Active site polymerase inhibitor nucleotides (ASPINs): Potential agents for chronic HBV cure regimens.

Chronic hepatitis B virus (HBV) infection affects 240 to 300 million people worldwide. In the nucleus of infected hepatocytes, the HBV genome is converted to covalently closed circular DNA (cccDNA), which persists and serves as a transcriptional template for viral progeny. Therefore, a long-term cure for chronic HBV infection will require elimination of cccDNA.

A randomized phase 1b trial of the active site polymerase inhibitor nucleotide ATI-2173 in patients with chronic hepatitis B virus infection.

ATI-2173 is an active site polymerase inhibitor nucleotide in development as part of a potentially curative regimen for chronic hepatitis B virus (HBV) infection. This study evaluated the safety, tolerability, pharmacokinetics (PK) and antiviral activity of ATI-2173. This was a phase 1b, randomized, double-blind, placebo-controlled trial in treatment-naive adults with chronic HBV infection conducted in the Republic of Moldova and Ukraine (ClinicalTrials.

Community Priority setting for Fetal Alcohol Spectrum Disorder Research in Australia.

Introduction: Fetal Alcohol Spectrum Disorder (FASD) is a neurodevelopmental disorder caused by prenatal alcohol exposure (PAE). FASD research is a rapidly growing field that crosses multiple disciplines. To ensure research is relevant and meaningful for people living with FASD, their families, and the broader public there is a need to engage community members in setting priorities for research.

Cumulative impact of cover crops on soil carbon sequestration and profitability in a temperate humid climate.

Although soil C sequestration with cover crops (CCs) has been linked with the potential of CCs in climate change mitigation, the long-term usage of CCs on soil C storage and farm-based economics have been widely overlooked. Therefore, in a CC experiment established in 2007 in a temperate humid climate, four CCs and a no-CC control were compared to evaluate their potential to sequester C and provide economic returns. Total amount of plant C added to soil with CCs translated into greater soil organic carbon (SOC) content by 10-20 Mg C ha than the no-CC control across both sites.

ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens.

ATI-2173 is a novel liver-targeted molecule designed to deliver the 5'-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5'-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development.

Recurrence of breast cancer after regional or general anaesthesia: a randomised controlled trial.

Background: Three perioperative factors impair host defence against recurrence during cancer surgery: the surgical stress response, use of volatile anaesthetic, and opioids for analgesia. All factors are ameliorated by regional anaesthesia-analgesia. We tested the primary hypothesis that breast cancer recurrence after potentially curative surgery is lower with regional anaesthesia-analgesia using paravertebral blocks and the anaesthetic propofol than with general anaesthesia with the volatile anaesthetic sevoflurane and opioid analgesia.

Evaluation of Thyroid Nodules.

This is a brief overview of the initial workup of patients with thyroid nodules. Most nodules are incidentally discovered, benign, and do not require surgery, but the clinician's job is to determine which nodules are concerning and what the appropriate workup should be. Ultrasound examination is the best imaging modality to evaluation thyroid nodules and, when biopsy is indicated, fine needle aspiration is the proper technique to sample thyroid nodules.

A six-year observational study of 31 children with early-onset scoliosis treated using magnetically controlled growing rods with a minimum follow-up of two years.

Aims: Magnetically controlled growing rod (MCGR) systems use non-invasive spinal lengthening for the surgical treatment of early-onset scoliosis (EOS). The primary aim of this study was to evaluate the performance of these devices in the prevention of progression of the deformity. A secondary aim was to record the rate of complications.

National analysis of testicular and scrotal trauma in the USA.

Background: To provide a descriptive analysis of scrotal and testicular trauma in the USA. Additionally, we hypothesized that motorcycle collision would have a higher association with scrotal or testicular trauma and subsequent scrotal or testicular operation, compared to a bicycle collision.

Methods: The National Trauma Data Bank (2007-2015) was queried to identify adult male patients with scrotal or testicular trauma.

1,300 Days and Counting: A Risk Model Approach to Preventing Retained Foreign Objects (RFOs).

Background: A retained foreign object (RFO) is a devastating surgical complication that typically results in additional surgeries, increased length of stay, and risk of infections and is potentially fatal. Memorial Sloan Kettering Cancer Center (MSKCC) convened a multidisciplinary task force to undertake an improvement initiative to reduce the frequency of RFO incidents.

Methods: A needs assessment was undertaken using focus group interviews, review of past RFOs, and operating room (OR) observations, and a comprehensive intervention plan was initiated.

An NIHR-approved two-year observational study on magnetically controlled growth rods in the treatment of early onset scoliosis.

Aims: The primary aim of this study was to evaluate the performance and safety of magnetically controlled growth rods in the treatment of early onset scoliosis. Secondary aims were to evaluate the clinical outcome, the rate of further surgery, the rate of complications, and the durability of correction.

Patients And Methods: We undertook an observational prospective cohort study of children with early onset scoliosis, who were recruited over a one-year period and followed up for a minimum of two years.

Ebola virus disease: an update on post-exposure prophylaxis.

The massive outbreak of Ebola virus disease in west Africa between 2013 and 2016 resulted in intense efforts to evaluate the efficacy of several specific countermeasures developed through years of preclinical work, including the first clinical trials for therapeutics and vaccines. In this Review, we discuss how the experience and data generated from that outbreak have helped to advance the understanding of the use of these countermeasures for post-exposure prophylaxis against Ebola virus infection. In future outbreaks, post-exposure prophylaxis could play an important part in reducing community transmission of Ebola virus by providing more immediate protection than does immunisation as well as providing additional protection for health-care workers who are inadvertently exposed over the course of their work.

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.

The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV.

Bacteruria and Urinary Tract Infections in the Elderly.

Both urinary tract infection (UTI) and asymptomatic bacteriuria (ASB) are common problems among elderly adults and represent a significant health care burden. Despite their frequency, differentiating between ASB and true UTI remains controversial among health care providers. Several challenges exist in the evaluation of urinary symptoms in the elderly patient.

A Randomized Trial of a Supplemental Alarm for Critically Low Systolic Blood Pressure.

Background: Intraoperative hypotension is associated with complications that might be ameliorated by earlier intervention. We therefore tested the primary hypothesis that a supplemental decision support alert for critically low systolic blood pressure (SBP) decreases the duration of intraoperative hypotension.

Methods: We enrolled adults having surgery and anesthetized by attending anesthesiologists or nurse anesthetists under attending supervision.

A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4.

Background & Aims: Samatasvir is a pan-genotypic inhibitor of the hepatitis C (HCV) non-structural protein 5A (NS5A). This study evaluated the antiviral activity, pharmacokinetics and safety of samatasvir monotherapy in treatment-naïve subjects infected with HCV genotype 1-4.

Methods: Thirty-four genotype 1 and thirty genotype 2, 3 or 4 subjects were randomized to receive for 3days placebo or samatasvir 25-100mg per day.

A review of alcohol-impaired driving: the role of blood alcohol concentration and complexity of the driving task.

The operation of a motor vehicle requires the integrity of sensory, motor, and intellectual faculties. Impairment of these faculties following the consumption of alcohol has been studied extensively through laboratory, closed-course and on-road driving, and epidemiological studies. The scientific literature was reviewed critically, with a focus on low-to-moderate blood alcohol concentrations (BAC ≤ 0.

IDX184 in combination with pegylated interferon-α2a and ribavirin for 2 weeks in treatment-naive patients with chronic hepatitis C.

Background: IDX184 is a liver-targeted nucleotide prodrug that selectively inhibits HCV NS5B polymerase.

Methods: This randomized, double-blind, placebo-controlled, ascending-dose study investigated the antiviral activity, safety and pharmacokinetics of IDX184 plus pegylated interferon-α2a and ribavirin (P/R) in treatment-naive patients with genotype-1 HCV. A total of 81 patients with baseline HCV RNA≥5 log10 IU/ml, alanine aminotransferase ≤3× upper limit of normal and compensated liver disease were dosed.

Short-term monotherapy with IDX184, a liver-targeted nucleotide polymerase inhibitor, in patients with chronic hepatitis C virus infection.

IDX184 is a liver-targeted prodrug of 2'-methylguanosine (2'-MeG) monophosphate. This study investigated the safety, tolerability, antiviral activity, and pharmacokinetics of IDX184 as a single agent in treatment-naïve patients with genotype-1 chronic hepatitis C virus (HCV) infection. Forty-one patients with baseline HCV RNA ≥ 5 log(10) IU/ml, alanine aminotransferase (ALT) ≤ 2.

First-in-human study of the pharmacokinetics and antiviral activity of IDX375, a novel nonnucleoside hepatitis C virus polymerase inhibitor.

IDX375 is a potent and selective palm-binding nonnucleoside inhibitor of the hepatitis C virus (HCV) genotype 1 polymerase. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics of IDX375 in healthy volunteers, as well as its antiviral activity in HCV-infected patients. IDX375, as a choline salt, was administered for 1 day to 40 healthy male volunteers (25- to 200-mg IDX375-equivalent single ascending doses and a 200-mg twice-daily [BID] dose) and three patients chronically infected with HCV genotype 1 (200 mg BID only).

Rapid decline of viral RNA in chronic hepatitis C patients treated once daily with IDX320: a novel macrocyclic HCV protease inhibitor.

Background: The addition of direct-acting antivirals to pegylated interferon-α plus ribavirin for the treatment of chronic HCV infection can result in an increased sustained viral response rate and may permit reduction in treatment duration. IDX320 is a potent non-covalent macrocyclic inhibitor of the HCV NS3/4A protease.

Methods: This was a randomized double-blind placebo-controlled single- and multiple-dose study to assess the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in healthy volunteers (HV) and patients with chronic HCV genotype 1 infection.

Recombination between variants from genital tract and plasma: evolution of multidrug-resistant HIV type 1.

Multidrug-resistant (MDR) HIV-1 presents a challenge to the efficacy of antiretroviral therapy (ART). To examine mechanisms leading to MDR variants in infected individuals, we studied recombination between single viral genomes from the genital tract and plasma of a woman initiating ART. We determined HIV-1 RNA sequences and drug resistance profiles of 159 unique viral variants obtained before ART and semiannually for 4 years thereafter.

Safety and efficacy of GSK2248761, a next-generation nonnucleoside reverse transcriptase inhibitor, in treatment-naive HIV-1-infected subjects.

GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days.

Short-course Combivir after single-dose nevirapine reduces but does not eliminate the emergence of nevirapine resistance in women.

Background: In the Treatment Options Preservation Study (TOPS) trial, 4 or 7 days of Combivir (CBV; zidovudine/lamivudine) with maternal single-dose nevirapine (sdNVP) significantly reduced the emergence of NVP resistance as determined by virus population genotyping. To detect NVP resistance with greater sensitivity, we analysed TOPS samples by allele-specific real-time PCR (ASP).

Methods: In a random subset of women from each arm of the trial, plasma samples from before and 6 weeks after sdNVP were analysed using ASP at codons 103, 181, 184 and 190.