Comparative report on the innovation groups

Work package four focuses on healthy organisations, defined as those that meet the dual needs of the organisation and its employees. The first phase involved individual interviews in one case study organisation in each partner country, examining workplace change and its impact on current quality of life. The second phase involved innovation groups, building on the interviews. This report focuses on the innovation groups. The aims of the innovation groups were: • to disseminate the analysis of the interviews to participants, • to address the challenges identified in this analysis in terms of the potential impacts on the dual agenda of enhancing quality of (working) life and workplace effectiveness, • to begin to engage participants in the collaborative development of small innovations that could help to meet these dual objectives

Physiotherapy for adults with joint hypermobility syndrome: A pilot randomised controlled trial

Background: Joint Hypermobility Syndrome (JHS) is a heritable disorder associated with laxity and pain in multiple joints. Physiotherapy is the mainstay of treatment but there is little research investigating its effectiveness. The aim of this study was therefore to conduct a pilot randomised controlled trial (RCT) to determine the feasibility of conducting a future definitive RCT. Methods: A comprehensive physiotherapy intervention was developed in conjunction with patients and healthcare professionals. It was then piloted and refined on the basis of patient and physiotherapist feedback. A parallel two-arm pilot RCT in two UK secondary care NHS Trusts compared 'Advice' against 'Advice & Physiotherapy'. Inclusion criteria were: >16 years, a diagnosis of JHS, and no other musculoskeletal conditions causing pain. The Advice intervention was a one-off session, supplemented by advice booklets from the Hypermobility Syndromes Association and Arthritis Research UK. All patients could ask questions specific to their circumstances and received tailored advice. Participants were then randomly allocated to 'Advice' (no further advice or physiotherapy) or 'Advice & Physiotherapy' (an additional six 30 minute sessions over 4 months). The Physiotherapy intervention was supported by a patient handbook and delivered on a one-to-one patient-therapist basis. It aimed to increase patients’ physical activity through developing knowledge, understanding and skills to better manage their condition. The primary outcome related to the feasibility of conducting a future definitive RCT. Qualitative interviews with patients and physiotherapists therefore formed a major component of data collection. Secondary outcomes included clinical measures (physical function, pain, global status, self-reported joint count, quality of life, exercise self-efficacy and adverse events); resource use (to estimate cost-effectiveness); and an estimate of the value of information from a future RCT. Outcomes were recorded at baseline, 4 months (at the end of physiotherapy) and 7 months (3 months following physiotherapy). Results: A total of n=29 participants were recruited to the pilot RCT. Recruitment was challenging, primarily due to a perceived lack of equipoise between Advice and Physiotherapy. The qualitative evaluation provided very clear guidance to inform a future RCT, including enhancement of the Advice intervention. Some patients reported that the Advice intervention was useful and the Physiotherapy intervention was evaluated very positively. The rate of return of questionnaires was low within the Advice group but reasonable in the Physiotherapy group. The Physiotherapy intervention showed evidence of promise in terms of primary and secondary clinical outcomes. The Advice arm experienced more adverse events. The value of information estimate indicated the potential for high value from a future RCT. Conclusion: A future definitive RCT of physiotherapy for JHS seems feasible, although the Advice intervention should be made more robust to address perceived equipoise and subsequent attrition

Detection of H3N8 influenza A virus with multiple mammalian-adaptive mutations in a rescued Grey seal (Halichoerus grypus) pup

Avian influenza A viruses (IAVs) in different species of seals display a spectrum of pathogenicity, from sub-clinical infection to mass mortality events. Here we present an investigation of avian IAV infection in a 3- to 4-month-old Grey seal (Halichoerus grypus) pup, rescued from St Michael’s Mount, Cornwall in 2017. The pup underwent medical treatment but died after two weeks; post-mortem examination and histology indicated sepsis as the cause of death. IAV NP antigen was detected by immunohistochemistry in the nasal mucosa, and sensitive real-time reverse transcription polymerase chain reaction assays detected trace amounts of viral RNA within the lower respiratory tract, suggesting that the infection may have been cleared naturally. IAV prevalence among Grey seals may therefore be underestimated. Moreover, contact with humans during the rescue raised concerns about potential zoonotic risk. Nucleotide sequencing revealed the virus to be of subtype H3N8. Combining a GISAID database BLAST search and time-scaled phylogenetic analyses, we inferred that the seal virus originated from an unsampled, locally circulating (in Northern Europe) viruses, likely from wild Anseriformes. From examining the protein alignments, we found several residue changes in the seal virus that did not occur in the bird viruses, including D701N in the PB2 segment, a rare mutation, and a hallmark of mammalian adaptation of bird viruses. IAVs of H3N8 subtype have been noted for their particular ability to cross the species barrier and cause productive infections, including historical records suggesting that they may have caused the 1889 pandemic. Therefore, infections such as the one we report here may be of interest to pandemic surveillance and risk and help us better understand the determinants and drivers of mammalian adaptation in influenza

Understanding the determinants of antimicrobial prescribing within hospitals: the role of "prescribing etiquette"

Background: There is limited knowledge of the key determinants of antimicrobial prescribing behavior (APB) in hospitals. An understanding of these determinants is required for the successful design, adoption, and implementation of quality improvement interventions in antimicrobial stewardship programs. Methods: Qualitative semistructured interviews were conducted with doctors (n = 10), pharmacists (n = 10), and nurses and midwives (n = 19) in 4 hospitals in London. Interviews were conducted until thematic saturation was reached. Thematic analysis was applied to the data to identify the key determinants of antimicrobial prescribing behaviors. Results: The APB of healthcare professionals is governed by a set of cultural rules. Antimicrobial prescribing is performed in an environment where the behavior of clinical leaders or seniors influences practice of junior doctors. Senior doctors consider themselves exempt from following policy and practice within a culture of perceived autonomous decision making that relies more on personal knowledge and experience than formal policy. Prescribers identify with the clinical groups in which they work and adjust their APB according to the prevailing practice within these groups. A culture of “noninterference” in the antimicrobial prescribing practice of peers prevents intervention into prescribing of colleagues. These sets of cultural rules demonstrate the existence of a “prescribing etiquette,” which dominates the APB of healthcare professionals. Prescribing etiquette creates an environment in which professional hierarchy and clinical groups act as key determinants of APB. Conclusions: To influence the antimicrobial prescribing of individual healthcare professionals, interventions need to address prescribing etiquette and use clinical leadership within existing clinical groups to influence practice

Emergency presentation of cancer and short-term mortality

Background:The short-term survival following a cancer diagnosis in England is lower than that in comparable countries, with the difference in excess mortality primarily occurring in the months immediately after diagnosis. We assess the impact of emergency presentation (EP) on the excess mortality in England over the course of the year following diagnosis. Methods:All colorectal and cervical cancers presenting in England and all breast, lung, and prostate cancers in the East of England in 2006-2008 are included. The variation in the likelihood of EP with age, stage, sex, co-morbidity, and income deprivation is modelled. The excess mortality over 0-1, 1-3, 3-6, and 6-12 months after diagnosis and its dependence on these case-mix factors and presentation route is then examined. Results:More advanced stage and older age are predictive of EP, as to a lesser extent are co-morbidity, higher income deprivation, and female sex. In the first month after diagnosis, we observe case-mix-adjusted excess mortality rate ratios of 7.5 (cervical), 5.9 (colorectal), 11.7 (breast ), 4.0 (lung), and 20.8 (prostate) for EP compared with non-EP. Conclusion:Individuals who present as an emergency experience high short-term mortality in all cancer types examined compared with non-EPs. This is partly a case-mix effect but EP remains predictive of short-term mortality even when age, stage, and co-morbidity are accounted for

Comparative micro-epidemiology of pathogenic avian influenza virus outbreaks in a wild bird population

Understanding the epidemiological dynamics of highly pathogenic avian influenza virus (HPAIV) in wild birds is crucial for guiding effective surveillance and control measures. The spread of H5 HPAIV has been well characterized over large geographical and temporal scales. However, information about the detailed dynamics and demographics of individual outbreaks in wild birds is rare and important epidemiological parameters remain unknown. We present data from a wild population of long-lived birds (mute swans; Cygnus olor) that has experienced three outbreaks of related H5 HPAIVs in the past decade, specifically, H5N1 (2007), H5N8 (2016) and H5N6 (2017). Detailed demographic data were available and intense sampling was conducted before and after the outbreaks; hence the population is unusually suitable for exploring the natural epidemiology, evolution and ecology of HPAIV in wild birds. We show that key epidemiological features remain remarkably consistent across multiple outbreaks, including the timing of virus incursion and outbreak duration, and the presence of a strong age-structure in morbidity that likely arises from an equivalent age-structure in immunological responses. The predictability of these features across a series of outbreaks in a complex natural population is striking and contributes to our understanding of HPAIV in wild birds

Investigating antibody neutralization of lyssaviruses using lentiviral pseudotypes: a cross-species comparison

Cross-neutralization between rabies virus (RABV) and two European bat lyssaviruses (EBLV-1 and -2) was analysed using lentiviral pseudotypes as antigen vectors. Glycoprotein (G-protein) cDNA from RABV challenge virus standard-11 (CVS-11) and EBLV-1 and -2 were cloned and co-expressed with human immunodeficiency virus (HIV) or murine leukemia virus (MLV) gag–pol and packageable green fluorescent protein (GFP) or luciferase reporter genes in human cells. The harvested lentiviral (HIV) vector infected over 40 % of baby hamster kidney (BHK) target cells, providing high-titre pseudotype stocks. Tests on blinded antibody-positive (n=15) and -negative (n=45) sera, predetermined by the fluorescent antibody virus neutralization (FAVN) test approved by the World Health Organization (WHO) and Office International des Epizooties (OIE), revealed that the CVS-11 pseudotype assay had 100 % concordance with FAVN and strongly correlated with neutralization titres (r2=0.89). Cross-neutralization tests using sera from RABV-vaccinated humans and animals on pseudotypes with CVS-11, EBLV-1 and EBLV-2 envelopes showed that the relative neutralization titres correlated broadly with the degree of G-protein diversity. Pseudotypes have three major advantages over live-virus neutralization tests: (i) they can be handled in low-biohazard-level laboratories; (ii) the use of reporter genes such as GFP or β-galactosidase will allow the assay to be undertaken at low cost in laboratories worldwide; (iii) each assay requires <10 μl serum. This robust microassay will improve our understanding of the protective humoral immunity that current rabies vaccines confer against emerging lyssaviruses, and will be applicable to surveillance studies, thus helping to control the spread of rabies

What characteristics of primary care and patients are associated with early death in patients with lung cancer in the UK?

Background: The UK has poor lung cancer survival rates and high early mortality, compared to other countries. We aimed to identify factors associated with early death, and features of primary care that might contribute to late diagnosis. Methods: All cases of lung cancer diagnosed between 2000 and 2013 were extracted from The Health Improvement Network database. Patients who died within 90 days of diagnosis were compared with those who survived longer. Standardised chest X-ray (CXR) and lung cancer rates were calculated for each practice. Results: Of 20 142 people with lung cancer, those who died early consulted with primary care more frequently prediagnosis. Individual factors associated with early death were male sex (OR 1.17; 95% CI 1.10 to 1.24), current smoking (OR 1.43; 95% CI 1.28 to 1.61), increasing age (OR 1.80; 95% CI 1.62 to 1.99 for age ≥80 years compared to 65–69 years), social deprivation (OR 1.16; 95% CI 1.04 to 1.30 for Townsend quintile 5 vs 1) and rural versus urban residence (OR 1.22; 95% CI 1.06 to 1.41). CXR rates varied widely, and the odds of early death were highest in the practices which requested more CXRs. Lung cancer incidence at practice level did not affect early deaths. Conclusions: Patients who die early from lung cancer are interacting with primary care prediagnosis, suggesting potentially missed opportunities to identify them earlier. A general increase in CXR requests may not improve survival; rather, a more timely and appropriate targeting of this investigation using risk assessment tools needs further assessment

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Individual Human Brain Areas Can Be Identified from Their Characteristic Spectral Activation Fingerprints

The human brain can be parcellated into diverse anatomical areas. We investigated whether rhythmic brain activity in these areas is characteristic and can be used for automatic classification. To this end, resting-state MEG data of 22 healthy adults was analysed. Power spectra of 1-s long data segments for atlas-defined brain areas were clustered into spectral profiles (“fingerprints”), using k-means and Gaussian mixture (GM) modelling. We demonstrate that individual areas can be identified from these spectral profiles with high accuracy. Our results suggest that each brain area engages in different spectral modes that are characteristic for individual areas. Clustering of brain areas according to similarity of spectral profiles reveals well-known brain networks. Furthermore, we demonstrate task-specific modulations of auditory spectral profiles during auditory processing. These findings have important implications for the classification of regional spectral activity and allow for novel approaches in neuroimaging and neurostimulation in health and disease