Assembly of a Three-Dimensional Multitype Bronchiole Coculture Model Using Magnetic Levitation

A longstanding goal in biomedical research has been to create organotypic cocultures that faithfully represent native tissue environments. There is presently great interest in representative culture models of the lung, which is a particularly challenging tissue to recreate in vitro. This study used magnetic levitation in conjunction with magnetic nanoparticles as a means of creating an organized three-dimensional (3D) coculture of the bronchiole that sequentially layers cells in a manner similar to native tissue architecture. The 3D coculture model was assembled from four human cell types in the bronchiole: endothelial cells, smooth muscle cells (SMCs), fibroblasts, and epithelial cells (EpiCs). This study represents the first effort to combine these particular cell types into an organized bronchiole coculture. These cell layers were first cultured in 3D by magnetic levitation, and then manipulated into contact with a custom-made magnetic pen, and again cultured for 48 h. Hematoxylin and eosin staining of the resulting coculture showed four distinct layers within the 3D coculture. Immunohistochemistry confirmed the phenotype of each of the four cell types and showed organized extracellular matrix formation, particularly, with collagen type I. Positive stains for CD31, von Willebrand factor, smooth muscle a-actin, vimentin, and fibronectin demonstrate the maintenance of the phenotype for endothelial cells, SMCs, and fibroblasts. Positive stains for mucin-5AC, cytokeratin, and E-cadherin after 7 days with and without 1% fetal bovine serum showed that EpiCs maintained the phenotype and function. This study validates magnetic levitation as a method for the rapid creation of organized 3D cocultures that maintain the phenotype and induce extracellular matrix formation

The Effects of Hepatitis C Treatment Eligibility Criteria on All-cause Mortality among People with Human Immunodeficiency Virus

Background The cost of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) prompted many payers to restrict treatment to patients who met non–evidence-based criteria. These restrictions have implications for survival of people with HCV, especially for people with human immunodeficiency virus (HIV)/HCV coinfection who are at high risk for liver disease progression. The goal of this work was to estimate the effects of DAA access policies on 10-year all-cause mortality among people with HIV. Methods The study population included 3056 adults with HIV in the Women’s Interagency HIV Study and Multicenter AIDS Cohort Study from 1 October 1994 through 30 September 2015. We used the parametric g-formula to estimate 10-year all-cause mortality under DAA access policies that included treating (i) all people with HCV; (ii) only people with suppressed HIV; (iii) only people with severe fibrosis; and (iv) only people with HIV suppression and severe fibrosis. Results The 10-year risk difference of treating all coinfected persons with DAAs compared with no treatment was –3.7% (95% confidence interval [CI], –9.1% to .6%). Treating only those with suppressed HIV and severe fibrosis yielded a risk difference of –1.1% (95% CI, –2.8% to .6%), with 51% (95% CI, 38%–59%) of coinfected persons receiving DAAs. Treating a random selection of 51% of coinfected persons at baseline decreased the risk by 1.9% (95% CI, –4.7% to .3%). Conclusions Restrictive DAA access policies may decrease survival compared to treating similar proportions of people with HIV/HCV coinfection with DAAs at random. These findings suggest that lives could be saved by thoughtfully revising access policies

Direct-Acting Antiviral Hepatitis C Treatment Cascade and Barriers to Treatment Initiation among US Men and Women with and without HIV

Background: People with HIV are disproportionately coinfected with hepatitis C virus (HCV) and experience accelerated liver-related mortality. Direct-acting antivirals (DAAs) yield high sustained virologic response (SVR) rates, but uptake is suboptimal. This study characterizes the DAA-era HCV treatment cascade and barriers among US men and women with or at risk for HIV. Methods: We constructed HCV treatment cascades using the Women's Interagency HIV Study (women, 6 visits, 2015-2018, n=2447) and Multicenter AIDS Cohort Study (men, 1 visit, 2015-2018, n=2221). Cascades included treatment-eligible individuals (ie, HCV RNA-positive or reported DAAs). Surveys captured self-reported clinical (eg, CD4), patient (eg, missed visits), system (eg, appointment access), and financial/insurance barriers. Results: Of 323/92 (women/men) treatment eligible, most had HIV (77%/70%); 69%/63% were black. HIV-positive women were more likely to attain cascade outcomes than HIV-negative women (39% vs 23% initiated, 21% vs 12% SVR); similar discrepancies were noted for men. Black men and substance users were treated less often. Women initiating treatment (vs not) reported fewer patient barriers (14%/33%). Among men not treated, clinical barriers were prevalent (53%). Conclusions: HIV care may facilitate HCV treatment linkage and barrier navigation. HIV-negative individuals, black men, and substance users may need additional support. Clinical trials registration: NCT00000797 (Women's Interagency HIV Study); NCT00046280 (Multicenter AIDS Cohort Study)

Comparison of Hepatitis B Virus Infection in HIV-Infected and HIV-Uninfected Participants Enrolled in a Multinational Clinical Trial: HPTN 052

Objective: Data comparing hepatitis B virus (HBV) infection in HIV-infected [HIV(+)], and HIV-uninfected [HIV(2)] individuals recruited into the same study are limited. HBV infection status and chronic hepatitis B (cHB) were characterized in a multinational clinical trial: HIV Prevention Trials Network (HPTN 052). Method: HBV infection status at enrollment was compared between HIV(+) (N = 1241) and HIV(-) (N = 1232) from 7 HBV-endemic countries. Hepatitis B e antigen and plasma HBV DNA were determined in cHB. Median CD4, median plasma HIV RNA, and prevalence of transaminase elevation were compared in HIV(+) with and without cHB. Significance was assessed with x2 Fisher exact and median tests. Results: Among all participants, 33.6% had HBV exposure without cHB (8.9% isolated HBV core antibody, "HBcAb"; 24.7% HBcAb and anti-HB surface antibody positive, "recovered"), 4.3% had cHB, 8.9% were vaccinated, and 53.5% were uninfected. Data were similar among HIV(+) and HIV(2) except for isolated HBcAb, which was more prevalent in HIV(+) than HIV(2) [10.1% vs. 7.7%, P = 0.046]. Median HBV DNA trended higher in HIV(+) than in HIV(2). In HIV (+) with cHB versus those without cHB, transaminase elevations were more prevalent (alanine aminotransferase # grade 2, 12% vs. 5.2%, P = 0.037; aspartate aminotransferase # grade 2, 26% vs. 6.0%, P, 0.001), CD4 trended lower, and HIV RNA was similar. Conclusions: HBV infection status did not differ by HIV infection status. HIV co-infection was associated with isolated HBcAb and a trend of increased HBV DNA. In HIV, cHB was associated with mild transaminase elevations and a trend toward lower CD4

The influence of the human genome on chronic viral hepatitis outcome A influência do genoma humano no curso das hepatites virais crônicas

The mechanisms that determine viral clearance or viral persistence in chronic viral hepatitis have yet to be identified. Recent advances in molecular genetics have permitted the detection of variations in immune response, often associated with polymorphism in the human genome. Differences in host susceptibility to infectious disease and disease severity cannot be attributed solely to the virulence of microbial agents. Several recent advances concerning the influence of human genes in chronic viral hepatitis B and C are discussed in this article: a) the associations between human leukocyte antigen polymorphism and viral hepatic disease susceptibility or resistance; b) protective alleles influencing hepatitis B virus (HBV) and hepatitis C virus (HCV) evolution; c) prejudicial alleles influencing HBV and HCV; d) candidate genes associated with HBV and HCV evolution; d) other genetic factors that may contribute to chronic hepatitis C evolution (genes influencing hepatic stellate cells, TGF-beta1 and TNF-alpha production, hepatic iron deposits and angiotensin II production, among others). Recent discoveries regarding genetic associations with chronic viral hepatitis may provide clues to understanding the development of end-stage complications such as cirrhosis or hepatocellular carcinoma. In the near future, analysis of the human genome will allow the elucidation of both the natural course of viral hepatitis and its response to therapy.<br>Os mecanismos que determinam o clearance ou a persistência da infecção viral nas hepatites virais crônicas não estão ainda bem identificados. O progresso no conhecimento sobre as ferramentas genéticas moleculares tem permitido detectar variações na resposta imune, que freqüentemente são associadas com polimorfismos do genoma humano. As diferenças na susceptibilidade do hospedeiro para as doenças infecciosas e a intensidade das doenças não podem ser atribuídas apenas à virulência do agente microbiano. Neste artigo são discutidos vários avanços recentes no conhecimento sobre a influência dos genes humanos nas hepatites crônicas B e C, a saber: a) As associações entre os polimorfismos HLA e a susceptibilidade ou resistência às doenças hepáticas virais; b) Alelos protetores influenciando as hepatites virais B (HVB) e C (HVC); c) Alelos prejudiciais influenciando HVB e HVC; d) Genes candidatos associados com a evolução clínica de HVB e HVC (genes que influenciam as células estreladas do fígado, a produção de TGF-beta1 e TNF-alfa, os depósitos de ferro hepáticos, a produção de angiotensina II, entre outros). O conhecimento das associações genéticas com as hepatites virais crônicas pode fornecer indícios para o pleno entendimento de como se desenvolvem as suas complicações terminais, como a cirrose e o carcinoma hepatocelular. Em futuro próximo, a análise do genoma humano será capaz de elucidar o curso natural de uma hepatite viral, bem como a sua resposta à terapêutica

Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts

Background: hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person's lifetime risk for cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and persons with genetic variants near interleukin-28B (IL-28B), the genetic basis is not well-understood.Objective: to evaluate the host genetic basis for spontaneous resolution of HCV infection.Design: 2-stage, genome-wide association study.Setting: 13 international multicenter study sites.Patients: 919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence).Measurements: frequencies of 792 721 single nucleotide polymorphisms (SNPs).Results: differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL-28B and included rs12979860 (overall per-allele OR, 0.45; P = 2.17 × 10?30) and 10 additional SNPs spanning 55 000 base pairs. On chromosome 6, allele frequency differences localized near genes for HLA class II and included rs4273729 (overall per-allele OR, 0.59; P = 1.71 × 10?16) near DQB1*03:01 and an additional 116 SNPs spanning 1 090 000 base pairs. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% (95% CI, 8.5% to 22.6%) and 15.8% (CI, 4.4% to 31.0%) of the variation in HCV resolution in persons of European and African ancestry, respectively. Replication of the chromosome 6 SNP, rs4272729, in an additional 745 persons confirmed the findings (P = 0.015).Limitation: epigenetic effects were not studied.Conclusion: IL-28B and HLA class II are independently associated with spontaneous resolution of HCV infection, and SNPs marking IL-28B and DQB1*03:01 may explain approximately 15% of spontaneous resolution of HCV infectio

Peer To Peer lending in Sweden : A comparative study between bank lending and Peer To Peer lending in the Swedish consumer credit market

Background: Peer to peer lending has in recent years emerged and become a popular way to borrow money, mostly in the US and the UK. Since the first company was established in 2005, several competitors have emerged, and P2P lending has grown on average by 84 % quarterly between the second quarter year 2007 and the second quarter year 2014 in the US. Lending Club, which is the largest player within P2P-lending, has since its start in 2008 carried loans of a total value of six billions USD. Aim: The purpose of the study is to identify and analyze P2P lending and its preconditions to operate on the Swedish consumer credit market. Completion: A qualitative approach was selected where the empirical data partly consist of primary data collected through interviews and partly of secondary data in the form of a literature study on P2P lending. The empirical data lays ground for a comparative institutional analysis in which the transaction costs of P2P lending is compared to traditional bank lending. Conclusion: The study shows that P2P lending in Sweden have higher transaction costs than traditional bank lending. The main reason for this is the uncertainty associated with P2P lending in the current situation. However, the study shows that P2P lending through technological innovation can maintain lower transaction costs in the assessment of a specific borrower's repayment capacity. For the concept to grow, society’s knowledge about P2P lending needs to increase and the legal framework needs to be more clearly defined.Bakgrund: Peer to peer-utlåning har under de senaste åren vuxit fram och blivit ett populärt sätt att låna på, främst i USA och Storbritannien. Sedan den första aktören grundades år 2005 har flera aktörer vuxit fram och i USA har P2P-utlåningen vuxit med 84 % per kvartal i snitt mellan andra kvartalet år 2007 och andra kvartalet år 2014. Lending Club, som är den största aktören inom P2P-utlåning, har sedan starten år 2008 förmedlat lån till ett värde av totalt 6 miljarder USD. Syfte: Studiens syfte är att kartlägga och analysera P2P-utlåning och dess förutsättningar att bedriva verksamhet på den svenska konsumentkreditmarknaden. Genomförande: Ett kvalitativt tillvägagångssätt har valts där empirin dels består av primärdata som insamlats genom intervjuer och dels av sekundärdata i form av en litteraturstudie på P2P-utlåning. Empirin ligger till grund för en komparativ institutionell analys där transaktionskostnaderna för utlåning genom P2P jämförs med traditionell bankutlåning. Slutsats: Studien visar på att P2P-utlåning håller högre transaktionskostnader än traditionell bankutlåning. Den största anledningen till detta är den osäkerhet som är förknippad med P2P-utlåning i dagsläget. Dock visar studien på att P2P-utlåning, genom teknologisk innovation, kan hålla lägre transaktionskostnader i bedömningen av en specifik låntagares återbetalningsförmåga. För att konceptet ska växa krävs det att den allmänna kunskapen om P2P-utlåning ökar, samt att regelverket under vilket P2P-aktörerna verkar blir tydligare definierat