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Reproductive genetic carrier screening (RGCS) provides people with information about their chance of having children with autosomal recessive or X-linked genetic conditions, enabling informed reproductive decision-making. RGCS is recommended to be offered to all couples during preconception or in early pregnancy. However, cost and a lack of awareness may prevent access. To address this, the Australian Government funded Mackenzie’s Mission—the Australian Reproductive Genetic Carrier Screening Project. Mackenzie’s Mission aims to assess the acceptability and feasibility of an easily accessible RGCS program, provided free of charge to the participant. In study Phase 1, implementation needs were mapped, and key study elements were developed. In Phase 2, RGCS is being offered by healthcare providers educated by the study team. Reproductive couples who provide consent are screened for over 1200 genes associated with >750 serious, childhood-onset genetic conditions. Those with an increased chance result are provided comprehensive genetic counseling support. Reproductive couples, recruiting healthcare providers, and study team members are also invited to complete surveys and/or interviews. In Phase 3, a mixed-methods analysis will be undertaken to assess the program outcomes, psychosocial implications and implementation considerations alongside an ongoing bioethical analysis and a health economic evaluation. Findings will inform the implementation of an ethically robust RGCS program.

PURPOSE: Genes associated with nonsyndromic hearing loss are commonly included in reproductive carrier screening panels, which are now routinely offered in preconception and prenatal care in many countries. However, there is debate whether hearing loss should be considered a medical condition appropriate for screening. This systematic review assessed research on opinions of those with a lived experience of deafness and the general public regarding genetic testing for deafness in the reproductive setting. METHODS: Search of 5 online databases yielded 423 articles, 20 of which met inclusion criteria. We assessed the quality of each study, extracted data, and performed thematic analysis on qualitative studies. RESULTS: Most studies indicated interest in the use of prenatal diagnosis for deafness. However, there were mixed views, and sometimes strongly held views, expressed regarding the reproductive options that should be available to those with an increased chance of having a child with deafness. Studies were small, from a limited number of countries, and most were too old to include views regarding preimplantation genetic testing. CONCLUSION: There is a broad range of views regarding the use of reproductive options for deafness. Further research is essential to explore the benefits and harms of including nonsyndromic hearing loss genes in carrier screening.

In the exploratory Phase II STEM-AMI (Stem Cells Mobilization in Acute Myocardial Infarction) trial, we reported that early administration of G-CSF (granulocyte colony-stimulating factor), in patients with anterior ST-segment-elevation myocardial infarction and left ventricular (LV) dysfunction after successful percutaneous coronary intervention, had the potential to significantly attenuate LV adverse remodeling in the long-term.The STEM-AMI OUTCOME CMR (Stem Cells Mobilization in Acute Myocardial Infarction Outcome Cardiac Magnetic Resonance) Substudy was adequately powered to evaluate, in a population showing LV ejection fraction ≤45% after percutaneous coronary intervention for extensive ST-segment-elevation myocardial infarction, the effects of early administration of G-CSF in terms of LV remodeling and function, infarct size assessed by late gadolinium enhancement, and myocardial strain.Within the Italian, multicenter, prospective, randomized, Phase III STEM-AMI OUTCOME trial, 161 ST-segment-elevation myocardial infarction patients were enrolled in the CMR Substudy and assigned to standard of care (SOC) plus G-CSF or SOC alone. In 119 patients (61 G-CSF and 58 SOC, respectively), CMR was available at baseline and 6-month follow-up. Paired imaging data were independently analyzed by 2 blinded experts in a core CMR lab. The 2 groups were similar for clinical characteristics, cardiovascular risk factors, and pharmacological treatment, except for a trend towards a larger infarct size and longer symptom-to-balloon time in G-CSF patients. ANCOVA showed that the improvement of LV ejection fraction from baseline to 6 months was 5.1% higher in G-CSF patients versus SOC (P=0.01); concurrently, there was a significant between-group difference of 6.7 mL/mEarly administration of G-CSF exerted a beneficial effect on top of SOC in patients with LV dysfunction after extensive ST-segment-elevation myocardial infarction in terms of global systolic function, adverse remodeling, scar size, and myocardial strain.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01969890.

We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts. A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases of interstitial lung disease (ILD) without interdisciplinary consultation. Diagnostic agreement was measured using the weighted kappa coefficient (κw). Prognostic discrimination between IPF and other ILDs was used to validate diagnostic accuracy for first-choice diagnoses of IPF and were compared using the C-index. A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (κw=0.65, IQR 0.53–0.72, p20 years of experience (C-index=0.72, IQR 0.0–0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70–0.72, p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 IQR 0.72–0.75). Experienced respiratory physicians at university-based institutions diagnose IPF with similar prognostic accuracy to IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts., Academic status, access to MDT meetings and clinician experience predict accuracy of a clinical diagnosis of IPF http://ow.ly/k43W30cTMg1

Background: Cell therapy with bone marrow (BM)-derived progenitors has emerged as a promising therapeutic for refractory angina (RA) patients. In the present study, we evaluated the safety and preliminary efficacy of transcatheter delivery of autologous BM-derived advanced therapy medicinal product CD133 + cells (ATMP-CD133) in RA patients, correlating perfusion outcome with cell function. Methods: In the phase I "Endocavitary Injection of Bone Marrow Derived CD133 + Cells in Ischemic Refractory Cardiomyopathy" (RECARDIO) trial, a total of 10 patients with left ventricular (LV) dysfunction (ejection fraction ≤ 45%) and evidence of reversible ischemia, as assessed by single-photon emission computed tomography (SPECT), underwent BM aspiration and fluoroscopy-based percutaneous endomyocardial delivery of ATMP-CD133. Patients were evaluated at 6 and 12 months for safety and preliminary efficacy endpoints. ATMP-CD133 samples were used for in vitro correlations. Results: Patients were treated safely with a mean number of 6.57 ± 3.45 × 10 6 ATMP-CD133. At 6-month follow-up, myocardial perfusion at SPECT was significantly ameliorated in terms of changes in summed stress (from 18.2 ± 8.6 to 13.8 ± 7.8, p = 0.05) and difference scores (from 12.0 ± 5.3 to 6.1 ± 4.0, p = 0.02) and number of segments with inducible ischemia (from 7.3 ± 2.2 to 4.0 ± 2.7, p = 0.003). Similarly, Canadian Cardiovascular Society and New York Heart Association classes significantly improved at follow-up vs baseline (p ≤ 0.001 and p = 0.007, respectively). Changes in summed stress score changes positively correlated with ATMP-CD133 release of proangiogenic cytokines HGF and PDGF-bb (r = 0.80, p = 0.009 and r = 0.77, p = 0.01, respectively) and negatively with the proinflammatory cytokines RANTES (r = - 0.79, p = 0.01) and IL-6 (r = - 0.76, p = 0.02). Conclusion: Results of the RECARDIO trial suggested safety and efficacy in terms of clinical and perfusion outcomes in patients with RA and LV dysfunction. The observed link between myocardial perfusion improvements and ATMP-CD133 secretome may represent a proof of concept for further mechanistic investigations. Trial registration: ClinicalTrials.gov, NCT02059681. Registered 11 February 2014.

P53 status may be a determinant of chemosensitivity of tumor cells; however, its involvement in cellular resistance to cisplatin remains uncertain. To investigate the relationships between p53 and the development of resistance to cisplatin, the p53 gene status was studied in ovarian carcinoma cell systems which included two cisplatin-resistant variants (IGROV-1/Pt 0.5 and IGROV-1/Pt 1) selected in vitro after prolonged drug exposure of the cisplatin-sensitive parental IGROV-1 cell line. IGROV-1/Pt 0.5 and IGROV-1/Pt 1 cell lines exhibited a degree of resistance of approximately 6 and 14, respectively, following 96-h exposure to the drug and were cross-resistant to other DNA-damaging agents (ionizing radiation and melphalan). Resistance to cisplatin paralleled a reduced cell susceptibility to cisplatin-induced apoptosis. DNA single-strand conformation polymorphism analysis of exons 5-9 demonstrated the presence of two mutants alleles at exon 8 in the two resistant cell lines, in contrast to the parental IGROV-1 cell line which exhibited the wild-type p53 gene. Direct DNA sequencing revealed that the mutations consist of two nucleotide changes in the DNA-binding domain at codons 270 (T/A) and 282 (C/T). The consecutive levels of p53 protein were lower in IGROV-1 than in IGROV-1/Pt cells. Following exposure to ionizing radiation or cisplatin, accumulation of the p53 protein was markedly enhanced only in the sensitive cells. Concomitantly, the expression of WAF-1 protein was strongly induced in the parental IGROV-1 cells, whereas WAF-1 protein remained undetectable in the IGROV-1/Pt 1 subline after DNA-damaging treatment. Consistent with this finding is the observation that ionizing radiation caused a different pattern of cell cycle perturbation in sensitive and resistant cells. Northern blot analysis demonstrated a marked reduction in bax mRNA levels in IGROV-1/Pt 1 cisplatin-resistant cells. Cotransfection assays with wild-type or mutant p53 expression plasmids and a reporter gene plasmid that utilized the bax gene promoter to drive transcription of chloramphenicol acetyltransferase were consistent with the role of p53 in regulation of bax expression in these cells. Taken together, these observations support a role for mutations of the p53 gene in the development of cisplatin resistance in ovarian cancer as a consequence of loss of the ability of p53 to transactivate bax, an apoptosis-inducing gene.

La condizione dei diritti della povertà appare oggi come una nuova emergenza. Uno dei compiti necessari di ogni politica di inclusione, che non voglia porsi al tempo stesso come una semplice omologazione all'ordine, dovrebbe essere la salvaguardia - anche all'interno di quella che è pur sempre un'imposizione del diritto - di ogni eventuale spazio che la povertà e la sua differenza siano ancora in grado di rivendicare, rispetto alla norma che ne ha 'cura'. Questo spazio della differenza potrebbe forse interrogarci nuovamente anche sulla verità dell'ordine economico che, ostinatamente, nonostante le sue crisi, la 'legge' continua a replicare e a difendere.

Il testo propone una riflessione circa il compito con cui l’offĭcĭo filosofico può essere nuovamente aggiornato nella condizione attuale. Compito che per la filosofia non può essere che quello di un esercizio della differenza inteso come esercizio della critica.

Il saggio intende analizzare l'attuale dibattito sul relativismo al di là del solito conflitto fra dogmatismo e universalismo, ma evidenziandone il rapporto con le forme di consumo sostenute dai valori veicolati dal marketing pubblicitario, con i quali il Consumatore è chiamato a definire modelli e forme di esistenza.

Il "miracolo" della TV, quello di cui oggi celebriamo la fine, insieme al suo trasferimento nel digitale e nel cyberspazio, non è tanto (o non solo) quello dell'informazione e della sua 'democraticità', fatto per molti versi in discussione e che Debord aveva già descritto nei termini della 'non-verità', ma ciò che questa 'menzogna' rende possibile: la costruzione di credibilità, attendibilità, che l'informazione (con la sua forma ambigua) riesce infine a realizzare.

Il saggio analizza la figura del Consumatore dal punto di vista etico, politico e giuridico, confrontandola con la figura del Cittadino che, nell'ordinamento occidentale, è il depositario dei diritti civili, politici e sociali. Da questo punto di vista, il Consumatore risulta figura molto più debole e priva di sostanziali diritti, se non quelli ad essa riconosciuti dalle regole del mercato.

Rationale: In the exploratory Phase II STEM-AMI (Stem Cells Mobilization in Acute Myocardial Infarction) trial, we reported that early administration of G-CSF (granulocyte colony-stimulating factor), in patients with anterior ST-segment–elevation myocardial infarction and left ventricular (LV) dysfunction after successful percutaneous coronary intervention, had the potential to significantly attenuate LV adverse remodeling in the long-term. Objective: The STEM-AMI OUTCOME CMR (Stem Cells Mobilization in Acute Myocardial Infarction Outcome Cardiac Magnetic Resonance) Substudy was adequately powered to evaluate, in a population showing LV ejection fraction ≤45% after percutaneous coronary intervention for extensive ST-segment–elevation myocardial infarction, the effects of early administration of G-CSF in terms of LV remodeling and function, infarct size assessed by late gadolinium enhancement, and myocardial strain. Methods and Results: Within the Italian, multicenter, prospective, randomized, Phase III STEM-AMI OUTCOME trial, 161 ST-segment–elevation myocardial infarction patients were enrolled in the CMR Substudy and assigned to standard of care (SOC) plus G-CSF or SOC alone. In 119 patients (61 G-CSF and 58 SOC, respectively), CMR was available at baseline and 6-month follow-up. Paired imaging data were independently analyzed by 2 blinded experts in a core CMR lab. The 2 groups were similar for clinical characteristics, cardiovascular risk factors, and pharmacological treatment, except for a trend towards a larger infarct size and longer symptom-to-balloon time in G-CSF patients. ANCOVA showed that the improvement of LV ejection fraction from baseline to 6 months was 5.1% higher in G-CSF patients versus SOC ( P =0.01); concurrently, there was a significant between-group difference of 6.7 mL/m 2 in the change of indexed LV end-systolic volume in favor of G-CSF group ( P =0.02). Indexed late gadolinium enhancement significantly decreased in G-CSF group only ( P =0.04). Moreover, over time improvement of global longitudinal strain was 2.4% higher in G-CSF patients versus SOC ( P =0.04). Global circumferential strain significantly improved in G-CSF group only ( P =0.006). Conclusions: Early administration of G-CSF exerted a beneficial effect on top of SOC in patients with LV dysfunction after extensive ST-segment–elevation myocardial infarction in terms of global systolic function, adverse remodeling, scar size, and myocardial strain. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01969890.

The aim of this study was to examine the association between biomarkers of polyunsaturated fatty acids (PUFA), such as omega-3 (ω-3) index and arachidonic acid (AA; 20:4 ω-6)/eicosapentaenoic acid (EPA; 20:5ω-3) ratio (AA/EPA), and the prevalence of running-related injuries (RRI) in a cohort of recreational runners. We performed a retrospective, observational study of 275 non-elite runners (mean age: 41.20 ± 12.47 years) who were not supplemented with ω-3 fatty acids. The training characteristics and RRI were recorded over a period of 12 months through a self-reported questionnaire. Using whole blood samples collected by finger prick, PUFA were quantified by gas chromatography and ω-3 index and AA/EPA ratio measured. A total of 191 RRI cases were reported, with an injury prevalence rate of 50.9% in the overall population. The injured runners ran a significantly greater weekly distance than uninjured subjects (53.54 ± 25.27 km/week; p = 0.007). In a multivariate regression analysis, the lowest number of RRI was associated with higher values of ω-3 index (β = - 0.237; 95% CI - 0.308 to - 0.164; R2 = 0.172; p

Cardiovascular disease (CVD) remains the leading cause of death today. Many of the biochemical alterations associated with the pathophysiology of CVD can be modified by adequate intakes of bioactive nutrients through a correct diet or supplementation. Recently, there has been growing public and clinical interest in cocoa polyphenols (CPs) and omega-3 (ω-3) fatty acids. A plethora of nutritional intervention trials and experimental studies demonstrates that consumption of these bioactive food compounds is beneficial to promote cardiovascular health. The purpose of this review is to summarize the major cardioprotective effects of CPs and ω-3 fatty acids, providing a scientific rationale for incorporating the combination of these molecules as a nutritional intervention in the prevention of CVD. Although several studies have shown the individual cardioprotective nature of these compounds, a combination treatment with CPs and ω-3 fatty acids may be a promising approach to enhance the preventive value of these molecules and reduce cardiovascular risk factors associated with aging. Therefore, this article also reviews some of the key studies on the interaction between CPs and the metabolism of ω-3 fatty acids.

Background: Extracorporeal cardiopulmonary resuscitation is increasingly recognised as a rescue therapy for refractory cardiac arrest, nevertheless data are scanty about its effects on neurologic and cardiac outcome. The aim of this study is to compare clinical outcome in patients with cardiac arrest of ischaemic origin (i.e. critical coronary plaque during angiography) and return of spontaneous circulation during conventional cardiopulmonary resuscitation vs refractory cardiac arrest patients needing extracorporeal cardiopulmonary resuscitation. Moreover, we tried to identify predictors of survival after successful cardiopulmonary resuscitation. Methods: We enrolled 148 patients with ischaemic cardiac arrest admitted to our hospital from 2011–2015. We compared clinical characteristics, cardiac arrest features, neurological and echocardiographic data obtained after return of spontaneous circulation (within 24 h, 15 days and six months). Results: Patients in the extracorporeal cardiopulmonary resuscitation group ( n=63, 43%) were younger (59±9 vs 63±8 year-old, p=0.02) with lower incidence of atherosclerosis risk factors than those with conventional cardiopulmonary resuscitation. In the extracorporeal cardiopulmonary resuscitation group, left ventricular ejection fraction was lower than conventional cardiopulmonary resuscitation at early echocardiography (19±16% vs 37±11 pConclusions: Extracorporeal cardiopulmonary resuscitation patients are younger and have less comorbidities than conventional cardiopulmonary resuscitation, but they have worse survival and lower early left ventricular ejection fraction. Survivors after extracorporeal cardiopulmonary resuscitation have a neurological outcome and recovery of heart function comparable to subjects with return of spontaneous circulation. Total cardiac arrest time is the only predictor of survival after cardiopulmonary resuscitation in both groups.

Background: Tissue availability of polyunsaturated fatty acids (PUFA) depends on several factors, including dietary intake, physical exercise, genetic variation, and metabolic turnover. However, there is limited evidence whether running training activity per se may influence indices associated with PUFA metabolism such as Omega-3 (ω-3) index and arachidonic acid (AA; 20:4ω-6)/eicosapentaenoic acid (EPA; 20:5ω-3) ratio. Objective: To examine the association between kilometers (Km) run per week and changes in ω-3 index and AA/EPA ratio. Methods: We conducted a retrospective, observational, cohort study of 257 non-elite runners (mean age: 40.85 ± 12.17 years) who consumed no fatty acid supplements and provided a blood sample for analysis. The whole blood samples were collected by finger sticks, stored on absorbent filter paper, and then PUFA were quantified by gas chromatography (GC) and ω-3 index and AA/EPA ratio measured. Results: In a multivariate linear regression model, a gradual decrease of the ω-3 index was observed with higher weekly running distance (β = −0.033; 95% CI −0.039 to −0.026; R2 = 0.447; p < 0.0001). We also found a progressive increase of the AA/EPA ratio in subjects who ran greater weekly distances (β = 0.092; 95% CI 0.038 to 0.146; R2 = 0.320; p = 0.001). No other significant associations were observed with other variables, including years of running training and weekly training frequency (hours/week). Finally, as expected, a significant inverse correlation between ω-3 index and AA/EPA ratio (β = −2.614; 95% CI −3.407 to −1.821; R2 = 0.336; p < 0.0001) was detected. Conclusions: These findings suggest that distance running training and its weekly volume may negatively contribute to changes of the ω-3 index and AA/EPA ratio. Further studies with greater sample size will be required to replicate and extend these data.

Among established techniques for the identification of either known or new mutations, denaturing gradient gel electrophoresis (DGGE) is one of the most effective. However, conventional DGGE is affected by major drawbacks that limit its routine application: the different denaturant gradient ranges and migration times required for different DNA fragments. We developed a modified version of DGGE for high-throughput mutational analysis, double gradient DGGE (DG-DGGE), by superimposing a porous gradient over the denaturant gradient, which maintains the zone-sharpening effect even during lengthy analyses. Because of this innovation, DG-DGGE achieves the double goals of retaining full effectiveness in the detection of mutations while allowing identical run time conditions for all fragments analyzed. Here we use retrospective analysis of a large number of well-characterized mutations and polymorphisms, spanning all predicted melting domains and the whole genomic sequence of three different genes—the cystic fibrosis transmembrane conductance regulator (CFTR), the β-globin, and the p53 genes—to demonstrate that DG-DGGE may be applied to the rapid scanning of any sequence variation.

Il presente lavoro intende approfondire un aspetto del pensiero di Foucault ancora poco indagato, per quanto ben noto e indicato da diversi studiosi come un aspetto essenziale del suo lavoro e, più in generale, del pensiero francese contemporaneo. Se i rapporti di Foucault con il pensiero nietzschiano sono infatti al centro di alcuni studi specifici, e se il pensiero di Nietzsche è ormai unanimemente indicato come uno dei riferimenti principali di Foucault, in realtà, le implicazioni di questo rapporto, e il modo in cui Foucault utilizza gli strumenti del pensiero nietzschiano, rimangono avvolti da una certa oscurità e risentono spesso di un’impostazione letteraria generalizzante. Al contrario, in modo approfondito e con risvolti originali, lo studio intende restituire all’interpretazione nietzschiana di Foucault una complessità per molti aspetti inedita. I temi che Foucault assume da Nietzsche e che costituiscono lo sfondo concettuale delle sue opere, dando forma al suo metodo critico, non sono infatti univoci, ma mostrano differenze specifiche a seconda dei diversi momenti del suo pensiero. Ripercorrendo per intero l’opera e la riflessione di Foucault, il libro mette quindi in luce le diverse letture di Nietzsche presenti in Foucault, per rivelare, allo stesso tempo, l’originalità dell’interpretazione foucaultiana rispetto a quella di altri autori contemporanei.

Procedendo per rapporti diretti con altri autori, da Lyotard a Hadot, da Blanchot a Jaspers e a Bachtin, da Nietzsche a Heidegger, il libro intende offrire una lettura del pensiero di Foucault approfondendo alcuni temi che ne caratterizzano il percorso e che in parte rimangono ancora poco indagati (com'è il caso, per esempio, del rapporto di Foucault con il "Formalismo russo"). Centro dell'analisi è il tentativo di chiarire la posizione di Foucault rispetto al post-moderno. La ripresa insistita, a partire dalla fine degli anni 70, dei temi relativi all'Illuminismo, alla modernità e all'entusiasmo, rappresenta certamente un segnale preciso del percorso che la teoria post-moderna ha avuto in Foucault, dopo le valorizzazioni del "dionisiaco". Ora, a partire da questi aspetti, siamo forse in grado di tentare un'ulteriore conclusione. Dopo la pubblicazione degli ultimi corsi al Collège de France sembra infatti possibile indicare con chiarezza la via d'uscita che Foucault aveva intrapreso rispetto alla al post-moderno, e su cui aveva indirizzato la propria "ontologia dell'attualità". Il tema dell'ascesi, l'assunsione di una regola di vita opposta al sistema e il coraggio di "dire la verità" sono infatti le "risposte" che il post-moderno non contemplava, e che ne costituiscono anche una chiara contestazione.