Treatment regimens for chronic hepatitis C have evolved over the past two decades. Starting with interferon monotherapy, the addition of ribavirin, the development of pegylated interferon, and ...finally to variable durations of therapy and viral guided therapy, the treatment paradigms continue to evolve. One of the most beneficial components of therapy, which was perhaps underestimated until recently, was the addition of ribavirin. While the mechanism of action has never been clearly defined, it does appear that its role is an indispensible one and many trials reflect this now. It is also clear that ribavirin will be an integral part of evolving small‐molecule therapies. The adverse event profile of ribavirin, namely hemolytic anemia, has led to further drug development of viable alternatives. Most of these compounds have not matched the efficacy and safety profiles of ribavirin. This chapter reviews the ribavirin analogs that have been investigated in human subjects.
Summary Background An outbreak of Zika virus infection was detected in Singapore in August, 2016. We report the first comprehensive analysis of a national response to an outbreak of Zika virus ...infection in Asia. Methods In the first phase of the outbreak, patients with suspected Zika virus infection were isolated in two national referral hospitals until their serum tested negative for the virus. Enhanced vector control and community engagement measures were deployed in disease clusters, including stepped-up mosquito larvicide and adulticide use, community participation in source reduction (destruction of mosquito breeding sites), and work with the local media to promote awareness of the outbreak. Clinical and epidemiological data were collected from patients with confirmed Zika virus infection during the first phase. In the second phase, admission into hospitals for isolation was stopped but vector control efforts continued. Mosquitoes were captured from areas with Zika disease clusters to assess which species were present, their breeding numbers, and to test for Zika virus. Mosquito virus strains were compared with human strains through phylogenetic analysis after full genome sequencing. Reproductive numbers and inferred dates of strain diversification were estimated through Bayesian analyses. Findings From Aug 27 to Nov 30, 2016, 455 cases of Zika virus infection were confirmed in Singapore. Of 163 patients with confirmed Zika virus infection who presented to national referral hospitals during the first phase of the outbreak, Zika virus was detected in the blood samples of 97 (60%) patients and the urine samples of 157 (96%) patients. There were 15 disease clusters, 12 of which had high Aedes aegypti breeding percentages. Captured mosquitoes were pooled into 517 pools for Zika virus screening; nine abdomen pools (2%) were positive for Zika virus, of which seven head and thorax pools were Zika-virus positive. In the phylogenetic analysis, all mosquito sequences clustered within the outbreak lineage. The lineage showed little diversity and was distinct from other Asian lineages. The estimated most recent common ancestor of the outbreak lineage was from May, 2016. With the deployment of vector control and community engagement measures, the estimated reproductive number fell from 3·62 (95% CI 3·48–3·77) for July 31 to Sept 1, 2016, to 1·22 (95% CI 1·19–1·24) 4 weeks later (Sept 1 to Nov 24, 2016). Interpretation The outbreak shows the ease with which Zika virus can be introduced and spread despite good baseline vector control. Disease surveillance, enhanced vector control, and community awareness and engagement helped to quickly curb further spread of the virus. These intensive measures might be useful for other countries facing the same threat. Funding National Medical Research Council Singapore, Centre for Infectious Disease Epidemiology and Research, and A*STAR Biomedical Research Council.
Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct ...thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a K
of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.
A culturally tailored virtual program could meet the survivorship needs of Asian American women breast cancer survivors (AABC). This study aims to determine the efficacy of a culturally tailored ...virtual information and coaching/support program (TICAA) in improving AABC's survivorship experience. A randomized clinical trial (NCT02803593) was conducted from January 2017 to June 2020 among 199 AABC. The intervention group utilized TICAA and the American Cancer Society ACS website while the control group used only ACS website for 12 weeks. The outcomes were measured using the SCNS-34SF (needs; primary), the MSAS-SF (symptoms; secondary), and the FACT-B (quality of life; secondary). The data were analyzed using an intent-to-treat approach. The intervention group showed significant reductions in their needs from the baseline (T0) to post 4 weeks (T1) and to post 12 weeks (T2). Although the changes were not statistically significant, the intervention group had decreased symptoms from T0 to T2 while the control group had an increase in their symptoms. The intervention group had a significant increase in their quality of life from T0 to T2. A culturally tailored virtual program could therefore improve quality of life in AABC patients. Trial Registration: To Enhance Breast Cancer Survivorship of Asian Americans (TICAA), NCT02803593, https://clinicaltrials.gov/ct2/show/NCT02803593?titles=TICAA&draw=2&rank=1.
The original therapy for chronic hepatitis B was conventional interferon, used for up to 24 weeks. This was replaced by peginterferon, which has similar efficacy, but is more convenient, with weekly ...dosing instead of daily or thrice weekly. Roughly one‐third of HBeAg‐positive patients respond with seroconversion during the treatment period. Those that respond often have baseline characteristics associated with interferon efficacy. Those that do not respond often require retreatment. This can be done with interferon, an oral antiviral or a combination of both. This chapter discusses the therapeutic options for patients who are non‐responders to interferon therapy.
Oligonucleotide probe arrays have enabled massively parallel analysis of gene expression levels from a single cDNA sample. Application of microarray technology to analyzing genomic DNA has been ...stymied by the sequence complexity of the entire human genome. A robust, single base-resolution direct genomic assay would extend the reach of microarray technology. We developed an array-based whole-genome genotyping assay that does not require PCR and enables effectively unlimited multiplexing. The assay achieves a high signal-to-noise ratio by combining specific hybridization of picomolar concentrations of whole genome-amplified DNA to arrayed probes with allele-specific primer extension and signal amplification. As proof of principle, we genotyped several hundred previously characterized SNPs. The conversion rate, call rate and accuracy were comparable to those of high-performance PCR-based genotyping assays.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background Arteriovenous fistula (AVF) formation for dialysis access is a common procedure. Fistula maturation is unpredictable. Preoperative duplex mapping may increase procedural success. We ...undertook a systematic review to assess the effect of preoperative duplex mapping on subsequent AVF patency. Methods The published literature was searched on PubMed and the Cochrane Library using the following keywords: ‘arteriovenous fistula,’ ‘venous mapping,’ ‘ultrasound,’ ‘hemodialysis,’ ‘vascular access,’ and ‘perioperative vessel mapping.’ Conference proceedings were hand searched for otherwise unpublished trials. Only randomized controlled trials in which preoperative duplex mapping was compared with clinical evaluation were eligible. Results Three trials (402 patients) were identified. More patients who underwent ultrasound successfully started using their fistula for dialysis access, although the difference did not reach statistical significance (174/214 vs 130/188; pooled odds ratio, 1.96; P = .11). Conclusions Preoperative duplex mapping may improve fistula maturation rates. However, the results do not reach statistical significance and there are no cost-effectiveness data. Further work is required.
Precision medicine promises to transform healthcare for groups and individuals through early disease detection, refining diagnoses and tailoring treatments. Analysis of large-scale genomic-phenotypic ...databases is a critical enabler of precision medicine. Although Asia is home to 60% of the world's population, many Asian ancestries are under-represented in existing databases, leading to missed opportunities for new discoveries, particularly for diseases most relevant for these populations. The Singapore National Precision Medicine initiative is a whole-of-government 10-year initiative aiming to generate precision medicine data of up to one million individuals, integrating genomic, lifestyle, health, social and environmental data. Beyond technologies, routine adoption of precision medicine in clinical practice requires social, ethical, legal and regulatory barriers to be addressed. Identifying driver use cases in which precision medicine results in standardized changes to clinical workflows or improvements in population health, coupled with health economic analysis to demonstrate value-based healthcare, is a vital prerequisite for responsible health system adoption.
This study utilized routine activity theory to examine the relationships between online behaviors, target suitability, and cyber and mobile phone–based bullying victimization in a nationally ...representative sample of youth from nine schools across Singapore. Key measures in all three categories—access to technology, online routine behaviors, and target suitability—were significant predictors of both forms of bullying victimization. In particular, females and victims of physical bullying were more likely to experience both forms of victimization. Access to technology and online routine behaviors predicted cyber and mobile phone–based bullying victimization differently. These findings demonstrate that routine activity theory is a viable framework to understand online bullying in non-Western nations, consistent with the existing literature on Western nations.
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