Evidence of continued injecting drug use after attaining sustained treatment-induced clearance of the hepatitis C virus: implications for reinfection

Background: People who inject drugs (PWID) are at the greatest risk of hepatitis C virus (HCV) infection, yet are often denied immediate treatment due to fears of on-going risk behaviour. Our principal objective was to examine evidence of continued injecting drug use among PWID following successful treatment for HCV and attainment of a sustained viral response (SVR). Methods: PWID who attained SVR between 1992 and June 2012 were selected from the National Scottish Hepatitis C Clinical Database. Hospitalisation and mortality records were sourced for these patients using record linkage techniques. Our primary outcome variable was any hospitalisation or death, which was indicative of injecting drugs post-SVR. Results: The cohort comprised 1170 PWID (mean age at SVR 39.6y; 76% male). The Kaplan Meier estimate of incurring the primary outcome after three years of SVR was 10.59% (95% CI, 8.75–12.79) After adjusting for confounding, the risk of an injection related hospital episode or death post-SVR was significantly increased with advancing year of SVR: AHR:1.07 per year (95% CI, 1.01–1.14), having a pre-SVR acute alcohol intoxication-related hospital episode: AHR:1.83 (95% CI, 1.29–2.60), and having a pre-SVR opiate or injection-related hospital episode: AHR:2.59 (95% CI, 1.84–3.64). Conclusion: Despite attaining the optimal treatment outcome, these data indicate that an increasing significant minority of PWID continue to inject post-SVR at an intensity which leads to either hospitalisation or death and increased risk of reinfection

Hepatitis C reinfection following treatment induced viral clearance among people who have injected drugs

Background: Although people who inject drugs (PWID) are an important group to receive Hepatitis C Virus (HCV) antiviral therapy, initiation onto treatment remains low. Concerns over reinfection may make clinicians reluctant to treat this group. We examined the risk of HCV reinfection among a cohort of PWID (encompassing all those reporting a history of injecting drug use) from Scotland who achieved a sustained virological response (SVR). Methods: Clinical and laboratory data were used to monitor RNA testing among PWID who attained SVR following therapy between 2000 and 2009. Data were linked to morbidity and mortality records. Follow-up began one year after completion of therapy, ending on 31st December, 2012. Frequency of RNA testing during follow-up was calculated and the incidence of HCV reinfection estimated. Cox proportional hazards regression was used to examine factors associated with HCV reinfection. Results: Among 448 PWID with a SVR, 277 (61.8%) were tested during follow-up, median 4.5 years; 191 (69%) received one RNA test and 86 (31%) received at least two RNA tests. There were seven reinfections over 410 person years generating a reinfection rate of 1.7/100 py (95% CI 0.7–3.5). For PWID who have been hospitalised for an opiate or injection related cause post SVR (11%), the risk of HCV reinfection was greater [AHR = 12.9, 95% CI 2.2–76.0, p = 0.002] and the reinfection rate was 5.7/100 py (95% CI 1.8–13.3). Conclusion: PWID who have been tested, following SVR, for HCV in Scotland appear to be at a low risk of reinfection. Follow-up and monitoring of this population are warranted as treatment is offered more widely

Antibodies against the gastrin-releasing peptide precursor pro-gastrin-releasing peptide reveal its expression in the mouse spinal dorsal horn

Gastrin-releasing peptide (GRP) in the spinal dorsal horn acts on the GRP receptor, and this signalling mechanism has been strongly implicated in itch. However, the source of GRP in the dorsal horn is not fully understood. For example, the BAC transgenic mouse line GRP::GFP only captures around 25% of GRP-expressing cells, and Grp mRNA is found in several types of excitatory interneuron. A major limitation in attempts to identify GRP-expressing neurons has been that antibodies against GRP cross-react with other neuropeptides, including some that are expressed by primary afferents. Here we have developed two antibodies raised against different parts of the precursor protein, pro-GRP. We show that labelling is specific, and that the antibodies do not cross-react with neuropeptides in primary afferents. Immunoreactivity was strongest in the superficial laminae, and the two antibodies labelled identical structures, including glutamatergic axons and cell bodies. The pattern of pro-GRP-immunoreactivity varied among different neurochemical classes of excitatory interneuron. Cell bodies and axons of all GRP-GFP cells were labelled, confirming reliability of the antibodies. Among the other populations, we found the highest degree of co-expression (>50%) in axons of NPFF-expressing cells, while this was somewhat lower (10–20%) in cells that expressed substance P and NKB, and much lower (<10%) in other classes. Our findings show that these antibodies reliably detect GRP-expressing neurons and axons, and that in addition to the GRP-GFP cells, excitatory interneurons expressing NPFF or substance P are likely to be the main source of GRP in the spinal dorsal horn

Measuring the impact of maternal critical care admission on short- and longer-term maternal and birth outcomes

PurposeFactors increasing the risk of maternal critical illness are rising in prevalence in maternity populations. Studies of general critical care populations highlight that severe illness is associated with longer-term physical and psychological morbidity. We aimed to compare short- and longer-term outcomes between women who required critical care admission during pregnancy/puerperium and those who did not. MethodsA cohort study including all women delivering in Scottish hospitals between 01/01/2005-31/12/2018, using national healthcare databases. The primary exposure was Intensive Care Unit (ICU) admission, whilst secondary exposures included High Dependency Unit admission. Outcomes included hospital readmission (1-year post-hospital discharge, 1-year mortality, psychiatric hospital admission, stillbirth and neonatal critical care admission). Multivariable Cox and logistic regression were used to report hazard ratios (HR) and odds ratios (OR) of association between ICU admission and outcomes. ResultsOf 762,918 deliveries, 1,449 (0.18%) women were admitted to ICU, most commonly due to post-partum haemorrhage (225, 15.5%) followed by eclampsia/pre-eclampsia (133, 9.2%). Over-half (53.8%) required mechanical ventilation. One-year hospital readmission was more frequent in women admitted to ICU compared with non-ICU populations (24.5% (n=299) vs 8.9% (n=68,029)). This association persisted after confounder adjustment (HR=1.93, 95%CI 1.33, 2.81, p&lt;0.001). Furthermore, maternal ICU admission was associated with increased 1-year mortality (HR=40.06, 95%CI 24.04,66.76, p&lt;0.001, stillbirth (OR=12.31, 95%CI 7.95,19.08,p&lt;0.001) and neonatal critical care admission (OR=6.99, 95%CI 5.64 ,8.67, p&lt;0.001) after confounder adjustment. ConclusionCritical care admission increases the risk of adverse short-term and long-term maternal, pregnancy and neonatal outcomes. Optimising long-term post-partum care may benefit maternal critical illness survivors.<br/

Pancreatic cancer survival trends in the US from 2001 to 2014: a CONCORD-3 study

Background Survival from pancreatic cancer is low worldwide. In the US, the 5-year relative survival has been slightly higher for women, whites and younger patients than for their counterparts, and differences in age and stage at diagnosis may contribute to this pattern. We aimed to examine trends in survival by race, stage, age and sex for adults (15-99 years) diagnosed with pancreatic cancer in the US. Methods This population-based study included 399,427 adults registered with pancreatic cancer in 41 US state cancer registries during 2001-2014, with follow-up to December 31, 2014. We estimated age-specific and age-standardized net survival at 1 and 5 years. Results Overall, 12.3% of patients were blacks, and 84.2% were whites. About 9.5% of patients were diagnosed with localized disease, but 50.5% were diagnosed at an advanced stage; slightly more among blacks, mainly among men. No substantial changes were seen over time (2001-2003, 2004-2008, 2009-2014). In general, 1-year net survival was higher in whites than in blacks (26.1% vs. 22.1% during 2001-2003, 35.1% vs. 31.4% during 2009-2014). This difference was particularly evident among patients with localized disease (49.6% in whites vs. 44.6% in blacks during 2001-2003, 60.1% vs. 55.3% during 2009-2014). The survival gap between blacks and whites with localized disease was persistent at 5 years after diagnosis, and it widened over time (from 24.0% vs. 21.3% during 2001-2003 to 39.7% vs. 31.0% during 2009-2014). The survival gap was wider among men than among women. Conclusions gaps in 1-and 5-year survival between blacks and whites were persistent throughout 2001-2014, especially for patients diagnosed with a localized tumor, for which surgery is currently the only treatment modality with the potential for cure

A historical analysis of herpes simplex virus promoter activation in vivo reveals distinct populations of latently infected neurones

Herpes simplex virus type 1 (HSV-1) has the capacity to establish a life-long latent infection in sensory neurones and also to periodically reactivate from these cells. Since mutant viruses defective for immediate-early (IE) expression retain the capacity for latency establishment it is widely assumed that latency is the consequence of a block in IE gene expression. However, it is not clear whether viral gene expression can precede latency establishment following wild-type virus infection. In order to address this question we have utilized a reporter mouse model system to facilitate a historical analysis of viral promoter activation in vivo. This system utilizes recombinant viruses expressing Cre recombinase under the control of different viral promoters and the Cre reporter mouse strain ROSA26R. In this model, viral promoter-driven Cre recombinase mediates a permanent genetic change, resulting in reporter gene activation and permanent marking of latently infected cells. The analyses of HSV-1 recombinants containing human cytomegalovirus major immediate-early, ICP0, gC or latency-associated transcript promoters linked to Cre recombinase in this system have revealed the existence of a population of neurones that have experienced IE promoter activation prior to the establishment of latency

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Expansion of HCV treatment access to people who have injected drugs through effective translation of research into public health policy:Scotland's experience

Seven years have elapsed since the Scottish Government launched its Hepatitis C Action Plan – a Plan to improve services to prevent transmission of infection, particularly among people who inject drugs (PWID), identify those infected and ensure those infected receive optimal treatment. The Plan was underpinned by industrial scale funding (around £100 million, in addition to the general NHS funding, will have been invested by 2015), and a web of accountable national and local multi-disciplinary multi-agency networks responsible for the planning, development and delivery of services. Initiatives ranged from the introduction of testing in specialist drug services through finger-prick blood sampling by non-clinical staff, to the setting of government targets to ensure rapid scale-up of antiviral therapy. The Plan was informed by comprehensive national monitoring systems, indicating the extent of the problem not just in terms of numbers infected, diagnosed and treated but also the more penetrative data on the number advancing to end-stage liver disease and death, and also through compelling modelling work demonstrating the potential beneficial impact of scaling-up therapy and the mounting cost of not acting. Achievements include around 50% increase in the proportion of the infected population diagnosed (38% to 55%); a sustained near two-and-a-half fold increase in the annual number of people initiated onto therapy (470 to 1050) with more pronounced increases among PWID (300 to 840) and prisoners (20 to 140); and reversing of an upward trend in the overall number of people living with chronic infection. The Action Plan has demonstrated that a Government-backed, coordinated and invested approach can transform services and rapidly improve the lives of thousands. Cited as “an impressive example of a national strategy” by the Global Commission on Drug Policy, the Scottish Plan has also provided fundamental insights of international relevance into the management of HCV among PWID

Responding to GPs' information resource needs: implementation and evaluation of a complementary medicines information resource in Queensland general practice

Background: Australian General Practitioners (GPs) are in the forefront of primary health care and in an excellent position to communicate with their patients and educate them about Complementary Medicines (CMs) use. However previous studies have demonstrated that GPs lack the knowledge required about CMs to effectively communicate with patients about their CMs use and they perceive a need for information resources on CMs to use in their clinical practice. This study aimed to develop, implement, and evaluate a CMs information resource in Queensland (Qld) general practice.Methods: The results of the needs assessment survey of Qld general practitioners (GPs) informed the development of a CMs information resource which was then put through an implementation and evaluation cycle in Qld general practice. The CMs information resource was a set of evidence-based herbal medicine fact sheets. This resource was utilised by 100 Qld GPs in their clinical practice for four weeks and was then evaluated. The evaluation assessed GPs' (1) utilisation of the resource (2) perceived quality, usefulness and satisfaction with the resource and (3) perceived impact of the resource on their knowledge, attitudes, and practice of CMs.Results: Ninety two out of the 100 GPs completed the four week evaluation of the fact sheets and returned the post-intervention survey. The herbal medicine fact sheets produced by this study were well accepted and utilised by Qld GPs. The majority of GPs perceived that the fact sheets were a useful resource for their clinical practice. The fact sheets improved GPs' attitudes towards CMs, increased their knowledge of those herbal medicines and improved their communication with their patients about those specific herbs. Eighty-six percent of GPs agreed that if they had adequate resources on CMs, like the herbal medicine fact sheets, then they would communicate more to their patients about their use of CMs.Conclusion: Further educational interventions on CMs need to be provided to GPs to increase their knowledge of CMs and to improve their communication with patients about their CMs use