Treatment as Prevention for Hepatitis C (TraP Hep C) - a nationwide elimination programme in Iceland using direct-acting antiviral agents

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesA nationwide programme for the treatment of all patients infected with hepatitis C virus (HCV) was launched in Iceland in January 2016. By providing universal access to direct-acting antiviral agents to the entire patient population, the two key aims of the project were to (i) offer a cure to patients and thus reduce the long-term sequelae of chronic hepatitis C, and (ii) to reduce domestic incidence of HCV in the population by 80% prior to the WHO goal of HCV elimination by the year 2030. An important part of the programme is that vast majority of cases will be treated within 36 months from the launch of the project, during 2016-2018. Emphasis is placed on early case finding and treatment of patients at high risk for transmitting HCV, that is people who inject drugs (PWID), as well as patients with advanced liver disease. In addition to treatment scale-up, the project also entails intensification of harm reduction efforts, improved access to diagnostic tests, as well as educational campaigns to curtail spread, facilitate early detection and improve linkage to care. With these efforts, Iceland is anticipated to achieve the WHO hepatitis C elimination goals well before 2030. This article describes the background and organization of this project. Clinical trial number: NCT02647879.Merck Astellas Gilead Gilead Sciences AbbVie BM

Vitamin D Induction of the Human Antimicrobial Peptide Cathelicidin in the Urinary Bladder

The urinary tract is frequently being exposed to potential pathogens and rapid defence mechanisms are therefore needed. Cathelicidin, a human antimicrobial peptide is expressed and secreted by bladder epithelial cells and protects the urinary tract from infection. Here we show that vitamin D can induce cathelicidin in the urinary bladder. We analyzed bladder tissue from postmenopausal women for expression of cathelicidin, before and after a three-month period of supplementation with 25-hydroxyvitamin D3 (25D3). Cell culture experiments were performed to elucidate the mechanisms for cathelicidin induction. We observed that, vitamin D per se did not up-regulate cathelicidin in serum or in bladder tissue of the women in this study. However, when the bladder biopsies were infected with uropathogenic E. coli (UPEC), a significant increase in cathelicidin expression was observed after 25D3 supplementation. This observation was confirmed in human bladder cell lines, even though here, cathelicidin induction occurred irrespectively of infection. Vitamin D treated bladder cells exerted an increased antibacterial effect against UPEC and colocalization to cathelicidin indicated the relevance of this peptide. In the light of the rapidly growing problem of resistance to common urinary tract antibiotics, we suggest that vitamin D may be a potential complement in the prevention of UTI

The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer

The role of vitamin D (VitD) in calcium and bone homeostasis is well described. In the last years, it has been recognized that in addition to this classical function, VitD modulates a variety of processes and regulatory systems including host defense, inflammation, immunity, and repair. VitD deficiency appears to be frequent in industrialized countries. Especially patients with lung diseases have often low VitD serum levels. Epidemiological data indicate that low levels of serum VitD is associated with impaired pulmonary function, increased incidence of inflammatory, infectious or neoplastic diseases. Several lung diseases, all inflammatory in nature, may be related to activities of VitD including asthma, COPD and cancer. The exact mechanisms underlying these data are unknown, however, VitD appears to impact on the function of inflammatory and structural cells, including dendritic cells, lymphocytes, monocytes, and epithelial cells. This review summarizes the knowledge on the classical and newly discovered functions of VitD, the molecular and cellular mechanism of action and the available data on the relationship between lung disease and VitD status

Association between cord blood 25-hydroxyvitamin D concentrations and respiratory tract infections in the first 6 months of age in a Korean population: a birth cohort study (COCOA)

PurposePrevious studies suggest that the concentration of 25-hydroxyvitamin D [25(OH)D] in cord blood may show an inverse association with respiratory tract infections (RTI) during childhood. The aim of the present study was to examine the influence of 25(OH)D concentrations in cord blood on infant RTI in a Korean birth cohort.MethodsThe levels of 25(OH)D in cord blood obtained from 525 Korean newborns in the prospective COhort for Childhood Origin of Asthma and allergic diseases were examined. The primary outcome variable of interest was the prevalence of RTI at 6-month follow-up, as diagnosed by pediatricians and pediatric allergy and pulmonology specialists. RTI included acute nasopharyngitis, rhinosinusitis, otitis media, croup, tracheobronchitis, bronchiolitis, and pneumonia.ResultsThe median concentration of 25(OH)D in cord blood was 32.0 nmol/L (interquartile range, 21.4 to 53.2). One hundred and eighty neonates (34.3%) showed 25(OH)D concentrations less than 25.0 nmol/L, 292 (55.6%) showed 25(OH)D concentrations of 25.0-74.9 nmol/L, and 53 (10.1%) showed concentrations of ≥75.0 nmol/L. Adjusting for the season of birth, multivitamin intake during pregnancy, and exposure to passive smoking during pregnancy, 25(OH)D concentrations showed an inverse association with the risk of acquiring acute nasopharyngitis by 6 months of age (P for trend=0.0004).ConclusionThe results show that 89.9% of healthy newborns in Korea are born with vitamin D insufficiency or deficiency (55.6% and 34.3%, respectively). Cord blood vitamin D insufficiency or deficiency in healthy neonates is associated with an increased risk of acute nasopharyngitis by 6 months of age. More time spent outdoors and more intensified vitamin D supplementation for pregnant women may be needed to prevent the onset of acute nasopharyngitis in infants

Testing in Mice the Hypothesis That Melanin Is Protective in Malaria Infections

Malaria has had the largest impact of any infectious disease on shaping the human genome, exerting enormous selective pressure on genes that improve survival in severe malaria infections. Modern humans originated in Africa and lost skin melanization as they migrated to temperate regions of the globe. Although it is well documented that loss of melanization improved cutaneous Vitamin D synthesis, melanin plays an evolutionary ancient role in insect immunity to malaria and in some instances melanin has been implicated to play an immunoregulatory role in vertebrates. Thus, we tested the hypothesis that melanization may be protective in malaria infections using mouse models. Congenic C57BL/6 mice that differed only in the gene encoding tyrosinase, a key enzyme in the synthesis of melanin, showed no difference in the clinical course of infection by Plasmodium yoelii 17XL, that causes severe anemia, Plasmodium berghei ANKA, that causes severe cerebral malaria or Plasmodium chabaudi AS that causes uncomplicated chronic disease. Moreover, neither genetic deficiencies in vitamin D synthesis nor vitamin D supplementation had an effect on survival in cerebral malaria. Taken together, these results indicate that neither melanin nor vitamin D production improve survival in severe malaria

A modern network approach to revisiting the positive and negative affective schedule (PANAS) construct validity

Introduction: The factor structure of the Positive and Negative Affective Schedule (PANAS) is still a topic of debate. There are several reasons why using Exploratory Graph Analysis (EGA) for scale validation is advantageous and can help understand and resolve conflicting results in the factor analytic literature. Objective: The main objective of the present study was to advance the knowledge regarding the factor structure underlying the PANAS scores by utilizing the different functionalities of the EGA method. EGA was used to (1) estimate the dimensionality of the PANAS scores, (2) establish the stability of the dimensionality estimate and of the item assignments into the dimensions, and (3) assess the impact of potential redundancies across item pairs on the dimensionality and structure of the PANAS scores. Method: This assessment was carried out across two studies that included two large samples of participants. Results and Conclusion: In sum, the results are consistent with a two-factor oblique structure.Fil: Flores Kanter, Pablo Ezequiel. Universidad Empresarial Siglo XXI; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garrido, Luis Eduardo. Pontificia Universidad Católica Madre y Maestra; República DominicanaFil: Moretti, Luciana Sofía. Universidad Empresarial Siglo XXI; Argentina. Pontificia Universidad Católica Madre y Maestra; República Dominicana. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Medrano, Leonardo. Universidad Empresarial Siglo XXI; Argentina. Pontificia Universidad Católica Madre y Maestra; República Dominicana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening. Clinical trial registered with www.clinicaltrials.gov (NCT01560624)

Human cathelicidin production by the cervix

hCAP18/LL-37 is the sole human cathelicidin; a family of host defence peptides with key roles in innate host defence. hCAP18/LL-37 is expressed primarily by neutrophils and epithelial cells, but its production and function in the lower genital tract is largely uncharacterised. Despite the significant roles for cathelicidin in multiple organs and inflammatory processes, its impact on infections that could compromise fertility and pregnancy is unknown. The aim of this study was to investigate cathelicidin production, regulation and function in the cervix. hCAP18/LL-37 was found to be present in cervicovaginal secretions collected from women in the first trimester of pregnancy and to be expressed at significantly higher levels in samples from women with alterations in vaginal bacterial flora characteristic of bacterial vaginosis. In endocervical epithelial cell lines, expression of the gene encoding hCAP18/LL-37 (CAMP) was not affected by TLR agonists, but was found to be up-regulated by both 1, 25 hydroxyvitamin D3 and 25 hydroxyvitamin D3. However, no association was found between serum levels of vitamin D and hCAP18/LL-37 concentrations in cervicovaginal secretions (n = 116). Exposure to synthetic LL-37 had a pro-inflammatory effect on endocervical epithelial cell lines, increasing secretion of inflammatory cytokine IL-8. Together these data demonstrate inducible expression of hCAP18/LL-37 in the female lower reproductive tract in vivo and suggest the capacity for this peptide to modulate host defence to infection in this system. Further investigation will elucidate the effects of hCAP18/LL-37 on the physiology and pathophysiology of labour, and may lead to strategies for the prevention of infection-associated preterm birth

Antiviral Activity and Increased Host Defense against Influenza Infection Elicited by the Human Cathelicidin LL-37

The extensive world-wide morbidity and mortality caused by influenza A viruses highlights the need for new insights into the host immune response and novel treatment approaches. Cationic Host Defense Peptides (CHDP, also known as antimicrobial peptides), which include cathelicidins and defensins, are key components of the innate immune system that are upregulated during infection and inflammation. Cathelicidins have immunomodulatory and anti-viral effects, but their impact on influenza virus infection has not been previously assessed. We therefore evaluated the effect of cathelicidin peptides on disease caused by influenza A virus in mice. The human cathelicidin, LL-37, and the murine cathelicidin, mCRAMP, demonstrated significant anti-viral activity in vivo, reducing disease severity and viral replication in infected mice to a similar extent as the well-characterized influenza virus-specific antiviral drug zanamivir. In vitro and in vivo experiments suggested that the peptides may act directly on the influenza virion rather than via receptor-based mechanisms. Influenza virus-infected mice treated with LL-37 had lower concentrations of pro-inflammatory cytokines in the lung than did infected animals that had not been treated with cathelicidin peptides. These data suggest that treatment of influenza-infected individuals with cathelicidin-derived therapeutics, or modulation of endogenous cathelicidin production may provide significant protection against disease