ResearchPad - 13 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Prognostic impact of pre-existing interstitial lung disease in non-HIV patients with <i>Pneumocystis</i> pneumonia]]> https://www.researchpad.co/article/elastic_article_12763 Pre-existing interstitial lung disease (ILD) is an independent prognostic risk factor for non- HIV Pneumocystis pneumonia (PCP). Prophylaxis for PCP is needed in patients with pre-existing ILD under immunosuppression. http://bit.ly/37BGZuK

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<![CDATA[Paneth cell α-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice]]> https://www.researchpad.co/article/N4cdc74ff-002c-45bb-8f1d-ad7f957c837c Crohn’s disease (CD) is an intractable inflammatory bowel disease, and dysbiosis, disruption of the intestinal microbiota, is associated with CD pathophysiology. ER stress, disruption of ER homeostasis in Paneth cells of the small intestine, and α-defensin misfolding have been reported in CD patients. Because α-defensins regulate the composition of the intestinal microbiota, their misfolding may cause dysbiosis. However, whether ER stress, α-defensin misfolding, and dysbiosis contribute to the pathophysiology of CD remains unknown. Here, we show that abnormal Paneth cells with markers of ER stress appear in SAMP1/YitFc, a mouse model of CD, along with disease progression. Those mice secrete reduced-form α-defensins that lack disulfide bonds into the intestinal lumen, a condition not found in normal mice, and reduced-form α-defensins correlate with dysbiosis during disease progression. Moreover, administration of reduced-form α-defensins to wild-type mice induces the dysbiosis. These data provide novel insights into CD pathogenesis induced by dysbiosis resulting from Paneth cell α-defensin misfolding and they suggest further that Paneth cells may be potential therapeutic targets.

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<![CDATA[Microparticle-mediated VZV propagation and endothelial activation]]> https://www.researchpad.co/article/N659fdc51-9299-4fd6-80c4-5b25afca9387

Objective

Varicella zoster virus (VZV) can spread anterogradely and infect cerebral arteries causing VZV vasculopathy and arterial ischemic stroke. In this study, we tested the hypothesis that virus-infected cerebrovascular fibroblasts undergo phenotypic changes that promote vascular remodeling and facilitate virus transmission in an in vitro model of VZV vasculopathy. The aims of this project were therefore to examine the changes that virus-infected human brain adventitial vascular fibroblasts (HBVAFs) undergo in an in vitro model of VZV vasculopathy and to identify disease biomarkers relating to VZV-related vasculopathy.

Methods

HBVAFs were infected with VZV, and their ability to migrate, proliferate, transdifferentiate, and interact with endothelial cells was studied with flow cytometry. Microparticles (MPs) released from these cells were isolated and imaged with transmission electron microscopy, and their protein content was analyzed with mass spectrometry. Circulating MP profiles were also studied in children with VZV and non-VZV vasculopathy and compared with controls.

Results

VZV-infected HBVAFs transdifferentiated into myofibroblasts with enhanced proliferative and migratory capacity. Interaction of VZV-infected HBVAFs with endothelial cells resulted in endothelial dysfunction. These effects were, in part, mediated by the release of MPs from VZV-infected HBVAFs. These MPs contained VZV virions that could transmit VZV to neighboring cells, highlighting a novel model of VZV cell-to-cell viral dissemination. MPs positive for VZV were significantly higher in children with VZV-related vasculopathy compared to children with non-VZV vasculopathy (p = 0.01) and controls (p = 0.007).

Conclusions

VZV-infected HBVAFs promote vascular remodeling and facilitate virus transmission. These effects were mediated by the release of apoptotic MPs that could transmit VZV infection to neighboring cells through a Trojan horse means of productive viral infection. VZV+ MPs may represent a disease biomarker worthy of further study.

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<![CDATA[How consistently do physicians diagnose and manage drug-induced interstitial lung disease? Two surveys of European ILD specialist physicians]]> https://www.researchpad.co/article/N7b39363e-f269-4f81-ba00-bda0f90d72ee

Introduction

Currently there are no general guidelines for diagnosis or management of suspected drug-induced (DI) interstitial lung disease (ILD). The objective was to survey a sample of current European practice in the diagnosis and management of DI-ILD, in the context of the prescribing information approved by regulatory authorities for 28 licenced drugs with a recognised risk of DI-ILD.

Methods

Consultant physicians working in specialist ILD centres across Europe were emailed two surveys via a website link. Initially, opinion was sought regarding various diagnostic and management options based on seven clinical ILD case vignettes and five general questions regarding DI-ILD. The second survey involved 29 statements regarding the diagnosis and management of DI-ILD, derived from the results of the first survey. Consensus agreement was defined as 75% or greater.

Results

When making a diagnosis of DI-ILD, the favoured investigations used (other than computed tomography) included pulmonary function tests, bronchoscopy and blood tests. The preferred method used to decide when to stop treatment was a pulmonary function test. In the second survey, the majority of the statements were accepted by the 33 respondents, with only four of 29 statements not achieving consensus when the responses “agree” and “strongly agree” were combined as one answer.

Conclusion

The two surveys provide guidance for clinicians regarding an approach to the diagnosis and management of DI-ILD in which the current evidence base is severely lacking, as demonstrated by the limited information provided by the manufacturers of the drugs associated with a high risk of DI-ILD that we reviewed.

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<![CDATA[Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study]]> https://www.researchpad.co/article/Nc37a7aa3-4d2f-449b-9abe-9a659eea3349

In patients with primary or secondary lung tumour treated with immune checkpoint inhibitors, immune-related pneumonitis is a rare adverse event but may evolve to respiratory failure. Prompt management is required and usually consists of treatment interruption and immunosuppressive drug administration. The aim of this study was to evaluate relationships between immune-related pneumonitis and pre-existing parenchymal status, especially tumour location and history of chest radiotherapy.

Computed tomography (CT) scans of patients with immune-related pneumonitis were retrospectively reviewed. Pattern, distribution and extent of pneumonitis were assessed in six lung regions. In patients who received radiotherapy, the extent of pneumonitis was evaluated according to the radiation field.

Among 253 patients treated with immunotherapy, 15 cases of immune-related pneumonitis were identified. 10 had previous or concomitant chest radiotherapy in addition to immunotherapy. At CT scan, 29 (33%) out of 88 regions encompassed the primary tumour (n=4), a lung metastasis (n=4) and/or radiation fields (n=21). A significantly higher prevalence of parenchymal involvement by immune-related pneumonitis occurred within areas of primary or metastatic malignancy and/or radiation field (97%) as compared to other areas (3%, p=0.009). Lung regions affected by the primary tumour, metastasis or radiotherapy had a higher probability of immune-related pneumonitis than others (OR 10.8, p=0.024). An organising pneumonia (OP) pattern was more frequent after radiotherapy (70% versus 0%, p=0.024), whereas nonspecific interstitial pneumonia features were more commonly seen in radiotherapy-naive patients (100% versus 10%, p=0.002).

In patients with primary or secondary lung tumour treated with immune checkpoint inhibitors, immune-related pneumonitis is preferentially located within lung areas involved by tumour and/or radiation fields.

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<![CDATA[Clinical implications of ANCA positivity in idiopathic pulmonary fibrosis patients]]> https://www.researchpad.co/article/N83272b0b-711c-41bf-9ab1-0dae269ded58

The diagnostic process of idiopathic interstitial pneumonias (IIPs) is complex and the underlying mechanisms that participate in these diseases still need to be fully understood. In 2015, the European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-Associated Interstitial Lung Disease introduced the term “interstitial pneumonia with autoimmune features” (IPAF) to identify subjects with IIP and features suggesting background autoimmunity but not characterisable connective tissue disease (CTD) [1]. The need for a proper clinical, serological and morphological assessment of IIP was highlighted to identify potential subjects with IPAF and CTD-ILD. However, the measurement of anti-neutrophil cytoplasmic antibodies (ANCAs) is not included in the definition of IPAF and ANCA serological testing is only recommended in idiopathic pulmonary fibrosis (IPF) when a clinical suspicion of vasculitis exists [2]. As current research evaluates the prognostic relevance of autoimmune features in IIP, the clinical importance of ANCA positivity still needs to be determined.

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<![CDATA[Increasing mortality rate due to rheumatoid arthritis-related lung diseases in Japan]]> https://www.researchpad.co/article/N3efdaab2-fd8a-429b-9edd-6e0892489812

The quality of life of rheumatoid arthritis (RA) patients has dramatically improved in the approximately two decades since biological agents were first introduced for its treatment [1]. However, whether current treatment strategies for RA have helped improve the prognosis of patients suffering from complications due to RA remains controversial. National data from the USA have shown that the mortality rate of RA-associated interstitial lung disease (ILD), a major complication associated with a poor prognosis in RA patients, seems to be gradually increasing, whereas the mortality rate of patients with any type of RA-associated disease has been decreasing [2].

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<![CDATA[The RNA exosome nuclease complex regulates human embryonic stem cell differentiation]]> https://www.researchpad.co/article/Ne8da9728-a5df-4d19-b6d8-4a6e659197f5

This work shows that the exosome modulates the levels of LINE-1 retrotransposons and specific miRNAs, lncRNAs, and mRNAs that encode developmental regulators or affect their expression. The exosome restrains stem cell differentiation in part by degrading transcripts encoding FOXH1, a transcription factor crucial for mesendoderm formation.

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<![CDATA[Skeletal muscle oxygenation and regional blood volume during incremental limb loading in interstitial lung disease]]> https://www.researchpad.co/article/Nbe39e102-5119-4541-b5e9-b874aa55d148

Introduction

Individuals with interstitial lung disease (ILD) exhibit reduced exercise capacity and exertional hypoxaemia. The role of peripheral (muscle) limitation to exercise tolerance in ILD is not well studied to date.

Methods

A prospective cross-sectional study examined skeletal muscle oxygen saturation (SmO2) and regional blood volume of the knee extensors and elbow flexors during incremental limb loading in healthy people and people with varying severity of ILD. Isotonic concentric exercise was performed on an isokinetic dynamometer. SmO2 and regional blood volume were measured by near-infrared spectroscopy over the vastus lateralis and biceps.

Results

Thirteen people who were dependent on oxygen, candidates for lung transplant and with severe ILD (forced vital capacity (FVC) 59±20% predicted), 10 people who were not oxygen dependent with mild ILD (FVC 81±17% predicted) and 13 healthy people (FVC 101±14% predicted) were included. Total haemoglobin, a marker of regional blood volume, was lower at task failure in the knee extensors in participants with severe ILD compared to healthy participants (p=0.05). At task failure for both knee-extensor loading and elbow-flexor loading, SmO2 was decreased to similar levels across all groups, but occurred at lower total workloads in the ILD groups (all p<0.01).

Conclusions

Overall, people with severe ILD had lower levels of total work and experienced less increase in blood volume in the knee extensors after knee-extensor loading compared to healthy people. Peripheral muscle dysfunction in severe ILD may have contributed to muscle deoxygenation at lower workloads.

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<![CDATA[Validation of a new serum granulocyte–macrophage colony-stimulating factor autoantibody testing kit]]> https://www.researchpad.co/article/N2afbccaf-a12c-475f-8986-8a7bd4972fab

Very recently, a modest but significant efficacy of granulocyte–macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported.

As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use.

As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL−1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP.

The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases.

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<![CDATA[Efficacy and safety of nintedanib in a Greek multicentre idiopathic pulmonary fibrosis registry: a retrospective, observational, cohort study]]> https://www.researchpad.co/article/N11b8cb90-736b-4915-90f2-e271e7c5d320

Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF). In a retrospective, real-world study across seven Greek hospitals, we evaluated the effectiveness and safety of nintedanib in routine clinical practice. Patients diagnosed with IPF, as per guideline criteria or multidisciplinary diagnosis, received nintedanib between January 2013 and January 2018.

We evaluated 244 patients: mean±sd age 71.8±7.5 years, 79.1% male, 45.1% current smokers and 33.1% ex-smokers at treatment initiation. At baseline, predicted forced vital capacity (FVC) was 73.3±20.7% and predicted diffusing capacity of the lungs for carbon monoxide (DLCO) was 42.6±16.7%. On average, patients spent 23.6±15.0 months on nintedanib. At 3 years, 78 patients had died, equating to a 3-year survival rate of 59.4% (unaffected by treatment discontinuation or dose reduction). FVC% pred and DLCO% pred were largely stable at 3 years, with no significant difference from baseline (FVC 73.3±20.7% pred versus 78±20.1% pred, p=0.074; DLCO 42.6±16.7% pred versus 40.4±18.1% pred, p=0.334). Of the 244 patients, 55.7% reported an adverse event. Gastrointestinal events were the most common (173 (77.2%) out of 224 total events) and 45.0% of patients experienced diarrhoea. Only 32 (13.1%) patients had to permanently discontinue nintedanib due to an adverse event.

This real-world study shows a 3-year survival rate of 59.4% and a low discontinuation rate due to adverse events. Our experience is consistent with previous findings in clinical trials of nintedanib in IPF.

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<![CDATA[Oral corticosteroid-sparing effects of reslizumab in the treatment of eosinophilic granulomatosis with polyangiitis]]> https://www.researchpad.co/article/N91eedf2c-d33a-4daf-abe6-3d9e353d75ad

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but devastating vasculitis characterised by perivascular eosinophilic inflammation, severe asthma, peripheral eosinophilia and sinonasal disease, frequently complicated by cardiac, neurological or renal involvement [1, 2]. The mainstay of therapy for EGPA is use of systemic corticosteroids (OCS), with or without concomitant immunosuppression with methotrexate, azathioprine, cyclophosphamide or rituximab [3, 4]. The long-term use of these agents is associated with significant drug-related morbidity and the risk of relapse in EGPA patients remains significant despite treatment [1, 5]. Interleukin (IL)-5 is a critical cytokine regulating eosinophil development, migration and activation [2]. In EGPA, high doses of the IL-5 neutralising antibody mepolizumab lead to improved disease control and reduced requirement for OCS therapy, with an excellent safety profile [6, 7]. Reslizumab is another IL-5 neutralising antibody currently licensed for the treatment of severe eosinophilic asthma [8]; however, there are – to our knowledge – no published data exploring the utility of reslizumab in the management of EGPA. Here, we report clinical and patient-reported outcomes in a cohort of treatment-refractory, OCS-dependent EGPA patients with severe asthma commenced on reslizumab.

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<![CDATA[Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis]]> https://www.researchpad.co/article/N0e6a9dad-9dbe-457a-a350-1071f1e934c0

Immune dysfunction determines morbidity and mortality in liver cirrhosis. Distinct AXL-expressing circulating monocytes, which regulate antimicrobial responses, expand with progression of the disease.

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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[Characterization of recombinant fructose-1,6-bisphosphatase gene mutations: evidence of inhibition/activation of FBPase protein by gene mutation]]> https://www.researchpad.co/article/5c94bd72d5eed0c48461325a

Specific residues of the highly regulated fructose-1,6-bisphosphatase (FBPase) enzyme serve as important contributors to the catalytic activity of the enzyme. Previous clinical studies exploring the genetic basis of hypoglycemia revealed two significant mutations in the coding region of the FBPase gene in patients with hypoglycemia, linking the AMP-binding site to the active site of the enzyme. In the present study, a full kinetic analysis of similar mutants was performed. Kinetic results of mutants Y164A and M177A revealed an approximate two to three-fold decrease in inhibitory constants (Ki’s) for natural inhibitors AMP and fructose-2,6-bisphosphate (F2,6-BP) compared with the Wild-type enzyme (WT). A separate mutation (M248D) was performed in the active site of the enzyme to investigate whether the enzyme could be activated. This mutant displayed an approximate seven-fold increase in Ki for F2,6-BP. Interfacial mutants L56A and L73A exhibited an increase in Ki for F2,6-BP by approximately five-fold. Mutations in the AMP-binding site (K112A and Y113A) demonstrated an eight to nine-fold decrease in AMP inhibition. Additionally, mutant M248D displayed a four-fold decrease in its apparent Michelis constant (Km), and a six-fold increase in catalytic efficiency (CE). The importance—and medical relevance—of specific residues for FBPase structural/functional relationships in both the catalytic site and AMP-binding site is discussed.

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<![CDATA[Tumor necrosis factor gene polymorphisms are associated with silicosis: a systemic review and meta-analysis]]> https://www.researchpad.co/article/5c800fdad5eed0c484a9679a

Studies investigating association between tumor necrosis factor (TNF) gene polymorphisms and silicosis susceptibility report conflicting results. The aim of this meta-analysis was to assess association between TNF gene polymorphisms and silicosis susceptibility. A systematic literature search was conducted to find relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of association. Finally, a total of 12 articles, involving 1990 silicosis patients and 1898 healthy controls were included in the meta-analysis. Overall, meta-analysis revealed a significant association between the TNF −308A allele and silicosis (OR = 1.348, 95%CI = 1.156–1.570, P<0.001). A significant association of AA+AG genotype of the TNF −308 A/G polymorphism with susceptibility to silicosis was also found (OR = 1.466, 95%CI = 1.226–1.753, P<0.001). After stratification by ethnicity, significant associations were detected under the genetic models (A allele and AA+AG genotype) for TNF −308A/G polymorphisms in the Asian population (P<0.05). Similarly, meta-analysis of the TNF −238A/G polymorphism revealed the same pattern as that shown by meta-analysis of TNF −308A/G. The meta-analysis suggests that the TNF −308A/G and −238A/G polymorphisms are associated with susceptibility to silicosis, especially in Asians.

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<![CDATA[The essential role of tumor suppressor gene ING4 in various human cancers and non-neoplastic disorders]]> https://www.researchpad.co/article/5c6863ccd5eed0c484023b64

Inhibitor of growth 4 (ING4), a member of the ING family discovered in 2003, has been shown to act as a tumor suppressor and is frequently down-regulated in various human cancers. Numerous published in vivo and in vitro studies have shown that ING4 is responsible for important cancer hallmarks such as pathologic cell cycle arrest, apoptosis, autophagy, contact inhibition, and hypoxic adaptation, and also affects tumor angiogenesis, invasion, and metastasis. These characteristics are typically associated with regulation through chromatin acetylation by binding histone H3 trimethylated at lysine 4 (H3K4me3) and through transcriptional activity of transcription factor P53 and NF-κB. In addition, emerging evidence has indicated that abnormalities in ING4 expression and function play key roles in non-neoplastic disorders. Here, we provide an overview of ING4-modulated chromosome remodeling and transcriptional function, as well as the functional consequences of different genetic variants. We also present the current understanding concerning the role of ING4 in the development of neoplastic and non-neoplastic diseases. These studies offer inspiration for pursuing novel therapeutics for various cancers.

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<![CDATA[Gene expression profiles analysis identifies a novel two-gene signature to predict overall survival in diffuse large B-cell lymphoma]]> https://www.researchpad.co/article/5c4b93e0d5eed0c48487d268

Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy, however, specific tumor-associated genes and signaling pathways are yet to be deciphered. Differentially expressed genes (DEGs) were computed based on gene expression profiles from GSE32018, GSE56315, and The Cancer Genome Atlas (TCGA) DLBC. Overlapping DEGs were then evaluated for gene ontology (GO), pathways enrichment, DNA methylation, protein–protein interaction (PPI) network analysis as well as survival analysis. Seventy-four up-regulated and 79 down-regulated DEGs were identified. From PPI network analysis, majority of the DEGs were involved in cell cycle, oocyte meiosis, and epithelial-to-mesenchymal transition (EMT) pathways. Six hub genes including CDC20, MELK, PBK, prostaglandin D2 synthase (PTGDS), PCNA, and CDK1 were selected using the Molecular Complex Detection (MCODE). CDC20 and PTGDS were able to predict overall survival (OS) in TCGA DLBC and in an additional independent cohort GSE31312. Furthermore, CDC20 DNA methylation negatively regulated CDC20 expression and was able to predict OS in DLBCL. A two-gene panel consisting of CDC20 and PTGDS had a better prognostic value compared with CDC20 or PTGDS alone in the TCGA cohort (P=0.026 and 0.039). Overall, the present study identified a set of novel genes and pathways that may play a significant role in the initiation and progression of DLBCL. In addition, CDC20 and PTGDS will provide useful guidance for therapeutic applications.

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<![CDATA[The association between peroxisome proliferator-activated receptor Δ rs3777744, rs3798343, and rs6922548 and coronary artery disease]]> https://www.researchpad.co/article/5c4b9410d5eed0c48487dc2a

Objective: The aim of the present study is to investigate the association between the single nucleotide polymorphism (SNP) sites of peroxisome proliferator-activated receptor Δ (PPARD) and the risk of coronary artery disease (CAD). To this end, a prospective observational single-center study of the clinical data from 880 subjects in a Chinese population was conducted. Methods: A total of 880 subjects, including 609 CAD patients and 271 control subjects, were selected for the present study. All inpatients had 4 ml of venous blood drawn after 12 h of fasting, and then clinical tests were conducted to obtain the biochemical parameters. CAD patients and Controls were distinguished by coronary angiography. Statistical analysis was conducted with SPSS software (ver 16.0). Results: A significant association between the G-alleles of PPARD rs3777744 and rs3798343 and a decreased risk for CAD was found. Moreover, we found an interaction between high fasting high-density lipoprotein cholesterol (HDL-C) serum levels, low serum glucose levels and their genotypes, ultimately decreasing the risk of CAD. Haplotype analysis was conducted on the three SNP sites, rs3777744 and rs3798343 to form a block [r2 = 0.79, D′ = 0.99). The A-C haplotypes were associated with an increased risk of CAD (odds ratio (OR), 95% confidence interval (CI): 1.321 (1.060–1.647), P=0.013], and the G-G haplotypes were associated with a decreased risk [OR, 95% CI: 0.714 (0.567–0.849), P=0.004]. Conclusions: Our study indicates a significant association between the G-alleles of PPARD rs3777744 and rs3798343 and a decreased CAD risk. In addition, genotypes interact with high serum HDL-C levels and low serum glucose levels, resulting in decreased prevalence of CAD.

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<![CDATA[Ascorbic acid improves parthenogenetic embryo development through TET proteins in mice]]> https://www.researchpad.co/article/5c4b940dd5eed0c48487dba6

The TET (Ten-Eleven Translocation) proteins catalyze the oxidation of 5mC (5-methylcytosine) to 5hmC (5-hydroxymethylcytosine) and play crucial roles in embryonic development. Ascorbic acid (Vc, Vitamin C) stimulates the expression of TET proteins, whereas DMOG (dimethyloxallyl glycine) inhibits TET expression. To investigate the role of TET1, TET2, and TET3 in PA (parthenogenetic) embryonic development, Vc and DMOG treatments were administered during early embryonic development. The results showed that Vc treatment increased the blastocyst rate (20.73 ± 0.46 compared with 26.57 ± 0.53%). By contrast, DMOG reduced the blastocyst rate (20.73 ± 0.46 compared with 11.18 ± 0.13%) in PA embryos. qRT-PCR (quantitative real-time PCR) and IF (immunofluorescence) staining results revealed that TET1, TET2, and TET3 expressions were significantly lower in PA embryos compared with normal fertilized (Con) embryos. Our results revealed that Vc stimulated the expression of TET proteins in PA embryos. However, treatment with DMOG significantly inhibited the expression of TET proteins. In addition, 5hmC was increased following treatment with Vc and suppressed by DMOG in PA embryos. Taken together, these results indicate that the expression of TET proteins plays crucial roles mediated by 5hmC in PA embryonic development.

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