Challenges and facilitators in repeated bio-behavioural surveys for blood-borne virus infections in Australian prisons.

BACKGROUND: Prison-based blood-borne virus (BBV) surveillance is essential for evaluation of prevention and treatment programs for high-risk populations, such as people who inject drugs who are over-represented amongst those incarcerated. Regular triennial surveillance has been in place in Australian prisons for almost two decades, but has been focused to date only on new prison entrants. Recently, the Australian Hepatitis and risk survey in prisons (AusHep study) was established to provide improved surveillance via an expanded bio-behavioural survey representative of all people in prison, including those sentenced and those on remand. This paper aims to identify the challenges and facilitators in conducting bio-behavioural surveys for BBV infections in prison settings. METHODS: Randomly selected individuals in 23 prisons, representative of prisons and people in prison (male/female, security classification, rural location, Aboriginal or Torres Strait Islander), were offered point-of-care testing for HIV and hepatitis C (HCV) antibodies, hepatitis B virus surface (HBs) antigen, and HCV RNA (if HCV antibody positive). Data regarding risk behaviours, harm reduction measures, and prior BBV testing and treatment were collected by interview. Data was also collected on the challenges and facilitators encountered during planning and implementation at each participating prison. RESULTS: In the first round, AusHep recruited 1599 participants (98 % participation, 89 % male, median age 35 years, 49 % ever injected drugs). Major implementation challenges included: slow and complex ethics and governance requirements in each jurisdiction, and challenging logistical arrangements and participant access constraints in the prisons. Major facilitators included use of point-of-care testing allowing immediate feedback of results, strong support from jurisdictional stakeholders in correction and public health sectors, flexibility in the timing and detailed planning for each site, and computer tablet-based data collection. CONCLUSION: The high participation and informative findings indicated clear feasibility of this improved surveillance system. Strong stakeholder engagement and flexibility in logistics facilitated successful implementation of multi-jurisdictional prison-based surveillance.

Shining a light on an additional clinical burden: work-related digital communication survey study - COVID-19 impact on NHS staff wellbeing.

Work-related communication volume within the United Kingdom's National Health Service (NHS) has had little systematic research previously. The impact of communication volume on work-life balance of healthcare staff in the NHS is also not known and has not been an area of focus or governance. COVID-19 led to a shift to non-physical work, with greater reliance on digital communication for clinical decision making. We sought to elucidate the relationship between communication, work-life balance, and COVID-19. An online survey was conducted to assess the platforms used to communicate professionally, the volume of and time spent on work-related communications, how this has changed from before to during COVID-19, and the effect on work-life balance. A total of 3047 healthcare staff provided consent and evaluable data. Emails were reported as the most frequently used communication tool, and the majority of staff asked, reported increased work-related communications due to COVID-19. Staff estimated receiving 14 emails on an average day before COVID-19. During the pandemic, staff estimated getting approximately 17 emails on an average day and 29 emails on a busy day. Work communications reportedly took up increased amounts of family and home time during COVID-19. A large proportion (36%) of staff were unable to switch off from work-related communications already before COVID-19, worsening (57%) during the pandemic. Work-related digital communication is a vital component of working in the NHS. We provide the first detailed data on the types, volume, and impact of such communication on NHS staff during the COVID-19 pandemic, compared to pre-pandemic levels. We found that 82% of staff support the need for NHS guidance on work-related communications to help manage overload, protect emotional wellbeing, and increase resilience. Further work is urgently needed in this area to tackle the negative impact of communication technologies (technostress) on work-life balance to reduce staff stress, burnout, and turnover or early retirement of some staff.

Safety and pharmacokinetics of EP-104IAR (sustained-release fluticasone propionate) in knee osteoarthritis: A randomized, double-blind, placebo-controlled phase 1 trial.

Objective: EP-104IAR is a novel, sustained-release, intra-articular (IA) formulation of the corticosteroid fluticasone propionate (FP), in development for the treatment of osteoarthritis (OA) pain. This study evaluated the safety, pharmacokinetics (PK) and efficacy of a single dose of EP-104IAR in patients with OA of the knee. Design: This was a multi-center, randomized, double-blind, placebo-controlled trial performed at 3 sites in Canada. Subjects with moderate to severe pain received either a single dose of the investigational product EP-104IAR (15 â€‹mg) or placebo (vehicle) and were evaluated for up to 42 weeks. The primary outcome measures were safety and PK. The study was not powered to assess efficacy, however patient reported outcome measures were analyzed to evaluate pain and symptom relief. Results: Thirty-two subjects were randomized (21 women, 11 men, mean age: 64.8 years). EP-104IAR was well tolerated. Average serum cortisol levels showed no clinically significant deviations compared to placebo and remained within the normal range of cortisol variation. Plasma PK concentrations were within acceptable safety margins, compared to marketed FP products. Synovial fluid FP levels were approximately 2 orders of magnitude higher and at efficacious concentrations for most subjects. Efficacy evaluations indicated that EP-104IAR provided an immediate improvement of OA symptoms and these effects persisted for 8-12 weeks consistently across all measures. Conclusions: This study provides evidence that 15 â€‹mg of EP-104IAR is well tolerated and has the potential for efficacy in OA patients. These data support further examination of EP-104IAR in larger clinical studies.

Human Herpes-8 virus copy to cell ratio: A diagnostic tool in primary effusion lymphoma.

Primary effusion lymphoma (PEL) is a serious sequel to Human Herpes Virus 8 (HHV8) infection in the immunosuppressed host. Usually requiring a cytological diagnosis, body cavity effusions are often referred for investigation for possible PEL. Although absence of HHV8 effectively refutes this, the presence of HHV8 DNA, though indicative is not diagnostic. Referred effusion and plasma samples from 10 patients with HHV8-related pleural and pericardial effusions were submitted for quantitative investigations. HHV8 DNA and human DNA from unseparated effusion extracts have been quantified allowing estimation of virus-to-cell ratios in effusion fluid. These ratios varied widely between 0.003 and 700. Five fluids had in excess of 106 HHV-8 DNA genome equivalents per ML (GEq/ML), ranging between 18 and 300 million GEq/ML. Four of these five effusions were from patients with cytologically proven PEL and had virus to cell (V:C) ratios between 100 and 700 to 1. The remaining high load effusion exhibited a ratio of 1.6 to 1 and came from a patient with extensive thoracic Kaposi's sarcoma. Five effusion fluids with low viral loads exhibited virus to cell ratios between 0.003 and 0.5. High effusion HHV8 load, though supportive of a diagnosis of PEL is less accurate than using virus to cell ratios.

Safety and Efficacy of a Topical Sodium Channel Inhibitor (TV-45070) in Patients With Postherpetic Neuralgia (PHN): A Randomized, Controlled, Proof-of-Concept, Crossover Study, With a Subgroup Analysis of the Nav1.7 R1150W Genotype.

OBJECTIVE: The objective was to evaluate the safety and efficacy of TV-45070 ointment, as a treatment for postherpetic neuralgia, and to explore the response in patients with the Nav1.7 R1150W gain-of-function polymorphism. MATERIALS AND METHODS: This was a randomized, placebo-controlled, 2-period, 2-treatment crossover trial. Patients with postherpetic neuralgia with moderate or greater pain received TV-45070 and placebo ointments, each applied twice daily for 3 weeks. The primary efficacy measure was the difference in change in mean daily pain score from baseline compared with the last week of placebo and active treatment. Secondary endpoints included responder rate analyses and a further exploratory analysis of response in carriers of the Nav1.7 R1150W polymorphism was conducted. RESULTS: Seventy patients were enrolled and 54 completed the study. TV-45070 was safe and well tolerated. No statistical difference was observed between treatments for the primary endpoint. However, the proportion of patients with ≥50% reduction in mean pain scores at week 3 was greater on TV-45070 than on placebo (26.8% vs. 10.7%, P=0.0039). Similarly, a greater proportion of patients on TV-45070 had a ≥30% reduction in mean pain scores at week 3 (39.3% on TV-45070 vs. 23.2% on placebo, P=0.0784). Of note, 63% of patients with the R1150W polymorphism versus 35% of wild-type carriers had a ≥30% reduction in mean pain score on TV-45070 at week 3 (no inferential analysis performed). CONCLUSIONS: The 50% responder analysis suggests a subpopulation may exist with a more marked analgesic response to TV-45070.The trend toward a larger proportion of responders within Nav1.7 R1150W carriers warrants further investigation.

Reprint of: Eating like you are overweight: the effect of overweight models on food intake in a remote confederate study.

There is consistent evidence that people model the eating behaviour of others. The extent to which people model the amount of food consumed by other people of different weight statuses has received less attention. Here we tested the effect on food consumption of exposing female participants to information about the food consumption of either normal/healthy weight or overweight individuals. Eighty female participants took part in a between-subjects experiment, in which we used a remote-confederate design and manipulated whether participants saw intake information about normal/healthy weight or overweight previous participants (remote confederates). Regardless of the weight-status of the remote confederates, participants ate more food when they believed that previous participants had eaten a large amount of food, in comparison with when they believed previous participants had eaten a smaller amount of food. These findings indicate that women may model the food intake of other women, even when they believe they are of a different weight status to themselves.

Eating like you are overweight: the effect of overweight models on food intake in a remote confederate study.

There is consistent evidence that people model the eating behaviour of others. The extent to which people model the amount of food consumed by other people of different weight statuses has received less attention. Here we tested the effect on food consumption of exposing female participants to information about the food consumption of either normal/healthy weight or overweight individuals. Eighty female participants took part in a between-subjects experiment, in which we used a remote-confederate design and manipulated whether participants saw intake information about normal/healthy weight or overweight previous participants (remote confederates). Regardless of the weight-status of the remote confederates, participants ate more food when they believed that previous participants had eaten a large amount of food, in comparison with when they believed previous participants had eaten a smaller amount of food. These findings indicate that women may model the food intake of other women, even when they believe they are of a different weight status to themselves.

Treatment of Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker.

Mutations in the SCN9A gene leading to deficiency of its protein product, Na(v)1.7, cause congenital indifference to pain (CIP). CIP is characterized by the absence of the ability to sense pain associated with noxious stimuli. In contrast, the opposite phenotype to CIP, inherited erythromelalgia (IEM), is a disorder of spontaneous pain caused by missense mutations resulting in gain-of-function in Na(v)1.7 that promote neuronal hyperexcitability. The primary aim of this study was to demonstrate that Na(v)1.7 antagonism could alleviate the pain of IEM, thereby demonstrating the utility of this opposite phenotype model as a tool for rapid proof-of-concept for novel analgesics. An exploratory, randomized, double-blind, 2-period crossover study was conducted in 4 SCN9A mutation-proven IEM patients. In each treatment period (2days), separated by a 2-day washout period, patients were orally administered XEN402 (400mg twice daily) or matching placebo. In 3 patients, pain was induced by heat or exercise during each treatment arm. A fourth patient, in constant severe pain, required no induction. Patient-reported outcomes of pain intensity and/or relief were recorded, and the time taken to induce pain was measured. The ability to induce pain in IEM patients was significantly attenuated by XEN402 compared with placebo. XEN402 increased the time to maximal pain induction and significantly reduced the amount of pain (42% less) after induction (P=.014). This pilot study showed that XEN402 blocks Na(v)1.7-mediated pain associated with IEM, thereby demonstrating target engagement in humans and underscoring the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept.

Evidence of person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus in a hematology unit.

We describe the first confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus that occurred in a hematology unit in the United Kingdom. Eleven cases of (H1N1) 2009 virus infection were identified, of which, ten were related as shown by sequence analysis of the hemagglutinin and neuraminidase genes. H275Y analysis demonstrated that 8 of 10 case patients had oseltamivir-resistant virus, with 4 of 8 case patients infected by direct transmission of resistant virus. Zanamivir should be considered as first-line therapy for influenza in patients with lymphopenic hematological conditions and uptake of influenza vaccination encouraged to further reduce the number of susceptible individuals.

Experiments on mixotrophic protists and catastrophic darkness.

Catastrophically darkened photic zone conditions in water bodies are postulated to be induced by a diversity of mechanisms that are recorded in the geological record, including asteroid and comet impacts and large-scale volcanic eruptions. Giant wildfires, such as those that followed the great fires in Siberia in 1915, have been directly shown to cause large reductions in sunlight penetrating to the ground. Previous studies on the response of phototrophs to sudden prolonged darkness have focused on the survival of axenic strains. In this paper, we describe laboratory experiments to investigate the survival and growth of isolated and mixed cultures of freshwater and marine mixotrophs after 6 months of darkness and in the low light that would follow these events. Mixotrophs could survive 6 months of darkness. Some species used dissolved organic carbon, which can be released from dead biomass after loss of light and was shown to improve feeding rates. Mixotrophs also improved the survival and subsequent growth of obligate phototrophs at low light levels when grown in mixed cultures. The ability of mixotrophs to switch from photosynthesis to heterotrophy following sudden darkening would not only allow them to survive but to grow and contribute to active food chains. The experiments suggest that, following the return of light, resumption of photosynthesis can be rapid. These experiments improve our understanding of the collapse of photosynthesis following catastrophic darkening and emphasize the important role of mixotrophy in the resilience of the photosynthetic biosphere during such periods. We speculate on the implications for the Cretaceous-Tertiary impact event and periods of global freezing.

Holiday haemodialysis and imported hepatitis C virus infection: a series of sixteen cases in two large haemodialysis units.

BACKGROUND: Patients in haemodialysis units are at an increased risk of blood borne virus infections. Birmingham city (West Midlands, UK) has a large number of its population from an ethnic origin other than white (30%). Recently due to the increase in number of haemodialysis centres abroad and particularly in the Indian Subcontinent, a large number of haemodialysis patients from these ethnic minorities are encouraged to take holidays in their countries of origin. OBJECTIVES: To present the data on a series of cases of holiday haemodialysis acquired hepatitis C virus (HCV) infections from two large dialysis units in Birmingham. STUDY DESIGN: In this retrospective study we have reviewed the case records of all patients in two large dialysis units who had holiday dialysis abroad and developed HCV infection after returning to the UK. RESULTS: A total of 16 patients from two large dialysis units in Birmingham who developed HCV infection after haemodialysing abroad mainly in the Indian Subcontinent are being described. This constituted 44% of the total HCV positive patients in the two haemodialysis units (16/36). The cases occurred over a period of 9 years between 2000 and 2008. The last twelve of these fifteen cases had been diagnosed in the past 17 months. There were 10 male patients with a mean age 62.8 years (range 26-84 years) and 6 female patients with a mean age of 57 years (range 44-68 years). HCV genotypes 1, 3 and 4 were found in 9, 4 and 3 patients, respectively. CONCLUSION: These cases underline the importance of enhanced surveillance and infection control procedures in haemodialysis units for patients who return after dialysing in resource poor countries. To the best of our knowledge this represents the largest series of imported HCV infection after holiday haemodialysis, and demonstrates clearly the significance of the perceived risk with increasing number of incident infections.

Treatment of children persistently infected with hepatitis B virus: seroconversion or suppression.

We have reviewed the current strategies regarding the treatment of persistent hepatitis B virus (HBV) in children and compared these with adult strategies. The options for achieving suppression of viral DNA replication versus hepatitis B e antigen to antibody seroconversion have been evaluated. The results of studies in different geographical locations have been confounded by HBV genotypes, as it is now clear that some genotypes respond better to treatment than others. Consideration needs to be given as to whether optimal treatment strategies developed for adults are directly applicable to children. In children, early seroconversion to allow improved long-term outcomes should be considered rather than embarking on the long-term complexities of managing patients on a combination of antiviral drugs to achieve viral suppression.

Discordant outcome of perinatal transmission of hepatitis C in twin pregnancies.

BACKGROUND: Mother to infant transmission of hepatitis C virus (HCV) is dependent on significant HCV viraemia being present in the mother. As yet there are no appropriate interventions to prevent perinatal transmission. The investigation of twin pregnancies where only one twin is infected may reveal further information relating to transmission and specific risks. Evaluation of these risks could affect decisions about the management of the deliveries of these mothers while more appropriate interventions are evaluated. STUDY DESIGN: The laboratory database was searched for all twins referred for testing at the Children's Hospital Liver Unit. The mothers and health care providers were contacted to gain more information about the pregnancies and deliveries of all of the twins. RESULTS: Four sets of twins had been investigated for HCV. In all cases only one twin had been infected. In three out of four cases the second twin had become infected. All of the twins were girls and the larger twin in each pair became infected. Premature rupture of membranes was associated with transmission in the only case in which the first-born became infected. There was no invasive foetal monitoring or episiotomy in any of the deliveries SUMMARY AND CONCLUSIONS: Transmission of HCV is more likely to affect the second twin, perhaps because placental separation during the delivery of the second twin exposes the infant to infection. Until effective interventions such as vaccination of newborns or antiviral treatment of mothers are evaluated, elective caesarean section could be recommended for HCV twin pregnancies in order to avoid premature membrane rupture and infection of the second twin.

Predictors of academic success in a Bachelor of Nursing course.

A longitudinal study of one Bachelor of Nursing course (n=181) was carried out to determine the relationship between academic outcomes and pre-entry qualifications and to discuss the progress and success of students with conventional and non-conventional qualifications. A multi-linear regression analysis was used to determine which pre-entry qualification best explained the variation in the course marks. Results identified that the number of GCSE A grades obtained significantly predicted success on the BN course. On the basis of this finding it has been suggested that the new AS levels, introduced as part of the reformed 16-19 curriculum, may have greater predictive value than current A levels since they allow a broader range of study. Students entering the course with non-conventional qualifications were found to achieve slightly lower marks throughout the course and had a high rate of attrition. Further research is needed to replicate these findings and to determine whether high grades in any specific subject, for example Biology, improve the predictive value of pre-entry qualifications.

A study of the vaccinia virus interferon-gamma receptor and its contribution to virus virulence.

Vaccinia virus (VV) strain Western Reserve gene B8R encodes a 43 kDa glycoprotein that is secreted from infected cells early in infection as a homodimer. This protein has amino acid similarity with the extracellular domain of cellular IFN-gamma receptor (IFN-gammaR) and binds and inhibits IFN-gamma from a wide range of species. Here we demonstrate that the B8R protein also inhibits equine IFN-gamma. The 5' end of the B8R mRNA has been mapped by primer extension analysis and the contribution of IFN-gammaRs to VV virulence was studied by the construction of a deletion mutant lacking the B8R gene (vDeltaB8R) and a revertant virus (vB8R-R) in which the B8R gene was re-inserted into the deletion mutant. A recombinant virus that expressed a soluble form of the mouse IFN-gammaR was also constructed and studied. The virulence of these viruses was tested in rodent models of infection. In mice, the loss of the VV IFN-gammaR did not affect virulence compared with WT and revertant viruses, consistent with the low affinity of the VV IFN-gammaR for mouse IFN-gamma. However, expression of the mouse soluble IFN-gammaR increased virus virulence slightly. In rabbit skin, loss of the VV IFN-gammaR produced lesions with histological differences compared with WT and revertant viruses. Lastly, the affinity constants of the VV IFN-gammaR for human and mouse IFN-gamma were determined by surface plasmon resonance.

The vaccinia virus B9R protein is a 6 kDa intracellular protein that is non-essential for virus replication and virulence.

Vaccinia virus (VV) strain Western Reserve gene B9R is shown to encode an intracellular 6 kDa protein that is expressed late during the infectious cycle. In vitro transcription and translation produced two polypeptides in the presence of microsomal membranes, but only the larger protein in the absence of membranes. The smaller protein sedimented with microsomes during centrifugation, suggesting it was inserted into the lipid membrane or into the microsomal lumen via the N-terminal hydrophobic signal sequence that was subsequently cleaved proteolytically. A VV mutant lacking B9R was constructed and found to replicate normally in cell culture and two in vivo models.

Resistance tests: what do clinical trials tell us?

Few routine laboratory tests have been evaluated by randomised controlled trials. Nevertheless, a number of such studies have been undertaken for genotypic and phenotypic HIV drug resistance assays. They are all based on a structure whereby patients are randomised to receive resistance tests or none (standards of care) at the time of acute viral failure, with the primary end points being the proportion with undetectable viral load at a time point 1224 weeks following randomisation. In other words, these studies assess the benefit afforded to clinicians by resistance data. We show that these studies vary in their results, and identify the potential factors associated with such variation. Although most studies demonstrate a clinical benefit of resistance testing, we argue that the opportunity for undertaking further such studies is probably gone and that effort should be focused on identifying more precisely the factors which determine the most cost-effective use of these expensive tests.