The Ubiquitin-Specific Protease 18 Promotes Hepatitis C Virus Production by Increasing Viral Infectivity.

BACKGROUND AND AIMS: Ubiquitin-specific protease 18 (USP18) is involved in immunoregulation and response to interferon- (IFN-) based treatment in patients chronically infected with hepatitis C virus (HCV). We investigated whether and how its upregulation alters HCV infection. METHODS: Overexpression of wild-type (USP18 WT) or catalytically inactive mutant (USP18 C64S) USP18 was examined for effects on HCV replication in the absence and presence of IFNα or IFNλ using both the HCV-infective model and replicon cells. The IFN signaling pathway was assessed via STAT1 phosphorylation (western blot) and downstream ISG expression (real-time PCR). Mechanistic roles were sought by quantifying microRNA-122 levels and J6/JFH1 infectivity of Huh7.5 cells. RESULTS: We found that overexpression of either USP18 WT or USP18 C64S stimulated HCV production and blunted the anti-HCV effect of IFNα and IFNλ in the infective model but not in the replicon system. Overexpressed USP18 showed no effect on Jak/STAT signaling nor on microRNA-122 expression. However, USP18 upregulation markedly increased J6/JFH1 infectivity and promoted the expression of the key HCV entry factor CD81 on Huh7.5 cells. CONCLUSIONS: USP18 stimulates HCV production and blunts the effect of both type I and III IFNs by fostering a cellular environment characterized by upregulation of CD81, promoting virus entry and infectivity.

Fast and accurate medication identification.

Much of the AI work in healthcare is focused around disease prediction in clinical settings, which is an important application that has yet to deliver in earnest. However, there are other fundamental aspects like helping patients and care teams interact and communicate in efficient and meaningful ways, which could deliver quadruple-aim improvements. After heart disease and cancer, preventable medical errors are the third leading cause of death in the United States. The largest subset of medical errors is medication error. Providing the right treatment plan for patients includes knowledge about their current medications and drug allergies, an often challenging task. The widespread growth of prescribing and consuming medications has increased the need for applications that support medication reconciliation. We show a deep-learning application that can help reduce avoidable errors with their attendant risk, i.e., correctly identifying prescription medication, which is currently a tedious and error-prone task. We demonstrate prescription-pill identification from mobile images in the NIH NLM Pill Image Recognition Challenge dataset. Our application recognizes the correct pill within the top-5 results at 94% accuracy, which compares favorably to the original competition winner at 83.3% for top-5 under comparable, though not identical configurations. The Institute of Medicine claims that better use of information technology can be an important step in reducing medication errors. Therefore, we believe that a more immediate impact of AI in healthcare will occur with a seamless integration of AI into clinical workflows, readily addressing the quadruple aim of healthcare.

Investigating cataract referral practices used by Australian optometrists.

BACKGROUND: The patient pathway to cataract surgery in Australia generally begins with optometric services; however, little is known about the cataract surgery referral criteria used by optometrists in Australia. METHODS: Members of Optometrists Association Australia were invited to complete an online survey in April 2013. The survey elicited information on practice demographics, professional characteristics of optometrists and cataract surgery referral considerations. RESULTS: We received responses from 533 of 4272 (13 per cent) practising optometrists. Over three-quarters (407 of 528, 77 per cent) indicated a visual acuity (VA) cataract referral benchmark of 6/9 to 6/12. Almost all respondents (499 out of 532, 94 per cent) stated they included glare sensitivity as part of their referral criteria, whereas a considerably lower proportion (40 of 528, eight per cent) used contrast sensitivity testing. Patient-centred factors such as hobbies (94 per cent) and driving (73 per cent) featured in the decision to refer patients sooner, while a patient not wanting surgery (79 per cent) was the most frequent reason cited for delaying referral. Respondents practising in more advantaged socioeconomic areas were 2.4 times more likely to refer privately (95% CI 1.6-3.6) and less likely to consider surgical costs as an important consideration (p < 0.001). Almost all respondents (97 per cent) who referred publicly discussed public hospital waiting times with their patients (median minimum wait estimate of 12 to 18 months), compared to the smaller proportion (64 per cent) of respondents discussing private waiting times (median minimum wait estimate of one to two months). CONCLUSION: While modest reductions in VA were sufficient to prompt referral for cataract surgery by Australian optometrists, patient-reported visual disability guided the optometrist's overall referral decision. Socioeconomic status of practice location influenced the choice to refer publicly versus privately and surgical costs were also considered.

Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity.

Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin-ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV-3) induced viral hepatitis. HRC 203 had greater anti-viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro-inflammatory cytokines interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) by macrophages. In vivo, untreated MHV-3-infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin- and HRC 203-treated mice with a marked reduction in biochemical [ALT(max) 964 +/- 128 IU/L (ribavirin); 848 +/- 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis (<10% in ribavirin/HRC 203 vs. 90% in untreated controls). Clinically, HRC 203-treated mice behaved normally, in contrast to ribavirin-treated mice, which developed lethargy and abnormal fur texture. In conclusion, targeted delivery of ribavirin to the liver alters the course of MHV-3 infection as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease, as well as inhibition of viral replication and production of inflammatory cytokines in vitro.