: 3.420, 95%CI: 1.258-9.293, overall p-value = 0.025), AF at baseline (HR: 1.896, 95%CI: 1.002-3.589, p = 0.036) and LVOT gradient (HR per mm Hg increase: 1.022, 95%CI: 1.007-1.024, p = 0.023)., Conclusions: Delay in SRT referral has significant impact on long-term outcome of patients with HOCM, particularly when >5 years from first detection of gradient, even when successful relief of symptoms and gradient is achieved. Earlier interventions are associated with lower complication rates and better prognosis, suggesting the importance of timely SRT to maximize treatment benefit and prevent late HOCM-related complications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Genomic testing for KRAS and NRAS mutations in clinical biopsies of various cancers is routinely performed to predict futility of anti-epidermal growth factor receptor (anti-EGFR) therapies. We hypothesized that RAS mutations could be detected and quantified at the protein level for diagnostic purposes using data-independent acquisition (DIA)-based mass spectrometry in formalin-fixed, paraffin-embedded (FFPE) tumor samples. We developed a targeted DIA assay that surveys the specific mass range of all possible peptides harboring activating mutations in KRAS exon 2. When the assay was applied to tumor samples with known KRAS or NRAS mutations (G12A, G12D, G12V, and G13D), RAS-mutant and wild-type peptides were successfully detected in 11 of 13 biopsy samples. Mutation statuses obtained by DIA were concordant with those obtained by DNA sequencing, and yields of mutant peptide (mutant peptide/[mutant + wild-type peptides]) exhibited linear correlation with yields of RAS-mutant mRNA. When applied to biopsy samples with failed DNA testing results, the DIA assay identified an additional RAS-mutated sample. SIGNIFICANCE: Proteomic detection of RAS mutations by DIA in tumor biopsies can provide solid evidence of mutant RAS protein regardless of the mutation types and sites in exon 2. This robust method could rescue samples that fail genomic testing due to insufficient tumor tissue or lack of sequenceable DNA. It can be used to explore the relationship between protein expression level of mutant RAS and therapeutic outcome., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Left ventricular hypertrophy may be a consequence of a hemodynamic overload or a manifestation of several diseases affecting different structural and functional proteins of cardiomyocytes. Among these, sarcomeric hypertrophic cardiomyopathy (HCM) represents the most frequent cause. In addition, several metabolic diseases lead to myocardial thickening, either due to intracellular storage (glycogen storage and lysosomal diseases), extracellular deposition (TTR and AL amyloidosis) or due to abnormal energy metabolism (mitochondrial diseases). The recognition of these rare causes of myocardial hypertrophy is important for family screening strategies, risk assessment, and treatment. Moreover, as there are specific therapies for some forms of HCM including enzyme substitution and chaperone therapies and specific treatments for TTR amyloidosis, a differential diagnosis should be sought in all patients with unexplained left ventricular hypertrophy. Diastolic dysfunction is a key feature of HCM and its phenocopies. Its assessment is complex and requires evaluation of several functional parameters and structural changes. Severe diastolic dysfunction carries a negative prognostic implication and its value in differential diagnosis is limited., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aim: Adherence to the Mediterranean Diet (MD) has been associated with a longer and better life. The aim of this study was to examine the effects of adherence to the MD, and of nutritional habits on endothelial progenitor (EPCs) and circulating progenitor (CPCs) cells in a cohort of nonagenarians enrolled within the Mugello Study, an epidemiological study aimed at investigating both clinically relevant geriatric items and various health issues, including those related to nutritional status., Methods and Results: Four hundred twenty-one nonagenarians (306 F, 115 M, mean age: 93.1 ± 3.2 years) were evaluated. Adherence to MD was assessed through the Mediterranean Diet Score. Elderly subjects who were in the fourth quartile of the Mediterranean diet score showed significantly higher EPCs than subjects grouped into the other three quartiles. After adjustment for confounders, elderly subjects who were in the highest quartile of adherence to the MD score reported to have EPCs' levels significantly higher than those who reported lower values of adherence to the MD. Furthermore, by analyzing different food categories, it was reported that daily consumption of olive oil and a higher consumption of fruit and vegetables showed higher CPCs CD34 + and EPCs CD34 + /KDR + than subjects with not daily or lower consumption., Conclusion: Our results support the hypothesis that the adherence to MD, as well as a daily consumption of olive oil and fruit and vegetables, characteristics of MD, may protect against the development of endothelial dysfunction through increasing EPCs and CPCs in older age., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: MHealth technologies are revolutionizing cardiovascular medicine. However, a low-cost, user-friendly smartphone-based electrocardiograph is still lacking. D-Heart® is a portable device that enables the acquisition of the ECG on multiple leads which streams via Bluetooth to any smartphone. Because of the potential impact of this technology in low-income settings, we determined the accuracy of D-Heart® tracings in the stratification of ECG morphological abnormalities, compared with 12-lead ECGs., Methods: Consecutive African patients referred to the Ziguinchor Regional Hospital (Senegal) were enrolled (n=117; 69 males, age 39±11years). D-Heart® recordings (3 peripheral leads plus V5) were obtained immediately followed by 12 lead ECGs and were assessed blindly by 2 independent observers. Global burden of ECG abnormalities was defined by a semi-quantitative score based on the sum of 9 criteria, identifying four classes of increasing severity., Results: D-Heart® and 12-lead ECG tracings were respectively classified as: normal: 72 (61%) vs 69 (59%); mildly abnormal: 42 (36%) vs 45 (38%); moderately abnormal: 3 (3%) vs 3 (3%). None had markedly abnormal tracings. Cohen's weighted kappa (k w ) test demonstrated a concordance of 0,952 (p<0,001, agreement 98,72%). Concordance was high as well for the Romhilt-Estes score (k w =0,893; p<0,001 agreement 97,35%). PR and QRS intervals comparison with Bland-Altman method showed good accuracy for D-Heart® measurements (95% limit of agreement ±20ms for PR and ±10ms for QRS)., Conclusions: D-Heart® proved effective and accurate stratification of ECG abnormalities comparable to the 12-lead electrocardiographs, thereby opening new perspectives for low-cost community cardiovascular screening programs in low-income settings., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: Subcutaneous ICD (S-ICD) is a promising option for Hypertrophic Cardiomyopathy (HCM) patients at risk of Sudden Cardiac Death (SCD). However, its effectiveness in terminating ventricular arrhythmias in HCM is yet unresolved., Methods: Consecutive HCM patients referred for S-ICD implantation were prospectively enrolled. Patients underwent one or two attempts of VF induction by the programmer. Successful conversion was defined as any 65J shock that terminated VF (not requiring rescue shocks). Clinical and instrumental parameters were analyzed to study predictors of conversion failure., Results: Fifty HCM patients (34 males, 40±16years) with a mean BMI of 25.2±4.4kg/m2 were evaluated. Mean ESC SCD risk of was 6.5±3.9% and maximal LV wall thickness (LVMWT) was 26±6mm. In 2/50 patients no arrhythmias were inducible, while in 7 (14%) only sustained ventricular tachycardia was induced and cardioverted. In the remaining 41 (82%) patients, 73 VF episodes were induced (1 episode in 14 and >1 in 27 patients). Of these, 4 (6%) spontaneously converted. In 68/69 (98%) the S-ICD successfully cardioverted, but failed in 1 (2%) patient, who needed rescue defibrillation. This patient was severely obese (BMI 36) and LVMWT of 25mm. VF was re-induced and successfully converted by the 80J reversed polarity S-ICD., Conclusions: Acute DT at 65J at the implant showed the effectiveness of S-ICD in the recognition and termination of VT/VF in all HCM patients except one. Extreme LVH did not affect the performance of the device, whereas severe obesity was likely responsible for the single 65J failure., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: A wide range of response rates have been reported in HER2-positive gastric cancer (GC) patients treated with trastuzumab. Other HER2-targeted therapies for GC have yet to show efficacy in clinical trials. These findings raise question about the ability of standard HER2 diagnostics to accurately distinguish between GC patients who would and would not benefit from anti-HER2 therapies., Patients and Methods: GC patients (n = 237), including a subset from the Trastuzumab in GC (ToGA) trial were divided into three groups based on HER2 status and history of treatment with standard chemotherapy or chemotherapy plus trastuzumab. We applied mass spectrometry-based proteomic analysis to quantify HER2 protein expression in formalin-fixed tumor samples. Using HER2 expression as a continuous variable, we defined a predictive protein level cutoff to identify which patients would benefit from trastuzumab. We compared quantitated protein level with clinical outcome and HER2 status as determined by conventional HER2 diagnostics., Results: Quantitative proteomics detected a 115-fold range of HER2 protein expression among patients diagnosed as HER2 positive by standard methods. A protein level of 1825 amol/µg was predicted to determine benefit from the addition of trastuzumab to chemotherapy. Trastuzumab treated patients with HER2 protein levels above this cutoff had twice the median overall survival (OS) of their counterparts below the cutoff (35.0 versus 17.5 months, P = 0.011). Conversely, trastuzumab-treated patients with HER2 levels below the cutoff had outcomes similar to HER2-positive patients treated with chemotherapy. (Progression-free survival = 7.0 versus 6.5 months: P = 0.504; OS = 17.5 versus 12.6 months: P = 0.520). HER2 levels were not prognostic for response to chemotherapy., Conclusions: Proteomic analysis of HER2 expression demonstrated a quantitative cutoff that improves selection of GC patients for trastuzumab as compared with current diagnostic methods., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Subcutaneous implantable cardioverter-defibrillator (S-ICD) is a promising option for patients with hypertrophic cardiomyopathy (HCM). Patients with HCM can present markedly abnormal electrocardiograms (ECGs), and there are no data on what percentage of patients with HCM fail the prerequisite S-ICD vector screening., Objective: The purpose of this study was to determine the failure rate of the prerequisite vector screening using 1 or 2 acceptable vectors stratified for risk profile for sudden cardiac death and predictors of failure., Methods: ECG recordings from consecutive patients with HCM simulating the S-ICD sensing vectors were analyzed with the S-ICD screening tool. Eligibility was defined by 1 or 2 appropriate vectors. Medical history, ultrasound characteristics, and 12-lead ECG characteristics were analyzed and the individual arrhythmic risk at 5 year was determined to study potential predictors of failure., Results: One hundred sixty-five (118 men; mean age 51 ± 16 years) patients were analyzed. Twenty-two patients (13%) had a high risk of sudden cardiac death, 33 (20%) had intermediate to high risk, and 110 (67%) had low risk. Twenty-six patients (16%) had no suitable vector, including 8 of 22 high-risk patients (36%). The primary cause of failure was high T-wave voltages in 25% of the vectors analyzed. T-wave inversions in >2 leads on the surface 12-lead ECG (odds ratio 15.6; 95% confidence interval 4.9-50.3; P < .001) and prior myectomy (odds ratio 8.4; 95% confidence interval 2.1-33.1; P = .002) were significantly associated with screening failure in a multivariable model., Conclusion: Currently available preimplant screening algorithms recommended by the manufacturer are associated with a significant failure rate in patients with HCM, particularly in the high-risk subgroup., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Screening in subjects with left ventricular hypertrophy (LVH) reveals a high prevalence of Fabry disease (FD). Often, a diagnosis is uncertain because characteristic clinical features are absent and genetic variants of unknown significance (GVUS) in the α-galactosidase A (GLA) gene are identified. This carries a risk of misdiagnosis, inappropriate counselling and extremely expensive treatment. We developed a diagnostic algorithm for adults with LVH (maximal wall thickness (MWT) of >12 mm), GLA GVUS and an uncertain diagnosis of FD., Methods: A Delphi method was used to reach a consensus between FD experts. We performed a systematic review selecting criteria on electrocardiogram, MRI and echocardiography to confirm or exclude FD. Criteria for a definite or uncertain diagnosis and a gold standard were defined., Results: A definite diagnosis of FD was defined as follows: a GLA mutation with ≤ 5% GLA activity (leucocytes, mean of reference value, males only) with ≥ 1 characteristic FD symptom or sign (neuropathic pain, cornea verticillata, angiokeratoma) or increased plasma (lyso)Gb3 (classical male range) or family members with definite FD. Subjects with LVH failing these criteria have a GVUS and an uncertain diagnosis. The gold standard was defined as characteristic storage in an endomyocardial biopsy on electron microscopy. Abnormally low voltages on ECG and severe LVH (MWT>15 mm) <20 years exclude FD. Other criteria were rejected due to insufficient evidence., Conclusions: In adults with unexplained LVH and a GLA GVUS, severe LVH at young age and low voltages on ECG exclude FD. If absent, an endomyocardial biopsy with electron microscopy should be performed., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: Whether uric acid (UA) serves as risk factor for cardiovascular diseases or as antioxidant defense has not yet been completely clarified. In this study we investigated the effects of UA on functional recovery in patients receiving cardiac rehabilitation., Methods and Results: 306 patients, 209 men and 97 women, age range 25-87 years (mean 68 ± 11), performed the 6-min walk test (6mWT) before and after the rehabilitation, and the increase in walking distance was considered as the outcome measure of the study. Baseline UA serum levels ranged from 1.0 to 10.9 mg/dL (mean 5.2 ± 1.7). As there was a significant (p = 0.005) age*UA levels interaction, patients were divided into two subgroups, less then 65 years (n. 103, 68 men and 35 women, mean age 56 ± 9) and 65 years or more (n. 203, 141 men and 62 women, mean age 74 ± 5). After adjusting for relevant confounders, higher UA levels remained independent positive predictors of the increase in walking distance in older (p < 0.001) but not in younger patients (p = 0.807)., Conclusions: Our findings show an independent association of higher UA levels with better functional recovery after cardiac rehabilitation selectively in elderly patients, suggesting that higher UA levels might reflect the decline in antioxidant defenses that occurs with advancing age. Future studies aimed at understanding the several contradictions concerning UA should, probably, address the issue within this perspective., (© 2013 Elsevier B.V. All rights reserved.)

Background: The 12-lead electrocardiogram (ECG) is considered an essential screening tool for hypertrophic cardiomyopathy (HCM). A vast array of ECG abnormalities has been described in HCM, although their relationship to left ventricle (LV) morphology and degree of hypertrophy appears elusive. Aim of this study was to assess the relationship of ECG patterns with the HCM phenotype assessed according to the novel opportunities offered by cardiac magnetic imaging (CMR)., Methods: CMR and 12-lead ECG were performed in 257 HCM patients. Severity of ECG abnormalities was defined by the sum of 9 criteria: abnormal cardiac rhythm, QRS duration ≥ 100 ms, Romhilt-Estes score ≥ 5, fascicular block (LAHB) and/or bundle-branch block (LBBB or RBBB), ST-T abnormalities, ST-T segment elevation ≥ 0.2 mV, prolonged QTc interval, pathological Q waves, absence of normal Q wave. Four ECG groups were identified: normal (0 criteria); mildly abnormal (1-3 criteria); moderately abnormal (4-6 criteria); markedly abnormal (7-9 criteria)., Results: There was a direct relationship between severity of ECG abnormalities and HCM phenotype. LV mass index was normal in most patients with normal ECG and progressively increased with each class of ECG score, from 70.9 ± 18.6g/m(2) in patients with normal ECG to 107.1 ± 55.1g/m(2) among those with markedly abnormal ECG (p=<0.0001). Likewise, the prevalence and extent of late gadolinium enhancement (LGE) increased significantly with the ECG score, from 37% in patients with normal ECG to 93% in patients with markedly abnormal ECG (overall p=0.0012). A normal ECG had a negative predictive accuracy of 96% for markedly increased LV mass (>91 g/m(2) for men and >69 g/m(2) for women), and of 100% for maximum LV thickness ≥ 30 mm., Conclusions: In a large HCM cohort, the number and severity of ECG abnormalities were directly related to phenotypic expression as revealed by CMR. Although false negative ECG findings remain a challenge in population screenings for HCM, a normal ECG proved effective in ruling out severe LV hypertrophy, suggesting potential implications for long-term follow-up of HCM patients and family members. A simple score for quantification of ECG abnormalities in HCM patients is proposed., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The occurrence and removal of 42 pharmaceuticals, belonging to different therapeutic groups (analgesics and anti-inflammatory drugs, anti-ulcer agent, psychiatric drugs, antiepileptic drug, antibiotics, ß-blockers, diuretics, lipid regulator and cholesterol lowering statin drugs and anti-histamines), were studied in the wastewater and sewage sludge trains of a full scale integrated treatment plant. The plant employs a biological nutrient removal (BNR) process for the treatment of municipal wastewater, and a single-stage mesophilic anaerobic co-digestion for the treatment of wasted activated sludge mixed with the organic fraction of municipal solid waste (OFMSW), followed by a short-cut nitrification-denitrification of the anaerobic supernatant in a sequential batch reactor. Influent and effluent wastewater, as well as thickened, digested and treated sludge were sampled and analyzed for the selected pharmaceuticals in order to study their presence and fate during the treatment. Twenty three compounds were detected in influent and effluent wastewater and eleven in sludge. Infiltration of groundwater in the sewer system led to a dilution of raw sewage, resulting in lower concentrations in wastewater (up to 0.7 μg/L in influent) and sludge (70 ng/g d.w.). Due to the dilution, overall risk quotient for the mixture of pharmaceuticals detected in effluent wastewater was less than one, indicating no direct risk for the aquatic environment. A wide range of removal efficiencies during the treatment was observed, i.e. <20% to 90%. The influent concentrations of the target pharmaceuticals, as polar compounds, were undoubtedly mostly affected by BNR process in the wastewater train, and less by anaerobic-co-digestion. Mass balance calculations showed that less than 2% of the total mass load of the studied pharmaceuticals was removed by sorption. Experimentally estimated distribution coefficients (<500 L/kg) also indicated that the selected pharmaceuticals preferably remain in the aqueous phase, and that biodegradation/transformation is the primary removal mechanism for these compounds during wastewater treatment., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background and Aim: Previous studies have shown that increased levels of C-reactive protein (CRP) predict cardiovascular events, including stroke, myocardial infarction and death from cardiovascular causes. Previous studies have also shown that increased levels of CRP are strong predictors of the progression of pre-existing carotid artery plaques. However, whether CRP is involved in the development of new plaques, that may or may not be associated with clinical events, in subjects with clean carotid arteries has been scarcely investigated., Methods and Results: 486 "InCHIANTI" Study participants (200 men and 286 women, 72% aged 65 years and over) free from carotid artery plaques at baseline, also underwent carotid artery scan three years later. We tested the association of baseline characteristics, cardiovascular risk factors and inflammatory markers with the development of new carotid artery plaques. Older participants were significantly more likely to develop new plaques. Independent of age, the relative risks of developing new plaques associated with heavy smoking and family history of atherosclerosis were 1.7 (95%CI 1.5-1.9) and 1.9 (95%CI 1.2-3.1), respectively. Participants with high (>3 μg/mL) and moderate (≥1 and ≤3 μg/mL) CRP levels had a relative risk of 2.2 (95%CI 1.9-2.6) and 1.9 (95%CI 1.6-2.3) respectively, when compared with subjects with low (<1 μg/mL) CRP levels. Surprisingly, risk factors such as hypertension, diabetes, dyslipidemia and overweight/obesity were not significant predictors of the development of new carotid artery plaques., Conclusions: High CRP levels independently predict the development of new plaques in older persons with carotid arteries free from atherosclerotic lesions., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Glycosaminoglycans are found in human tissues including plasma. They encompass chondroitin sulphates, heparan sulphate/heparin, hyaluronic acid, and keratan sulphate. Glycosaminoglycans, in particular heparan sulphate and heparin, are strongly associated with plasma proteins, so that their purification results quite difficult., Methods: In order to study the distribution of glycosaminoglycans in plasma subfractions, we developed a novel method that allows their identification even if they were still associated with proteins or peptides. Plasma was fractionated following the procedure of Cohn-Oncley, and each fraction was treated with proteases. After centrifugation, glycosaminoglycan/protein complexes in the supernatant were analysed using a modified cellulose acetate electrophoresis which allowed identification of glycosaminoglycans in mixtures of glycosaminoglycans/proteins., Results: Chondroitin sulphate was recovered in cryoprecipitate and in all Cohn-Oncley fractions. Glycosaminoglycans belonging to the class of heparan sulphate/heparin, however, were recovered in the cryoprecipitate and in fractions I and IV-1, and, in smaller amount, in fraction II+III., Conclusions: Since the largest amount of plasma proteins is partitioned in Factions II+III and V, these results demonstrate that heparan sulphate/heparin are not randomly distributed in Cohn-Oncley fractions and are associated with certain plasma proteins. This association might play a role in the physiological function of heparan sulphate/heparin, regulating hemostasis and atherogenesis.

An Italian version of the Sickness Impact Profile (SIP) obtained by professional and nonprofessional translators was checked for cross-cultural equivalence using a back-translation method followed by two scaling studies. The first scaling study involved 30 health professionals who ranked the items within each category for severity of dysfunction. By comparing Italian and US average ranks, 14 highly discordant items were identified. A revised translation was evaluated in a new study involving 120 observers stratified by age (< 65 versus > or = 65 years) and profession (health versus non health professionals) into 4 groups of the same size. The Italian and American item rank orders were almost equivalent, independently of the age and profession of the observers (93% of the ranks showing differences < 2), suggesting that this Italian version of SIP is cross-culturally unbiased. However, older age was associated with higher variability in the rank orders, and some caution is required for use in the geriatric population.

The anaerobic digestion of source separated organic fraction of municipal solid wastes was studied by using a stirred 3 cubic meter working volume reactor fed on a semicontinuous basis. The behaviour and performance of the digester at various organic loading rates was illustrated with particular regard to turnover of the gas production rate during a cycle in the digester feed.