Antiviral therapy in acute viral hepatitis B: why and when

Acute viral hepatitis B is cleared in more than 95% of patients, while the remainder ones may develop either chronic HBV infection or, rarely, fulminant hepatitis

Invasive mould infections in solid organ transplant patients: modifiers and indicators of disease and treatment response

Invasive mould infections, in particular invasive aspergillosis (IA), are comparatively frequent complications of immunosuppression in patients undergoing solid organ transplantation (SOT). Guidelines provide recommendations as to the procedures to be carried out to diagnose and treat IA, but only limited advice for SOT recipients. Literature review and expert consensus summarising the existing evidence related to prophylaxis, diagnosis, treatment and assessment of response to IA and infections by Mucorales in SOT patients Response to therapy should be assessed early and at regular intervals. No indications of improvement should lead to a prompt change of the antifungal treatment, to account for possible infections by Mucorales or other moulds such as Scedosporium. Imaging techniques, especially CT scan and possibly angiography carried out at regular intervals during early and long-term follow-up and coupled with a careful clinical diagnostic workout, should be evaluated as diagnostic tools and outcome predictors, and standardised to improve therapy monitoring. The role of biomarkers such as the galactomannan test and PCR, as well as selected inflammation parameters, has not yet been definitively assessed in the SOT population and needs to be studied further. The therapeutic workup should consider a reduction of immunosuppressive therapy. The role of immunosuppression and immune tolerance mechanisms in the response to invasive fungal infection treatment is an important factor in the SOT population and should not be underestimated. The choice of the antifungal should consider not only their toxicity but also their effects on the immune system, two features that are intertwined

Capsaicin-induced corneal sensory denervation and healing impairment are reversed by NGF treatment.

PURPOSE. We aimed to evaluate the nerve growth factor (NGF) pathway and its influence on corneal healing mechanisms in normal conditions and in an animal model of corneal denervation induced by capsaicin. METHODS. Peripheral sensory damage was induced in rat pups by subcutaneous injection of capsaicin and the effects evaluated by hot-plate test, corneal nerve count, and tear secretion. Corneal damage was induced in capsaicin-treated and -untreated rats by epithelial scraping. Healing rate; NGF pathway (NGF, tyrosine kinase A [TrkA], p75); and the stem cell marker p63 were evaluated by RT-PCR, ELISA, Western blot, and immunohistochemistry. The effects of exogenous NGF administration as eye drop formulation were also tested. RESULTS. Capsaicin treatment induced a significant reduction of peripheral sensitivity, corneal innervation, tear secretion, and corneal healing rate. The ocular effects of capsaicin treatment were associated with an NGF pathway alteration. NGF eye drop treatment aided corneal healing mechanisms through a significant increase in the NGF receptors TrkA and p75, and in the stem cell marker p63. CONCLUSIONS. In this study, we show that an alteration in the NGF pathway is responsible for a delay in corneal healing in an animal model of sensory denervation. Moreover, we show that NGF eye drop administration modulates corneal innervation, epithelial cell healing, and corneal stem cells. These findings may trigger further research on the role of the NGF pathway in limbal stem cell deficiency. (Invest Ophthalmol Vis Sci. 2012; 53:8280‐8287) DOI:10.1167/iovs.12-1059

T-helper 17 lymphocytes in ocular cicatricial pemphigoid

T-helper 17 lymphocytes (Th17) were identified in the healthy conjunctiva and in patients with ocular cicatricial pemphigoid (OCP), a disease characterized by chronic ocular surface inflammation

Relationship between physical growth, motor performance, biological maturation and chronological age in boys

Os objetivos desse estudo foram: a) comparar o desempenho motor e características antropométricas de jovens em diferentes estágios maturacionais em faixas etárias específicas (10-11, 12, 13, 14, 15-16 anos de idade); b) na faixa etária de 10 a 16 anos, verificar a contribuição relativa conjunta de caracter ísticas antropométricas, das idades cronológica e biológica (estágio de pilosidade) e de medidas de desempenho motor, nos resultados dos testes de SEMO (agilidade), salto horizontal e corrida de 30 m (velocidade). A amostra foi composta por 268 jovens do sexo masculino entre 10 e 16 anos de idade(M = 13,6; DP = 1,5) freqüentadores de um programa de iniciação esportiva. O conhecimento do estágio maturacional em que o jovem se encontrava não contribuiu na explicação da variabilidade dos resultados em nenhuma das medidas de desempenho motor realizadas. Concluiu-se que, em jovens de faixa etária semelhante, aqueles em estágios maturacionais mais adiantados tenderam a apresentar uma maior massa corporal e estatura, mas não apresentaram diferenças significantes na maioria das compara ções entre as variáveis de desempenho motor nos diferentes grupos considerados.The purposes of this study were: a) to compare the motor performance and anthropometric characteristics of youngsters with different maturation stages in specific age ranges (10-11, 12, 13, 14, 15-16 years); b) in the age range of 10 to 16 years, to verify the relative grouped contribution of anthropometric characteristics, biological age (pubic hair stage), chronological age and motor performance measures, in the results of the SEMO's test (agility), standing long jump and 30 m run (velocity). The sample was composed of 268 boys participants of a sport initiation program, with ages between 10 to 16 years (M = 13,6; SD = 1,53). The knowledge of the youth's maturacional status had no interference on performance variability explanation in the motor tests. In conclusion, boys with similar age range and advanced maturation status, showed a tendency to have a bigger body mass and to be higher than their peers, but significant differences were not found in most comparisons of motor performance variables in the different groups considered

Risk of Hepatocellular Carcinoma after HCV Clearance by Direct-Acting Antivirals Treatment. Predictive Factors and Role of Epigenetics

Abstract: Direct-acting antivirals (DAAs) induce a rapid virologic response (SVR) in up to 99% of chronic hepatitis C patients. The role of SVR by DAAs on the incidence or recurrence of carcinoma (HCC) is still a matter of debate, although it is known that SVR does not eliminate the risk of HCC. In this review, we made an updated analysis of the literature data on the impact of SVR by DAAs on the risk of HCC as well as an assessment of risk factors and the role of epigenetics. Data showed that SVR has no impact on the occurrence of HCC in the short–medium term but reduces the risk of HCC in the medium–long term. A direct role of DAAs in the development of HCC has not been demonstrated, while the hypothesis of a reduction in immune surveillance in response to the rapid clearance of HCV and changes in the cytokine pattern influencing early carcinogenesis remains to be further elucidated. HCV induces epigenetic alterations such as modifications of the histone tail and DNA methylation, which are risk factors for HCC, and such changes are maintained after HCV clearance. Future epigenetic studies could lead to identify useful biomarkers and therapeutic targets. Cirrhosis has been identified as a risk factor for HCC, particularly if associated with high liver stiffness and α-fetoprotein values, diabetes and the male sex. Currently, considering the high number and health cost to follow subjects’ post-HCV clearance by DAAs, it is mandatory to identify those at high risk of HCC to optimize management

Nattokinase historical sketch on experimental and clinical evidence

Nattokinase (NK) is a protease derived from food used mainly in the Japanese diet that has several properties. The main activity is related to improving fibrinolytic activities. Other activities have been demonstrated in the regulation of blood pressure by the action toward angiotensin proteases and in the antiplatelet activities. NK can be given orally and reaches its maximal concentration after 12 hours. In addition, an antithrombotic activity based on various NK activities has been proposed. First, increased fibrinolytic activity increases thrombus dissolution and/or the formation of atherosclerotic plaques; second, its enhanced antiplatelet action adds to clot dissolution. All activities have been studied in animals and humans in vitro and in vivo. Relevant adverse effects of NK therapy have not been described, however clinical experience is restricted to case series and volunteers and is not based on clinical studies, thus clinical trials are required to confirm

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19