The implementation of a hepatitis C testing service in community pharmacies: I-COPTIC consensus statement.

OBJECTIVES: This aimed to develop a blueprint for an effective community pharmacy Hepatitis C virus (HCV) testing service by producing a consensus statement. STUDY DESIGN: This was a modified Delphi process. METHODS: We recruited a heterogenous panel of experts (who had been involved in the setup or delivery of a community pharmacy HCV testing service) by purposive and chain referral methods. We had three rounds of a modified Delphi process. The first was a series of questions with free text responses and was analysed using thematic analysis, and the second and third were statements for the respondents to rate using a 7-point Likert scale. Consensus was predefined in a published protocol, and the results were reviewed by a public and patient involvement panel before the statement was finalised. RESULTS: We had 24 participants, including community and hospital-based pharmacists, local pharmaceutical committee members, charity representatives (Hepatitis C Trust), local clinical service lead, nurse specialists and doctors. The response rate of the first, second and third rounds were 100%, 96% and 88%, respectively. After the third round, we had 60 statements that reached consensus. We discussed the accepted statements with a patient and public involvement group. We used these statements to produce the I-COPTIC statement and a graphical summary. CONCLUSIONS: We developed a blueprint for the design of a gold standard community pharmacy HCV testing service. We believe this will support the successful implementation of community pharmacy testing for HCV. Community pharmacy testing is an important service to help achieve and maintain HCV elimination.

Fungal pathogens of cereal crops: Proteomic insights into fungal pathogenesis, host defense, and resistance.

Fungal infections of cereal crops pose a significant risk to global food security through reduced grain production and quality, as well as contamination of animal feed and human products for consumption. To combat fungal disease, we need to understand how the pathogen adapts and survives within the hostile environment of the host and how the host's defense response can be modulated for protection from disease. Such investigations offer insight into fungal pathogenesis, host immunity, the development of resistance, and mechanisms of action for currently-used control strategies. Mass spectrometry-based proteomics provides a technologically-advanced platform to define differences among fungal pathogens and their hosts at the protein level, supporting the discovery of proteins critical for disease, and uncovering novel host responses driving susceptibly or resistance of the host. In this Review, we explore the role of mass spectrometry-based proteomics in defining the intricate relationship between a pathogen and host during fungal disease of cereal crops with a focus on recent discoveries derived from the globally-devastating diseases of Fusarium head blight, Rice blast, and Powdery mildew. We highlight advances made for each of these diseases and discuss opportunities to extrapolate findings to further our fight against fungal pathogens on a global scale.

Altered synaptic glutamate homeostasis contributes to cognitive decline in young APP/PSEN1 mice.

Non-convulsive epileptiform activity is a common and under-studied comorbidity of Alzheimer's disease that may significantly contribute to onset of clinical symptoms independently of other neuropathological features such as ß-amyloid deposition. We used repeated treatment with low dose kainic acid (KA) to trigger sub-threshold epileptiform activity in young (less than 6 months) wild-type (WT) and APP/PSEN1 mice to test the role of disruption to the glutamatergic system in epileptiform activity changes and the development of memory deficits. Short-term repeated low-dose KA (five daily treatments with 5 mg/kg, IP) impaired long-term potentiation in hippocampus of APP/PSEN1 but not WT mice. Long-term repeated low-dose KA (fourteen weeks of bi-weekly treatment with 7.5-10 mg/kg) led to high mortality in APP/PSEN1 mice. KA treatment also impaired memory retention in the APP/PSEN1 mice in a Morris water maze task under cognitively challenging reversal learning conditions where the platform was moved to a new location. Four weeks of bi-weekly treatment with 5 mg/kg KA also increased abnormal spike activity in APP/PSEN1 and not WT mice but did not impact sleep/wake behavioral states. These findings suggest that hyperexcitability in Alzheimer's disease may indeed be an early contributor to cognitive decline that is independent of heavy ß-amyloid-plaque load, which is absent in APP/PSEN1 mice under 6 months of age.

Evaluation of the BD MAX™ MDR-TB assay in a real-world setting for the diagnosis of pulmonary and extra-pulmonary TB.

Tuberculosis in London occurs at a rate of 19 cases per 100,000 population, with a significant proportion diagnosed as extra-pulmonary infection. At Barts Health NHS Trust, our TB rates are much higher than the London average and approximately 60% cases are extra-pulmonary in nature. We evaluated the BD MAX™ MDR-TB assay as a molecular tool for rapid diagnosis of TB. One hundred twenty-eight specimens, encompassing pulmonary (70) and extra-pulmonary (58) infection, were tested using the BD MAX™ MDR-TB assay and compared with smear and liquid culture results, to determine PCR performance. The BD MAX™ MDR-TB assay was also compared with the Xpert MTB/RIF assay, where applicable. TB was successfully detected in 50/66 Mycobacterium tuberculosis culture positive specimens, with additional detections in 2 of the culture negative specimens. The BD MAX™ MDR-TB assay demonstrated higher sensitivity with the pulmonary samples (92%) compared with the extra-pulmonary samples (52%), although the performance with fluids and biopsies demonstrated greater potential than the remaining extra-pulmonary samples. Rifampicin and/or isoniazid resistance was successfully detected by the BD MAX™ in 2/3 samples, where WGS susceptibility results were available. The BD MAX™ MDR-TB assay was comparable with the performance of the Xpert MTB/RIF assay. TB can successfully be diagnosed, in both pulmonary and extra-pulmonary samples, using the BD MAX™ MDR-TB assay.

Assessing the quality, reliability and readability of online health information regarding systemic lupus erythematosus.

Introduction Systemic lupus erythematosus (SLE) has complex pathophysiology and treatments, and patients often use the internet to better understand their condition. This report systematically assesses the quality, reliability and readability of online information. Methods The search term 'systemic lupus erythematosus' was used with Google™, Bing™ and Yahoo™ search engines sequentially. The first 25 websites returned ('hits') for each search engine (total 75 websites) were compiled. The search terms 'SLE' and 'lupus' were used in separate Google searches to assess for commonality. After removal of excluded hits, websites were assessed using the DISCERN instrument, Journal of the American Medical Association benchmarks and Gunning Fog Index for quality, reliability and readability and presence of 'Health on the Net Code' (HoN) standardisation recorded. Results There was a large degree of commonality among hits from the three different search engines using the search term 'systemic lupus erythematosus', as well as hits returned for the three different search terms using Google. The mean DISCERN score was 47.7 (SD 13.2) for 'systemic lupus erythematosus', 46.4 (SD 14.2) for 'SLE' and 45.2 (SD 10.1) for 'lupus', with no statistically significant difference. The mean number of JAMA benchmarks (maximum four) present for the 'systemic lupus erythematosus', 'SLE' and 'lupus' searches was 1.3 (SD 1.2), 1.4 (SD 1.3) and 1.2 (SD 1.0), respectively, with no statistically significance difference. The average readability of hits for the three different search terms was 9.3 (SD 3.4), 10.0 (SD 3.1) and 11.1 (SD 2.7), with no statistically significant difference. Conclusion There was a large degree of commonality of hits among the different search engines and the utilised search terms but they are not synonymous. Regardless of search term, the overall quality of websites was fair, whilst reliability was poor. Websites appearing higher in searches did not score better. Presence of the HoN did not represent better quality. Readability was higher than recommended for near-universal understanding. There was no difference in quality, reliability or readability of websites using the search terms 'systemic lupus erythematosus', 'SLE' or 'lupus', with some high-scoring websites appearing in only one search term result. This study reminds clinicians to direct patients to high-quality websites rather than rely on search engines.

Immunotherapeutic strategies in antiphospholipid syndrome.

Antiphospholipid syndrome is an autoimmune condition, characterised by the persistent presence of antiphospholipid antibodies and either thrombosis or obstetric morbidity. The cornerstone of therapy is long-term anticoagulation to reduce morbidity and mortality; however, better understanding of the immunological pathways may direct us to develop future therapeutic strategies. We provide an overview of the current understanding of the immunopathogenesis of this perplexing condition and its associated morbidities and current evidence for some of the immunotherapeutic strategies.

Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry for the identification of Neisseria gonorrhoeae.

Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS) was compared with the API NH biochemical method for the identification of Neisseria gonorrhoeae in routine clinical samples. A retrospective review of laboratory records for 1090 isolates for which both biochemical and MALDI-TOF MS identifications were available was performed. Cases of discrepant results were examined in detail for evidence supportive of a particular organism identification. Of 1090 isolates, 1082 were identified as N. gonorrhoeae by API NH. MALDI-TOF MS successfully identified 984 (91%) of these after one analysis, rising to 1081 (99.9%) after two analyses, with a positive predictive value of 99.3%. For those isolates requiring a repeat analysis, failure to generate an identifiable proteomic signature was the reason in 76% of cases, with alternative initial identifications accounting for the remaining 24%. MALDI-TOF MS identified eight isolates as N. gonorrhoeae that were not identified as such by API NH-examination of these discrepant results suggested that the MALDI-TOF MS identification may be the more reliable. MALDI-TOF MS is at least as accurate and reliable a method of identifying N. gonorrhoeae as API NH. We propose that MALDI-TOF MS could potentially be used as a single method for N. gonorrhoeae identification in routine cases by laboratories with access to this technology.

Systematic review with meta-analysis: coffee consumption and the risk of cirrhosis.

BACKGROUND: Liver cirrhosis is a large burden on global health, causing over one million deaths per year. Observational studies have reported an inverse association between coffee and cirrhosis. AIMS: To perform a systematic review and meta-analysis to characterise the relationship between coffee consumption and cirrhosis. METHODS: We searched for studies published until July 2015 that reported odds ratios, relative risks (RR) or hazard ratios for cirrhosis stratified by coffee consumption. We calculated RRs of cirrhosis for an increase in daily coffee consumption of two cups for each study and overall. We performed analyses by study design, type of cirrhosis and mortality. We assessed the risk of bias in each study and the overall quality of evidence for the effect of coffee on cirrhosis. RESULTS: We identified five cohort studies and four case-control studies involving 1990 cases and 432 133 participants. We observed a dose-response in most studies and overall. The pooled RR of cirrhosis for a daily increase in coffee consumption of two cups was 0.56 (95% CI 0.44-0.68; I(2) 83.3%). The RR pooled from cohort studies for a daily increase of two cups was 0.58 (95% CI 0.41-0.76; I(2) 91.1%) and from case-control studies it was 0.52 (95% CI 0.40-0.63; I(2) 0.0%). The pooled RR of alcoholic cirrhosis for a daily increase of two cups was 0.62 (95% CI 0.51-0.73; I(2) 0%) and of death from cirrhosis it was 0.55 (95% CI 0.35-0.74; I(2) 90.3%). CONCLUSION: This meta-analysis suggests that increasing coffee consumption may substantially reduce the risk of cirrhosis.

Recent advances in polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is a chronic inflammatory disorder of unknown cause characterised by the subacute onset of shoulder and pelvic girdle pain, and early morning stiffness in men and women over the age of 50 years. Due to the lack of a gold standard investigation, diagnosis is based on a clinical construct and laboratory evidence of inflammation. Heterogeneity in the clinical presentation and disease course of PMR has long been recognised. Aside from the evolution of alternative diagnoses, such as late-onset rheumatoid arthritis, concomitant giant cell arteritis is also recognised in 16-21% of cases. In 2012, revised classification criteria were released by the European League Against Rheumatism and American College of Rheumatology in order to identify a more homogeneous population upon which future studies could be based. In this article, we aim to provide an updated perspective on the pathogenesis and diagnosis of PMR, with particular focus on imaging modalities, such as ultrasound and whole body positron emission tomography/computed tomography, which have advanced our current understanding of this disease. Future treatment directions, based on recognition of the key cytokines involved in PMR, will also be explored.

Innate and adaptive genetic pathways in HCV infection.

Infection with hepatitis C virus (HCV) leads to a wide spectrum of clinical manifestations. This heterogeneity is underpinned by the host immune response and the genetic factors that govern it. Polymorphisms affecting both the innate and adaptive immunity determine the outcome of exposure. However the innate immune system appears to play a greater role in determining treatment-associated responses. Overall the effects of IFNL3/4 appear dominant over other polymorphic genes. Understanding how host genetics determines the disease phenotype has not been as intensively studied. This review summarizes our current understanding of innate and adaptive immunogenetic factors in the outcome of HCV infection. It focuses on how they relate to resolution and the progression of HCV-related liver disease, in the context of current and future treatment regimes.

Food safety objective approach for controlling Clostridium botulinum growth and toxin production in commercially sterile foods.

As existing technologies are refined and novel microbial inactivation technologies are developed, there is a growing need for a metric that can be used to judge equivalent levels of hazard control stringency to ensure food safety of commercially sterile foods. A food safety objective (FSO) is an output-oriented metric that designates the maximum level of a hazard (e.g., the pathogenic microorganism or toxin) tolerated in a food at the end of the food supply chain at the moment of consumption without specifying by which measures the hazard level is controlled. Using a risk-based approach, when the total outcome of controlling initial levels (H(0)), reducing levels (ΣR), and preventing an increase in levels (ΣI) is less than or equal to the target FSO, the product is considered safe. A cross-disciplinary international consortium of specialists from industry, academia, and government was organized with the objective of developing a document to illustrate the FSO approach for controlling Clostridium botulinum toxin in commercially sterile foods. This article outlines the general principles of an FSO risk management framework for controlling C. botulinum growth and toxin production in commercially sterile foods. Topics include historical approaches to establishing commercial sterility; a perspective on the establishment of an appropriate target FSO; a discussion of control of initial levels, reduction of levels, and prevention of an increase in levels of the hazard; and deterministic and stochastic examples that illustrate the impact that various control measure combinations have on the safety of well-established commercially sterile products and the ways in which variability all levels of control can heavily influence estimates in the FSO risk management framework. This risk-based framework should encourage development of innovative technologies that result in microbial safety levels equivalent to those achieved with traditional processing methods.

Preschoolers' knowledge about hospital and emergency equipment and care.

BACKGROUND: Information about preschoolers' understanding of hospital and emergency care and medical equipment is needed. OBJECTIVE: The current study contributed to our understanding of young children's health literacy in these areas. CONCLUSIONS: Findings indicated that preschool-age children had more accurate knowledge of an emergency care as opposed to a hospital scenario. Also, young children tended to recount their experiences when discussing what they knew, supporting the idea that they acquire schemas for this information. Parents tended to overestimate their children's knowledge. Children did not mention school as a place where they learned about hospital care and those health professionals working in school settings may be uniquely positioned to teach young children about hospital care. Children may absorb more information in this environment, and assessing whether this is true remains an area for future research.

Health-related quality of life among informal caregivers assisting people with multiple sclerosis.

OBJECTIVE: To identify factors affecting the health-related quality of life (HRQOL) of informal caregivers assisting people with (multiple sclerosis) MS who have greater functional impairment. METHODS: Data were collected in a national survey of 530 people who provided informal care to people with MS. Multiple linear regression models analyzed these data. RESULTS: Poorer overall health for the person with MS, stronger agreement by caregivers that care giving was burdensome or emotionally draining, and the caregiver's need for mental health counseling in the past 12 months were associated with lower mental dimensions of HRQOL for the informal caregiver. Greater caregiver satisfaction with the access the person with MS had to MS-focused care was associated with higher mental dimensions of HRQOL among caregivers. CONCLUSIONS: Increasing access to MS-focused care could improve not only the health of people with MS, but also improve the mental dimensions of caregiver HRQOL. Our findings highlight the importance of addressing the mental health needs of informal caregivers assisting people with MS.

Short-term metabolic change is associated with improvement in measures of diabetic neuropathy: a 1-year placebo cohort analysis.

AIMS: Randomized clinical trials have frequently shown improvement in diabetic sensorimotor polyneuropathy in placebo-treated participants, counter to the prevailing concept that it deteriorates with time. We aimed to determine the variables associated with this paradoxical nerve function improvement. METHODS: Participants with diabetic sensorimotor polyneuropathy randomized to placebo in a multi-centre, double-blind study were evaluated for the primary outcome of 1-year change in the summed sensory nerve conduction velocity of the bilateral sural and non-dominant median nerves. Association with clinical and biochemical variables measured at 13 time points were examined. RESULTS: The 134 participants had mild to moderate diabetic sensorimotor polyneuropathy of 4.6 years' duration and mean 1-year improvement of 2.0 ± 8.0 m/s. Primary outcome measures were available for 122 participants (91%). In multivariate analyses, the change in HbA(1c) and serum triglycerides from baseline to 2 months demonstrated the strongest association, even independent of baseline and end-of-study levels. According to quintiles of change, we determined thresholds: participants with salutary improvement in HbA(1c) (exceeding a drop of -0.8%) or whose triglycerides did not increase (by 0.32 mmol/l or more) experienced significant improvement (2.9 m/s), while those with salutary levels of both these variables had an exaggerated improvement (5.1 m/s). In comparison, those with non-salutary changes in both variables experienced a loss of -4.9 m/s (ANOVA P=0.0014). CONCLUSIONS: In mild to moderate diabetic sensorimotor polyneuropathy, short-term improvements in glycaemic control and serum triglyceride levels have an independent, additive and durable effect on restoration of nerve function.

Intravascular large B cell lymphoma: an elusive cause of pyrexia of unknown origin diagnosed postmortem.

Intravascular large B cell lymphoma (IVLBCL) is a rare cause of pyrexia of unknown origin. Because of its protean clinical manifestations, diagnosis is elusive and is often made postmortem. We report here a case of IVLBCL that evaded diagnosis despite multiple investigations in vivo for pyrexia of unknown origin over a 5‐month period.

Carbetocin versus oxytocin for the prevention of postpartum haemorrhage following caesarean section: the results of a double-blind randomised trial.

OBJECTIVE: To compare the effectiveness of carbetocin and oxytocin when they are administered after caesarean section for prevention of postpartum haemorrhage (PPH). STUDY DESIGN: Double-blind randomised single centre study (1:1 ratio). SETTING: Teaching hospital in Bristol, UK with 6000 deliveries per annum. POPULATION: Women at term undergoing elective or emergency caesarean section under regional anaesthesia, excluding women with placenta praevia, multiple gestation and placental abruption. METHODS: Women were randomised to receive either carbetocin 100 microg or oxytocin 5 IU intravenously after the delivery of the baby. Perioperative care was otherwise normal and use of additional oxytocics was at the discretion of the operating obstetrician. Analysis was by intention to treat. PRIMARY OUTCOME MEASURE: The proportion of women in each arm of the trial that needed additional pharmacological oxytocic interventions. RESULTS: Significantly more women needed additional oxytocics in the oxytocin group (45.5% versus 33.5%, Relative risk 0.74, 95% CI 0.57-0.95). The majority of women had oxytocin infusions. There were no significant differences in the secondary outcomes, including major PPH, blood transfusions and fall in haemoglobin. CONCLUSIONS: Carbetocin is associated with a reduced use of additional oxytocics. It is unclear whether this may reduce rates of PPH and blood transfusions.

Reliability and validity of the modified Toronto Clinical Neuropathy Score in diabetic sensorimotor polyneuropathy.

INTRODUCTION: A reliable and valid clinical tool to capture symptoms and signs of diabetic sensorimotor polyneuropathy (DSP) for use in clinical research trials is urgently needed. The validated Toronto Clinical Neuropathy Score (TCNS) was modified to improve sensitivity to early DSP changes. We aimed to assess the reproducibility of this modified tool, the mTCNS and to determine its validity relative to the precursor TCNS. METHODS: Sixty-five patients (six Type 1, 59 Type 2 diabetes) with diabetes duration 13 +/- 8 years were accrued from four study sites and examined on 2 days for internal consistency and inter- and intra-rater reliability of the mTCNS. In the absence of a single quantitative gold-standard measure for DSP, results of the mTCNS were compared with the precursor TCNS for the purpose of estimating validity. RESULTS: Internal consistency of the two domains within the mTCNS was good (Cronbach's alpha 0.78). Very good inter-rater reliability for the mTCNS was demonstrated by an intra-class correlation coefficient for the mTCNS of 0.87 (95% confidence interval, 0.79-0.91), which was similar in magnitude to that of the TCNS (0.83; 95% confidence interval, 0.75-0.89). Intra-rater reliability testing of the mTCNS showed moderate to good correlation for individual symptoms and sensory tests (Cohen's kappa values of 0.54-0.73). The mTCNS shared moderate correlation with the precursor TCNS (Pearson correlation coefficient, 0.58). DISCUSSION: The mTCNS, a clinical score with higher face validity for tracking mild to moderate DSP, has sufficient reliability and validity relative to its precursor TCNS for use in clinical research.

Remission in schizophrenia: the relationship to baseline symptoms and changes in symptom domains during a one-year study.

The concepts of partial recovery and remission have become increasingly important for the evaluation of the effectiveness of schizophrenia therapeutics. The relationship of baseline symptoms and changes in symptoms to remission of psychosis was evaluated. Fifty-six outpatients with residual schizophrenia completed a double-blind trial of olanzapine versus haloperidol and were then enrolled into a one-year open-label trial of olanzapine. Out of these 56 subjects, 13 (23%) met remission criteria at the beginning of the open-label treatment and were excluded. During the one-year study, 7/43 (16%) subjects met remission criteria. These subjects had significantly lower baseline ratings for tardive dyskinesia (TD) than subjects who did not achieve remission (1.8 +/- 1.5 vs. 4.2 +/- 4.6, P = 0.03). As expected, remitted subjects had significantly greater improvements in Brief Psychiatric Rating Scale total scores, positive subscale scores and scale for the Assessment of Negative Symptoms total scores. Remitted subjects also experienced a significantly greater improvement in depressive symptoms (P = 0.001), activation (P = 0.005), and Clinical Global Impressions scores (P < 0.001), as well as greater improvements in extrapyramidal symptoms (P = 0.007) and TD (P < 0.001). These results suggest that the relationship of depressive symptoms and improved side effects to the construct of remission in schizophrenia may deserve special attention. Future studies should aim to relate remission criteria to functional outcomes, cognition, and other important symptom domains.