ResearchPad - 40 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Characterisation of buried blast loading]]> https://www.researchpad.co/article/N97187253-6563-4419-ae0b-a85e0d7feacc While it is well known that detonation of shallow-buried high explosive charges generally results in above-surface loading which is greatly amplified compared with the same detonation in air, uncertainty persists as to the mechanisms leading to this effect. The work presented in this paper is a systematic investigation into the mechanisms of load transfer in buried blast events. This paper details the results from a parametric study into the mechanisms and magnitudes of load transfer following a shallow-buried explosion, where spatial and temporal load distributions are directly measured on a rigid surface using an array of Hopkinson pressure bars. In particular, the investigation has looked at the influence of both geometrical confinement and geotechnical conditions on the loading. The parametric study was separated into four main threads: the influence of physical confinement; gravimetric moisture content; stand-off distance and depth of burial; and soil material/particle size distribution. This study allows a direct observation of the contributions of each of these distinct parameters, and in particular the ability to discern how each parameter influences the temporal form and spatial distribution of the loading.

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<![CDATA[The variation of grain size distribution in rock granular material in seepage process considering the mechanical–hydrological–chemical coupling effect: an experimental research]]> https://www.researchpad.co/article/N0e6c100f-bf56-4e0a-b780-cbe5890eac9b

As a common solid waste in geotechnical engineering, rock granular material should be properly treated and recycled. Rock granular material often coexists with water when it is used as the filling material in geotechnical engineering. Water flowing in rock granular materials is a complex progress with the mechanical–hydrological–chemical (MHC) coupling effect, i.e. the water scours in the gaps and spaces in the rock granular material structure, produces chemical reactions with rock grains, rock grains squeeze each other under the water pressure and compression leading to re-breakage and producing secondary rock grains, and the fine rock grains are migrated with water and rushed out. In this process, rock grain size distribution (GSD) changes, it affects the physical and mechanical characteristics of the rock granular materials, and even influences the seepage stability of the rock granular materials. To study the variation of GSD in the rock granular material considering the MHC coupling effect after the seepage process, seepage experiments of rock grain samples are carried out and analysed in this paper. The result is expected to have a positive impact on further studies of the properties of the rock granular material.

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<![CDATA[Numerical simulation on fracturing behaviour of hard roofs at different levels during extra-thick coal seam mining]]> https://www.researchpad.co/article/Ne92c3a34-1cb3-4f23-8cfb-ad34b0c9e040

In fully mechanized caving mining of extra-thick coal seams, the movement range of overburden is wide, resulting in the breakage of multilayer hard roofs in overlying large spaces. However, the characteristics, morphology and impact effect of hard roofs at different levels are different and unclear. In this study, a secondary development was used in the numerical simulation software ABAQUS, and the caving of rock strata in the finite-element software was realized. The bearing stress distribution, fracturing morphology and impact energy characteristics of hard roofs at different levels were studied to reflect the action and difference of hard roof failure on the working face; thus, revealing the mechanism of the strong ground pressure in stopes, and providing a theoretical basis for the safe and efficient mining of extra-thick coal seams with hard roofs.

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<![CDATA[Utilization of metakaolin-based geopolymer as a mud-cake solidification agent to enhance the bonding strength of oil well cement–formation interface]]> https://www.researchpad.co/article/N089adae7-2535-4254-99f4-a0753c58e3f2

This research work designed a novel mud-cake solidification method to improve the zonal isolation of oil and gas wells. The calculation methodology of mud-cake compressive strength was proposed. The optimal formula of activator and solid precursors, the proper activating time and the best activator concentration were determined by the compressive strength test. The effects of solid precursors on the properties of drilling fluid were evaluated. Test results show that the respective percentage of bentonite, metakaolin, slag and activator is 1 : 1 : 0.3 : 0.8, as well as the optimum ratio of Na2SiO3/NaOH is 40 : 1. The optimum concentration of activator is 0.21 and the activating time should be more than 10 min. The solid precursors did not show any bad influence on the rheological property of drilling fluids. Even though the compressive strength decreased when the solid precursors blended with barite, the strength values can still achieve 8 MPa. The reaction of metakaolin and activator formed cross-link structure in the mud-cake matrix, which enhanced the connection of the loose bentonite particles, lead to the significant enhancement of shear bonding strength and hydraulic bonding strength. This mud-cake solidification method provides a new approach to improve the quality of zonal isolation.

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<![CDATA[COL4A1-related autosomal recessive encephalopathy in 2 Turkish children]]> https://www.researchpad.co/article/N92f3a2c7-0fe5-4ced-ab42-ae91ad9b01b6

Objective

This study presents the neurologic phenotypes of 2 brothers with a novel homozygous COL4A1 mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases.

Methods

Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents.

Results

We have identified a homozygous missense mutation in COL4A1 (p.Gly1278Ser, NM_001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease.

Conclusions

COL4A1 has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that COL4A1-related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotype-phenotype correlations remain to be established.

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<![CDATA[Maize defective kernel5 is a bacterial TamB homologue required for chloroplast envelope biogenesis]]> https://www.researchpad.co/article/N9c1c8244-f067-452f-8dd9-754c84146579

Zhang et al. show that the maize dek5 locus is required for chloroplast envelope biogenesis and encodes a TamB-like protein. Bacterial TamB proteins facilitate insertion of β-barrel outer membrane proteins, indicating plastids have a conserved mechanism for envelope membrane biogenesis.

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<![CDATA[Response-level processing during visual feature search: Effects of frontoparietal activation and adult age]]> https://www.researchpad.co/article/N62021aba-2a5d-4803-8bde-29d5be7b55df

Previous research suggests that feature search performance is relatively resistant to age-related decline. However, little is known regarding the neural mechanisms underlying the age-related constancy of feature search. In this experiment, we used a diffusion decision model of reaction time (RT), and event-related functional magnetic resonance imaging (fMRI) to investigate age-related differences in response-level processing during visual feature search. Participants were 80 healthy, right-handed, community-dwelling individuals, 19–79 years of age. Analyses of search performance indicated that targets accompanied by response-incompatible distractors were associated with a significant increase in the nondecision-time (t0) model parameter, possibly reflecting the additional time required for response execution. Nondecision time increased significantly with increasing age, but no age-related effects were evident in drift rate, cautiousness (boundary separation, a), or in the specific effects of response compatibility. Nondecision time was also associated with a pattern of activation and deactivation in frontoparietal regions. The relation of age to nondecision time was indirect, mediated by this pattern of frontoparietal activation and deactivation. Response-compatible and -incompatible trials were associated with specific patterns of activation in the medial and superior parietal cortex, and frontal eye field, but these activation effects did not mediate the relation between age and search performance. These findings suggest that, in the context of a highly efficient feature search task, the age-related influence of frontoparietal activation is operative at a relatively general level, which is common to the task conditions, rather than at the response level specifically.

Electronic supplementary material

The online version of this article (10.3758/s13414-019-01823-3) contains supplementary material, which is available to authorized users.

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<![CDATA[Contribution of normal aging to brain atrophy in MS]]> https://www.researchpad.co/article/N6475fbba-0f1d-4623-9bc0-c35c7013e9f6

Objective

To identify the top brain regions affected by MS-specific atrophy (i.e., atrophy in excess of normal aging) and to test whether normal aging and MS-specific atrophy increase or decrease in these regions with age.

Methods

Six hundred fifty subjects (2,790 MRI time points) were analyzed: 520 subjects with relapse-onset MS from a 5-year prospective cohort with annual standardized 1-mm 3D T1-weighted images (3DT1s; 2,483 MRIs) and 130 healthy controls with longitudinal 3DT1s (307 MRIs). Rates of change in all FreeSurfer regions (v5.3) and Structural Image Evaluation Using Normalization of Atrophy (SIENA) were estimated with mixed-effects models. All FreeSurfer regions were ranked by the MS-specific atrophy slope/standard error ratio (βMS × time/SEβMS × time). In the top regions, age was added as an effect modifier to test whether MS-specific atrophy varied by age.

Results

The top-ranked regions were all gray matter structures. For SIENA, normal aging increased from 0.01%/y at age 30 years to −0.31%/y at age 60 years (−0.11% ± 0.032%/decade, p < 0.01), whereas MS-specific atrophy decreased from −0.38%/y at age 30 years to −0.12%/y at age 60 years (0.09% ± 0.035%/decade, p = 0.01). Similarly, in the thalamus, normal aging increased from −0.15%/y at age 30 years to −0.62%/y at age 60 years (−0.16% ± 0.079%/decade, p < 0.05), and MS-specific atrophy decreased from −0.59%/y at age 30 years to −0.05%/y at age 60 years (0.18% ± 0.08%/decade, p < 0.05). In the putamen and caudate, normal aging and MS-specific atrophy did not vary by age.

Conclusions

For SIENA and thalamic atrophy, the contribution of normal aging increases with age, but does not change in the putamen and caudate. This may have substantial implications to understand the biology of brain atrophy in MS.

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<![CDATA[Untangling normal aging from disease-related brain atrophy in MS]]> https://www.researchpad.co/article/Nf10589fe-173b-431e-8788-944f39e1938f ]]> <![CDATA[Vitamin D enhances responses to interferon-β in MS]]> https://www.researchpad.co/article/Na0a29217-f952-4c3b-ae9a-68f48d141a8b

Objective

To determine the effect of vitamin D3 on interferon-β (IFN-β) response and immune regulation in MS mononuclear cells (MNCs).

Methods

MNCs from 126 subjects, including therapy-naive patients with different forms of MS, plus patients with MS receiving IFN-β or glatiramer treatment, plus healthy controls were incubated in vitro with IFN-β-1b ± vitamin D3 (calcitriol). Activation of the IFN-β–induced transcription factor, p-Y-STAT1, and antiviral myxovirus A (MxA) protein was measured with flow cytometry and Western blots; serum proteins were measured with a customized 31-protein multiplex assay.

Results

Vitamin D enhanced in vitro IFN responses, as measured by induction of p-Y-STAT1 and MxA in MNCs, T cells, and monocytes. Vitamin D augmentation of IFN responses was seen in untreated and in IFN-β-1b–treated MS. The combination of vitamin D plus IFN-β reduced Th1 and Th17 cytokines, and increased Th2 responses, reversing the effect of IFN-β alone. Exacerbations and progression in untreated patients reduced the vitamin D enhancement of IFN responses. Vitamin D had less effect on IFN response in clinically stable glatiramer-treated than in IFN-β–treated patients.

Conclusion

Vitamin D enhances IFN-β induction of multiple proteins and also reverses the Th1/Th2 bias in MS seen with IFN-β alone. The combination of vitamin D and IFN-β has potential benefit in ameliorating MS.

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<![CDATA[Identification of circulating MOG-specific B cells in patients with MOG antibodies]]> https://www.researchpad.co/article/N6b5d861c-2119-40be-b4a4-9c1646602c0c

Objective

To identify circulating myelin oligodendrocyte glycoprotein (MOG)-specific B cells in the blood of patients with MOG antibodies (Abs) and to determine whether circulating MOG-specific B cells are linked to levels and epitope specificity of serum anti-MOG-Abs.

Methods

We compared peripheral blood from 21 patients with MOG-Abs and 26 controls for the presence of MOG-specific B cells. We differentiated blood-derived B cells in vitro in separate culture wells to Ab-producing cells via engagement of Toll-like receptors 7 and 8. We quantified the anti-MOG reactivity with a live cell–based assay by flow cytometry. We determined the recognition of MOG epitopes with a panel of mutated variants of MOG.

Results

MOG-Ab–positive patients had a higher frequency of MOG-specific B cells in blood than controls, but MOG-specific B cells were only detected in about 60% of these patients. MOG-specific B cells in blood showed no correlation with anti-MOG Ab levels in serum, neither in the whole group nor in the untreated patients. Epitope analysis of MOG-Abs secreted from MOG-specific B cells cultured in different wells revealed an intraindividual heterogeneity of the anti-MOG autoimmunity.

Conclusions

This study shows that patients with MOG-Abs greatly differ in the abundance of circulating MOG-specific B cells, which are not linked to levels of MOG-Abs in serum suggesting different sources of MOG-Abs. Identification of MOG-specific B cells in blood could be of future relevance for selecting patients with MOG-Abs for B cell–directed therapy.

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<![CDATA[Atti del 52° Congresso Nazionale]]> https://www.researchpad.co/article/N40742df4-0c85-42be-960e-c80df7e02214

Nel promuovere e gestire i cambiamenti necessari per coniugare pratiche sicure ed efficaci con l’efficienza, l’equità e la sostenibilità dei servizi sanitari, essenziale è la conoscenza, la diffusione e l’adesione alle raccomandazioni per la pratica professionale derivanti da linee guida (LG). In Italia la Legge 24/2017 (“Disposizioni in materia di sicurezza delle cure e della persona assistita, nonché in materia di responsabilità professionale degli esercenti le professioni sanitarie”), stabilendo che “gli esercenti le professioni sanitarie, nell’esecuzione delle prestazioni sanitarie con finalità preventive, diagnostiche, terapeutiche, palliative, riabilitative e di medicina legale, si attengono, salve le specificità del caso concreto, alle raccomandazioni previste dalle linee guida pubblicate ed elaborate da enti e istituzioni pubblici e privati nonché dalle società scientifiche e dalle associazioni tecnico-scientifiche delle professioni sanitarie iscritte in apposito elenco”, ha rinnovato l’impulso legislativo, culturale, professionale e scientifico alla diffusione delle LG nel Servizio Sanitario Nazionale. L’attuale quadro regolamentare italiano prevede che la loro produzione venga garantita sulla base degli standard di predisposizione e valutazione della qualità metodologica definiti dal Centro Nazionale per l’Eccellenza Clinica (CNEC) dell’Istituto Superiore di Sanità, punto di riferimento per l’attuazione del nuovo Sistema Nazionale Linee Guida (istituito con il DM 27 febbraio 2018) (https://snlg.iss.it).

Secondo la vigente definizione adottata dal CNEC, le LG sono uno “strumento di supporto decisionale finalizzato a consentire che, fra opzioni alternative, sia adottata quella che offre un migliore bilancio fra benefici ed effetti indesiderati, tenendo conto della esplicita e sistematica valutazione delle prove disponibili, commisurandola alle circostanze peculiari del caso concreto e condividendola-laddove possibile-con il paziente o i caregiver”. Le linee guida servono dunque a supportare i processi decisionali che connotano la pratica professionale preventiva, diagnostica, terapeutica e assistenziale, ma anche le scelte manageriali e le politiche sanitarie. Ai diversi livelli del sistema sanitario, infatti, la disponibilità di LG è fondamentale per contrastare alcune delle criticità sistemiche della sanità connesse, tra l’altro, all’erogazione di cure di qualità sub-ottimale, alla variazione ingiustificata di pratiche ed esiti e alle diseguaglianze, in un quadro di risorse limitate.

Se dunque oggi il valore delle linee guida per la pratica clinica è indiscutibile in tutti gli ambiti disciplinari della medicina, peculiare è il significato, professionale e organizzativo, che le stesse possono assumere nello sviluppo e nella specifica applicazione alla sanità pubblica. In particolare, la sanità pubblica si caratterizza per: la forte eterogeneità nelle evidenze scientifiche disponibili (non di rado costituite solamente da studi osservazionali), l’adozione di un approccio di population health e la frequente individuazione di target costituiti da persone sane, la molteplicità (anche in relazione all’importanza attribuita dagli stakeholder coinvolti) degli ambiti di produzione di linee guida (www.who.int/publications/guidelines), degli interventi sanitari e degli outcome individuati nei contesti reali (e non di ricerca), condizionati da una molteplicità di variabili culturali, organizzative, socio-economiche e ambientali.

Spesso le raccomandazioni prodotte in sanità pubblica sono destinate ad avere un impatto quali-quantitativamente molto rilevante sul sistema sanitario e necessitano di modelli in grado di prevederne l’implementazione, non sempre agevolmente correlabili alle evidenze scientifiche disponibili a priori. Altresì, il percorso di costruzione del consenso e implementazione degli interventi è articolato e complesso. In misura maggiore rispetto ad altre discipline mediche, i comportamenti degli operatori non si basano solo sulle conoscenze tecnico-scientifiche disponibili (talora limitate e non sempre esplicitamente generalizzabili), ma risentono e sono condizionati da dettati normativi, meccanismi di consenso locale, eterogeneità di strutture erogatrici e risorse (professionali, organizzative e tecnologiche), nonché da relazioni con una molteplicità di portatori di interesse dentro e fuori il sistema sanitario (che a loro volta esprimono valori e preferenze anche contrastanti).

Il metodo scelto dal CNEC (e adottato anche dall’Agenzia Italiana del Farmaco per le valutazioni di propria competenza) per la produzione di linee guida è il metodo GRADEGrading of Recommendations Assessment, Development and Evaluation – che costituisce oggi la principale cornice riferimento per la valutazione di affidabilità delle prove scientifiche e per la formulazione di raccomandazioni cliniche basate sulle evidenze in sanità: viene utilizzato da più di 100 organizzazioni in tutto il mondo comprendenti anche l’Organizzazione Mondiale della Sanità e il National Institute for Health and Care Excellence (www.gradeworkinggroup.org). Il GRADE assicura standardizzazione e trasparenza della procedura con cui viene valutata la qualità delle prove disponibili e la forza delle raccomandazioni per la produzione di linee guida, favorendo una valutazione integrata della qualità metodologica delle prove disponibili con altri aspetti che devono essere considerati per sviluppare e stabilire la forza di una raccomandazione, mediante i cosiddetti Evidence to Decision Framework, quali: priorità della problematica trattata (es. impatto sanitario, variabilità, costi), benefici e rischi attesi, valori e preferenze dei pazienti, costo-efficacia, accettabilità, fattibilità ed equità. Il GRADE offre un approccio flessibile e pragmatico che può essere applicato sia alla produzione di una linea guida ex novo che all’adattamento di linee guida già esistenti, per le quali si applicano gli schemi di GRADE-ADOLOPMENT, calibrati su un determinato contesto culturale e organizzativo. Il panel di esperti (gruppi di lavoro multidisciplinari e multistakeholder che sistematicamente devono coinvolgere anche utenti/cittadini) definisce chiaramente la domanda di ricerca, il protocollo condiviso secondo l’acronimo PICO (Patient-Intervention-Comparator-Outcome) per l’analisi della qualità delle prove di evidenza ed esprimere giudizi sui diversi criteri di valutazione necessari alla formulazione e valutazione della forza delle raccomandazioni. Mediante una gestione trasparente (e una particolare attenzione alla disclosure e alla gestione dei conflitti di interesse dei membri dei panel), fortemente ancorata al mondo reale, con il processo di “evidence to decision” il GRADE si pone l’obiettivo di ordinare per gradi la forza delle raccomandazioni espresse dai panel di esperti in modo da offrire strumenti interpretativi e decisionali per pazienti/utenti, clinici e decisori sanitari. La rappresentatività e il coinvolgimento con modalità strutturate di tutte le figure competenti e rilevanti per i quesiti e sulle raccomandazioni in oggetto costituisce un aspetto fondamentale di qualità e credibilità della linea guida.

Accanto alla chiara affinità tra metodo GRADE e logiche epidemiologiche e di centralità di un approccio multidimensionale, multidisciplinare e inter-professionale che caratterizza il processo decisionale in sanità pubblica, è interessante evidenziare l’opportunità della promozione dell’applicazione del GRADE per gli igienisti sia nella veste di proponenti, esperti per gli ambiti tecnico-scientifici di propria competenza e destinatari “professionali” delle raccomandazioni, che in qualità di manager e decisori che possono essere coinvolti nei panel (anche su pratiche di non esclusiva pertinenza della sanità pubblica), nonché, naturalmente di metodologi, parte dei team di revisione della letteratura e a supporto dell’utilizzo del metodo stesso che richiede una specifica formazione e competenza.

Gli indirizzi sulle LG comprendono anche la fase di implementazione attinente come a partire dalle raccomandazioni prodotte e diffuse si riesce ad incidere sui comportamenti professionali, ovvero colmare il gap tra ricerca e pratica professionale. Questo richiede leadership e facilitazione del giusto mix di interventi (preferibilmente multifattoriali) di supporto al cambiamento (audit & feedback, interventi formativi mirati, processi di consenso locali, uso di strumenti di comunicazione, ecc), calibrati su ostacoli e fattori favorenti l’adozione delle linee guida. L’implementazione di LG promuove la gestione e la condivisione di informazioni, conoscenze e pratiche che favoriscono un approccio trasversale rispetto alle funzioni e ai team di lavoro che promuove l’integrazione (sia all’interno che con l’esterno delle organizzazioni sanitarie) e può assicurare processi decisionali più affidabili ed efficienti.

La coerenza tra raccomandazioni per l’ottimizzazione dell’efficacia e altre dimensioni della qualità dell’intervento sanitario (quali sicurezza, accessibilità ed equità) con le esigenze di efficienza e razionalità organizzativa dei servizi configura un importante ancoraggio delle LG al paradigma emergente del valore in sanità. Costruire una sanità basata sul valore implica una chiara analisi del profilo di efficacia degli interventi sanitari e la disponibilità di robusti strumenti valutativi e infrastrutture digitali di supporto alla misurazione accurata e tempestiva dei dati epidemiologici della popolazione, da trasformare in informazioni cliniche rilevanti per integrare e analizzare tutti i passaggi (e i risultati ottenuti) del ciclo di assistenza in oggetto e da correlare costantemente con i costi sostenuti dal sistema sanitario. Massimizzare il valore, ovvero gli esiti prodotti in relazione alle risorse a disposizione, per gli individui e le popolazioni presuppone l’adozione di criteri di finanziamento e di gestione delle risorse (umane e organizzative) e soluzioni tecnologiche che facilitino la costruzione di reti e percorsi, da coniugare con la capacità di tradurre i risultati della ricerca sanitaria e le best practice in raccomandazioni. D’altro canto, la diffusione di pratiche sicure, efficaci e appropriate consente di concorrere in maniera determinante all’uniformità di tassonomia, modelli e comportamenti professionali in contesti decisionali affini, ovvero di contribuire a standardizzare l’operatività dei servizi, aspetto quest’ultimo rilevante nel contesto della sanità pubblica italiana e delle sue articolazioni operative territoriali.

L’adozione di linee guida ovviamente presenta anche aspetti di criticità, legati all’effettiva traduzione dei risultati della ricerca e dell’innovazione in comportamenti professionali diffusi e virtuosi; ma anche all’adeguatezza delle LG e dei correlati processi decisionali di fronte a quesiti o target di popolazione per loro natura complessi, come quelli che si incontrano per esempio nel produrre indirizzi che siano effettivamente rispondenti alle esigenze di prevenzione e personalizzazione dell’assistenza del “paziente complesso”. A ciò vanno aggiunte alcune difficoltà organizzative e professionali che connotano l’odierna fase di avvio della concreta applicazione del metodo GRADE allo sviluppo delle raccomandazioni per la pratica clinica proposto nel “nuovo Sistema Nazionale Linee Guida”. Per esempio, rispetto alla sanità pubblica, pur esistendo oggi molte LG autorevoli e di diffusa applicazione, queste spesso risultano essere datate e realizzate con meccanismi di consenso e formulazione delle raccomandazioni di tipo tradizionale, rendendo dunque necessari aggiornamenti e adattamenti secondo le menzionate modalità di lavoro proposte a livello nazionale e internazionale per produrre linee guida di alta qualità.

Per operare nel quadro della nuova cornice metodologica sulle LG, ai medici e agli altri professionisti sanitari, ai manager e ai policy maker della sanità, al mondo accademico e alle società scientifiche è richiesto un investimento prioritario nella gestione di conoscenze fondate su un approccio scientifico, strutturato e trasparente alla definizione dell’efficacia e dell’appropriatezza degli interventi medici. In questo contesto nazionale, per gli igienisti in collaborazione con tutti gli attori della Sanità Pubblica, è strategico un impegno permanente sulla tematica delle linee guida, da sostenere anche mediante azioni di formazione, condivisione di conoscenza e di comunicazione. Valorizzare l’applicazione critica di strumenti per governare i processi decisionali secondo logiche di partecipazione e fiducia reciproca tra gli stakeholder è fondamentale per il perseguimento degli obiettivi di ottimizzazione della qualità e della sostenibilità nel Servizio Sanitario Nazionale, a beneficio dei cittadini-pazienti e della società nella sua globalità.

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<![CDATA[Quantitative 7T MRI does not detect occult brain damage in neuromyelitis optica]]> https://www.researchpad.co/article/5c973e41d5eed0c48496b30c

Objective

To investigate and compare occult damages in aquaporin-4 (AQP4)-rich periependymal regions in patients with neuromyelitis optica spectrum disorder (NMOSD) vs healthy controls (HCs) and patients with multiple sclerosis (MS) applying quantitative T1 mapping at 7 Tesla (T) in a cross-sectional study.

Methods

Eleven patients with NMOSD (median Expanded Disability Status Scale [EDSS] score 3.5, disease duration 9.3 years, age 43.7 years, and 11 female) seropositive for anti-AQP4 antibodies, 7 patients with MS (median EDSS score 1.5, disease duration 3.6, age 30.2 years, and 4 female), and 10 HCs underwent 7T MRI. The imaging protocol included T2*-weighted (w) imaging and an MP2RAGE sequence yielding 3D T1w images and quantitative T1 maps. We semiautomatically marked the lesion-free periependymal area around the cerebral aqueduct and the lateral, third, and fourth ventricles to finally measure and compare the T1 relaxation time within these areas.

Results

We did not observe any differences in the T1 relaxation time between patients with NMOSD and HCs (all p > 0.05). Contrarily, the T1 relaxation time was longer in patients with MS vs patients with NMOSD (lateral ventricle p = 0.056, third ventricle p = 0.173, fourth ventricle p = 0.016, and cerebral aqueduct p = 0.048) and vs HCs (third ventricle p = 0.027, fourth ventricle p = 0.013, lateral ventricle p = 0.043, and cerebral aqueduct p = 0.005).

Conclusion

Unlike in MS, we did not observe subtle T1 changes in lesion-free periependymal regions in NMOSD, which supports the hypothesis of a rather focal than diffuse brain pathology in NMOSD.

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<![CDATA[Cystatin C for predicting all-cause mortality and rehospitalization in patients with heart failure: a meta-analysis]]> https://www.researchpad.co/article/5c800fe2d5eed0c484a96867

Circulating cystatin C (cys-C/CYC) has been identified as an independent predictor of all-cause mortality in patients with coronary artery disease and the general population. This meta-analysis aimed to systematically evaluate the association between elevated cys-C level and all-cause mortality and rehospitalization risk amongst patients with heart failure (HF). PubMed and Embase databases were searched until December 2017. All prospective observational studies that reported a multivariate-adjusted risk estimate of all-cause mortality and/or rehospitalization for the highest compared with lowest cys-C level in HF patients were included. Ten prospective studies involving 3155 HF patients were included. Meta-analysis indicated that the highest compared with lowest cys-C level was associated with an increased risk of all-cause mortality (hazard ratio (HR): 2.33; 95% confidence intervals (CI): 1.67–3.27; I2 = 75.0%, P<0.001) and combination of mortality/rehospitalization (HR: 2.06; 95%CI: 1.58–2.69; I2 = 41.6%, P=0.181). Results of stratified analysis indicated that the all-cause mortality risk was consistently found in the follow-up duration, cys-C cut-off value or type of HF subgroup. Elevated cys-C level is possibly associated with an increased risk of all-cause mortality and rehospitalization in HF patients. This increased risk is probably independent of creatinine or estimated glomerular filtration rate (eGFR).

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<![CDATA[Serum profile of cytokines and their genetic variants in metabolic syndrome and healthy subjects: a comparative study]]> https://www.researchpad.co/article/5c6863f1d5eed0c484023c8a

Aim: To identify genetic variants in promoter areas of IL-6 -174 G>C and TNF-α -308 G>A in metabolic syndrome (Met S) and controls and associate them with Met S and serum cytokine levels.

It was a cross-sectional study, including 224 cases of Met S and 200 controls. A fasting blood sample was taken and biochemical parameters including serum glucose, insulin, lipid profile, interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) were measured. Restriction fragment length polymorphism was used to identify the genetic variants of IL-6 and TNF-α. Serum levels of IL-6 and TNF-α and insulin resistance were significantly higher in cases than the controls. IL-6 showed significant positive correlation with HOMA-IR and TNF-α. CC genotype of IL-6 was associated with the increased risk of Met S (P=0.016, OR for CC vs GC+GG = 2.33, CI: 1.15–4.71). There was no significant difference of TNF-α genotypes between the cases and the controls. Serum TNF-α and IL-6 levels were significantly higher in AA and CC genotypes of TNF-α (-308 G>A) and IL-6 (-174 G>C) as compared with the GG (P=0.00 and P=0.001). Significant correlation of IL-6 with TNF-α and insulin resistance was observed that may provide us a therapeutic target for preventing metabolic derangements from insulin resistance.

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<![CDATA[Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy]]> https://www.researchpad.co/article/5c5f19d1d5eed0c484699d64

Objective

To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1).

Methods

Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed.

Results

We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region.

Conclusions

We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.

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<![CDATA[Real-world validation of the 2017 McDonald criteria for pediatric MS]]> https://www.researchpad.co/article/5c5f19ddd5eed0c484699dd0

Objective

To compare the diagnostic accuracy of the McDonald 2017 vs the McDonald 2010 criteria to predict a second attack of MS (clinically definite MS [CDMS]) at the first attack of acquired demyelinating syndromes (ADS).

Methods

One hundred sixty-four children (aged <18 years) with an incident attack of ADS were included in a prospective multicenter study between June 2006 and December 2016. Brain (and spinal if available) MRI was performed ≤3 months after symptom onset. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were compared at baseline between the 2010 and 2017 criteria.

Results

Among the 164 patients, 110 patients (67%) presented without encephalopathy (ADS–, female 63%; median age 14.8 years, IQR 11.3–16.1years) and 54 (33%) with encephalopathy (acute disseminated encephalomyelitis [ADEM], female 52%; median age 4.0 years, IQR 2.6–6.1 years). Of the 110 ADS– patients, 52 (47%) were diagnosed with CDMS within a median follow-up of 4.5 years (IQR 2.6–6.7 years). The sensitivity was higher for the 2017 criteria than for the 2010 criteria (83%; 95% CI 67–92, vs 49%; 95% CI 33–65; p < 0.001), but the specificity was lower (73%; 95% CI 59–84 vs 87%; 95% CI 74–94, p = 0.02). At baseline, 48 patients fulfilled the 2017 criteria compared with 27 patients when using the 2010 criteria. The results for children aged <12 years without encephalopathy were similar. In patients with ADEM, 8% fulfilled the 2010 criteria and 10% the 2017 criteria at baseline but no patient fulfilled the criteria for CDMS.

Conclusions

The McDonald 2017 criteria are more sensitive than the McDonald 2010 criteria for predicting CDMS at baseline. These criteria can also be applied in children aged <12 years without encephalopathy but not in children with ADEM.

Classification of evidence

This study provides Class II evidence that in children with ADS, the 2017 McDonald criteria are more sensitive but less specific than the 2010 McDonald criteria for predicting CDMS.

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<![CDATA[The deregulation of STIM1 and store operative calcium entry impaired aortic smooth muscle cells contractility in aortic medial degeneration]]> https://www.researchpad.co/article/5c4b93dad5eed0c48487d17f

Background: Microarray analysis of clinical aortic samples suggested a potential role for stromal interaction molecule 1 (STIM1) in the modulation of aortic medial degeneration (AMD), despite the uncertainty about STIM1 in normal aortic smooth muscle cells (ASMCs). Here, we aimed to explore changes in STIM1 expression in AMD, and the possible mechanisms. Methods: An AMD model was established using auto-delivery of angiotensin II (Ang II) into ApoE−/− mice. We assessed the effects of SKF96365, a STIM1 inhibitor, in AMD model and in vitro cultured ASMCs. Elastic van Gieson (EVG) staining was used to visualize elastic fiber injury. Mitochondria changes were viewed by TEM. Cytoplasmic calcium was quantified by measuring fluo-4 staining in a flow cytometer. Mechanical stretching device was used to mimic stretching that ASMCs experience in vivo. Cell apoptosis was determined by using Annexin V/propidium iodide (PI) staining. The expression of STIM1, contractile related proteins (α-smooth muscle actin (α-SMA), myosin light chain (MLC)), endoplasmic reticulum (ER) stress-related proteins (CHOP, activating transcription factor 6 (ATF-6)) and smad2/3 were assessed by Western blotting, immunohistochemistry (IHC), and immunofluorescence (IF). Results: SKF96365 exacerbated aortic injury in the AMD model. SKF96365 reduced cytoplasmic calcium concentration in ASMCs, caused mitochondrial swelling, and elevated the expression of ATF-6 and CHOP. SKF96365 decreased the expression of MLC and α-SMA in ASMCs, causing them to be vulnerable to mechanical stretch. SKF96365 suppressed smad2/3 activation after treatment with transforming growth factor (TGF) β1 (TGFβ1). Conclusions: STIM1 is indispensable in ASMCs. Interfering with STIM1 exaggerated the AMD process by modulating the expression of contractile proteins, inducing ER stress in ASMCs.

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<![CDATA[Functional and structural studies of tolloid-like 1 mutants associated with atrial-septal defect 6]]> https://www.researchpad.co/article/5c4b93e5d5eed0c48487d36e

Inactive mammalian tolloid-like 1 (tll1) and mutations detected in tolloid-like 1 (TLL1) have been linked to the lack of the heart septa formation in mice and to a similar human inborn condition called atrial-septal defect 6 (ASD6; OMIM 613087, formerly ASD II). Previously, we reported four point mutations in TLL1 found in approximately 20% of ASD6 patients. Three mutations in the coding sequence were M182L, V238A, and I629V. In this work, we present the effects of these mutations on TLL1 function. Three recombinant cDNA constructs carrying the mutations and one wild-type construct were prepared and then expressed in HT-1080 cells. Corresponding recombinant proteins were analyzed for their metalloendopeptidase activity using a native substrate, chordin. The results of these assays demonstrated that in comparison with the native TLL1, mutants cleaved chordin and procollagen I at significantly lower rates. CD analyses revealed significant structural differences between the higher order structure of wild-type and mutant variants. Moreover, biosensor-based assays of binding interactions between TLL1 variants and chordin demonstrated a significant decrease in the binding affinities of the mutated variants. The results from this work indicate that mutations detected in TLL1 of ASD6 patients altered its metalloendopeptidase activity, structure, and substrate-binding properties, thereby suggesting a possible pathomechanism of ASD6.

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<![CDATA[AMPK: a therapeutic target of heart failure—not only metabolism regulation]]> https://www.researchpad.co/article/5c4b93d6d5eed0c48487d0f5

Heart failure (HF) is a serious disease with high mortality. The incidence of this disease has continued to increase over the past decade. All cardiovascular diseases causing dysfunction of various physiological processes can result in HF. AMP-activated protein kinase (AMPK), an energy sensor, has pleiotropic cardioprotective effects and plays a critical role in the progression of HF. In this review, we highlight that AMPK can not only improve the energy supply in the failing heart by promoting ATP production, but can also regulate several important physiological processes to restore heart function. In addition, we discuss some aspects of some potential clinical drugs which have effects on AMPK activation and may have value in treating HF. More studies, especially clinical trials, should be done to evaluate manipulation of AMPK activation as a potential means of treating HF.

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