Centralisation of specialist cancer surgery services in two areas of England: the RESPECT-21 mixed-methods evaluation

Background: Centralising specialist cancer surgical services is an example of major system change. High-volume centres are recommended to improve specialist cancer surgery care and outcomes. Objective: Our aim was to use a mixed-methods approach to evaluate the centralisation of specialist surgery for prostate, bladder, renal and oesophago-gastric cancers in two areas of England [i.e. London Cancer (London, UK), which covers north-central London, north-east London and west Essex, and Greater Manchester Cancer (Manchester, UK), which covers Greater Manchester]. Design: Stakeholder preferences for centralising specialist cancer surgery were analysed using a discrete choice experiment, surveying cancer patients (n = 206), health-care professionals (n = 111) and the general public (n = 127). Quantitative analysis of impact on care, outcomes and cost-effectiveness used a controlled before-and-after design. Qualitative analysis of implementation and outcomes of change used a multisite case study design, analysing documents (n = 873), interviews (n = 212) and non-participant observations (n = 182). To understand how lessons apply in other contexts, we conducted an online workshop with stakeholders from a range of settings. A theory-based framework was used to synthesise these approaches. Results: Stakeholder preferences – patients, health-care professionals and the public had similar preferences, prioritising reduced risk of complications and death, and better access to specialist teams. Travel time was considered least important. Quantitative analysis (impact of change) – only London Cancer’s centralisations happened soon enough for analysis. These changes were associated with fewer surgeons doing more operations and reduced length of stay [prostate –0.44 (95% confidence interval –0.55 to –0.34) days; bladder –0.563 (95% confidence interval –4.30 to –0.83) days; renal –1.20 (95% confidence interval –1.57 to –0.82) days]. The centralisation meant that renal patients had an increased probability of receiving non-invasive surgery (0.05, 95% confidence interval 0.02 to 0.08). We found no evidence of impact on mortality or re-admissions, possibly because risk was already low pre-centralisation. London Cancer’s prostate, oesophago-gastric and bladder centralisations had medium probabilities (79%, 62% and 49%, respectively) of being cost-effective, and centralising renal services was not cost-effective (12% probability), at the £30,000/quality-adjusted life-year threshold. Qualitative analysis, implementation and outcomes – London Cancer’s provider-led network overcame local resistance by distributing leadership throughout the system. Important facilitators included consistent clinical leadership and transparent governance processes. Greater Manchester Cancer’s change leaders learned from history to deliver the oesophago-gastric centralisation. Greater Manchester Cancer’s urology centralisations were not implemented because of local concerns about the service model and local clinician disengagement. London Cancer’s network continued to develop post implementation. Consistent clinical leadership helped to build shared priorities and collaboration. Information technology difficulties had implications for interorganisational communication and how reliably data follow the patient. London Cancer’s bidding processes and hierarchical service model meant that staff reported feelings of loss and a perceived ‘us and them’ culture. Workshop – our findings resonated with workshop attendees, highlighting issues about change leadership, stakeholder collaboration and implications for future change and evaluation. Limitations: The discrete choice experiment used a convenience sample, limiting generalisability. Greater Manchester Cancer implementation delays meant that we could study the impact of only London Cancer changes. We could not analyse patient experience, quality of life or functional outcomes that were important to patients (e.g. continence). Future research: Future research may focus on impact of change on care options offered, patient experience, functional outcomes and long-term sustainability. Studying other approaches to achieving high-volume services would be valuable. Study registration: ational Institute for Health and Care Research (NIHR) Clinical Research Network Portfolio reference 19761

Outbreak of acute gastroenteritis in an air force base in Western Greece

BACKGROUND: On the 20(th )September 2005, soldiers and staff at the Air Force base in Western Greece experienced an outbreak of acute gastroenteritis. The purpose of this study was to identify the agent and the source of the outbreak in order to develop control measures and to avoid similar outbreaks in the future. METHODS: A case-control analytical approach was employed with 100 randomly selected cases and 66 controls. Patients completed standardized questionnaires, odds ratios were calculated and statistical significance was determined using χ(2 )test. In addition, to identify the source of the infection, we performed bacteriological examination of food samples (included raw beef, cooked minced meat, grated cheese and grated cheese in sealed package) collected from the cuisine of the military unit. RESULTS: More than 600 out of the 1,050 individuals who ate lunch that day, became ill. The overall attack rate, as the military doctor of the unit estimated it, was at least 60%. The overall odds ratio of gastroenteritis among those who had lunch was 370 (95% CI: 48–7700) as compared to those who didn't eat lunch. Among the symptoms the most prominent were watery diarrhoea (96%) and abdominal pain (73%). The mean incubation period was 9 h and the median duration of the symptoms was 21 h. In the bacteriological examination, Staphylococcus aureus was detected in a sample of raw beef (2,000 cfu per g) and in two samples of grated cheese; leftover cheese from lunch (7,800 cfu per g) and an unopened package purchased from the market (3,000 cfu per g). CONCLUSION: The findings of this study suggest that the aetiological agent of this outbreak was S. aureus. The food vehicle was the grated cheese, which was mixed with the beef and served for lunch in the military unit. This outbreak highlights the capacity of enterotoxin-producing bacteria to cause short term, moderately-severe illness in a young and healthy population. It underscores the need for proper food handling practices and reinforces the public health importance of timely notification of such outbreaks

Modeling anthropometric indices in relation to 10-year (2002-2012) incidence of cardiovascular disease, among apparently healthy individuals:the ATTICA study

Aims: Body fat accumulation is implicated in the development of cardiovascular disease (CVD). Our objective was to explore potential associations between anthropometric indices and the 10-year CVD incidence in Greek adults without previous CVD. Methods: During 2001–2, we enrolled 3042 adults without CVD from the general population of Attica, Greece. In 2011–2, the 10-year study follow-up was performed, recording the CVD incidence in 1958 participants with baseline body mass index (BMI) ≥18.5 kg/m2. Results: The study 10-year CVD incidence was 15.8%, exhibiting a gradual increase according to the baseline body mass index (BMI) category. Baseline BMI ≥30 kg/m2 was related with significantly higher 10-year CVD risk compared to BMI <25 kg/m2, even after adjustment for age and other known CVD risk factors. Baseline BMI, waist circumference, waist-to-hip ratio, waist-to-height ratio and waist-to-hip-to-height ratio were independently associated with the 10-year CVD risk in multi-adjusted models. Gender-specific analyses showed that these associations were more evident in men compared to women, with baseline BMI exhibiting an independent association with the 10-year CVD incidence in men. Conclusions: Our results indicate that even simple anthropometric indices exhibit independent associations with CVD risk in a representative sample of the Greek general population without previous CVD

MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load.

Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10years (range: 5·4months-37years, IQR=17·9years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with LS/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094T>C

Evolution of a Core Gene Network for Skeletogenesis in Chordates

The skeleton is one of the most important features for the reconstruction of vertebrate phylogeny but few data are available to understand its molecular origin. In mammals the Runt genes are central regulators of skeletogenesis. Runx2 was shown to be essential for osteoblast differentiation, tooth development, and bone formation. Both Runx2 and Runx3 are essential for chondrocyte maturation. Furthermore, Runx2 directly regulates Indian hedgehog expression, a master coordinator of skeletal development. To clarify the correlation of Runt gene evolution and the emergence of cartilage and bone in vertebrates, we cloned the Runt genes from hagfish as representative of jawless fish (MgRunxA, MgRunxB) and from dogfish as representative of jawed cartilaginous fish (ScRunx1–3). According to our phylogenetic reconstruction the stem species of chordates harboured a single Runt gene and thereafter Runt locus duplications occurred during early vertebrate evolution. All newly isolated Runt genes were expressed in cartilage according to quantitative PCR. In situ hybridisation confirmed high MgRunxA expression in hard cartilage of hagfish. In dogfish ScRunx2 and ScRunx3 were expressed in embryonal cartilage whereas all three Runt genes were detected in teeth and placoid scales. In cephalochordates (lancelets) Runt, Hedgehog and SoxE were strongly expressed in the gill bars and expression of Runt and Hedgehog was found in endo- as well as ectodermal cells. Furthermore we demonstrate that the lancelet Runt protein binds to Runt binding sites in the lancelet Hedgehog promoter and regulates its activity. Together, these results suggest that Runt and Hedgehog were part of a core gene network for cartilage formation, which was already active in the gill bars of the common ancestor of cephalochordates and vertebrates and diversified after Runt duplications had occurred during vertebrate evolution. The similarities in expression patterns of Runt genes support the view that teeth and placoid scales evolved from a homologous developmental module

Lumbar segmental mobility disorders: comparison of two methods of defining abnormal displacement kinematics in a cohort of patients with non-specific mechanical low back pain

BACKGROUND: Lumbar segmental rigidity (LSR) and lumbar segmental instability (LSI) are believed to be associated with low back pain (LBP), and identification of these disorders is believed to be useful for directing intervention choices. Previous studies have focussed on lumbar segmental rotation and translation, but have used widely varying methodologies. Cut-off points for the diagnosis of LSR & LSI are largely arbitrary. Prevalence of these lumbar segmental mobility disorders (LSMDs) in a non-surgical, primary care LBP population has not been established. METHODS: A cohort of 138 consecutive patients with recurrent or chronic low back pain (RCLBP) were recruited in this prospective, pragmatic, multi-centre study. Consenting patients completed pain and disability rating instruments, and were referred for flexion-extension radiographs. Sagittal angular rotation and sagittal translation of each lumbar spinal motion segment was measured from the radiographs, and compared to a reference range derived from a study of 30 asymptomatic volunteers. In order to define reference intervals for normal motion, and define LSR and LSI, we approached the kinematic data using two different models. The first model used a conventional Gaussian definition, with motion beyond two standard deviations (2sd) from the reference mean at each segment considered diagnostic of rotational LSMD and translational LSMD. The second model used a novel normalised within-subjects approach, based on mean normalised contribution-to-total-lumbar-motion. An LSMD was then defined as present in any segment that contributed motion beyond 2sd from the reference mean contribution-to-normalised-total-lumbar-motion. We described reference intervals for normal segmental mobility, prevalence of LSMDs under each model, and the association of LSMDs with pain and disability. RESULTS: With the exception of the conventional Gaussian definition of rotational LSI, LSMDs were found in statistically significant prevalences in patients with RCLBP. Prevalences at both the segmental and patient level were generally higher using the normalised within-subjects model (2.8 to 16.8% of segments; 23.3 to 35.5% of individuals) compared to the conventional Gaussian model (0 to 15.8%; 4.7 to 19.6%). LSMDs are associated with presence of LBP, however LSMDs do not appear to be strongly associated with higher levels of pain or disability compared to other forms of non-specific LBP. CONCLUSION: LSMDs are a valid means of defining sub-groups within non-specific LBP, in a conservative care population of patients with RCLBP. Prevalence was higher using the normalised within-subjects contribution-to-total-lumbar-motion approach

Induction of Heme Oxygenase-1 Can Halt and Even Reverse Renal Tubule-Interstitial Fibrosis

Background: The tubule-interstitial fibrosis is the hallmark of progressive renal disease and is strongly associated with inflammation of this compartment. Heme-oxygenase-1 (HO-1) is a cytoprotective molecule that has been shown to be beneficial in various models of renal injury. However, the role of HO-1 in reversing an established renal scar has not yet been addressed. Aim: We explored the ability of HO-1 to halt and reverse the establishment of fibrosis in an experimental model of chronic renal disease. Methods: Sprague-Dawley male rats were subjected to unilateral ureteral obstruction (UUO) and divided into two groups: non-treated and Hemin-treated. To study the prevention of fibrosis, animals were pre-treated with Hemin at days -2 and -1 prior to UUO. To investigate whether HO-1 could reverse established fibrosis, Hemin therapy was given at days 6 and 7 post-surgery. After 7 and/or 14 days, animals were sacrificed and blood, urine and kidney tissue samples were collected for analyses. Renal function was determined by assessing the serum creatinine, inulin clearance, proteinuria/creatininuria ratio and extent of albuminuria. Arterial blood pressure was measured and fibrosis was quantified by Picrosirius staining. Gene and protein expression of pro-inflammatory and pro-fibrotic molecules, as well as HO-1 were performed. Results: Pre-treatment with Hemin upregulated HO-1 expression and significantly reduced proteinuria, albuminuria, inflammation and pro-fibrotic protein and gene expressions in animals subjected to UUO. Interestingly, the delayed treatment with Hemin was also able to reduce renal dysfunction and to decrease the expression of pro-inflammatory molecules, all in association with significantly reduced levels of fibrosis-related molecules and collagen deposition. Finally, TGF-beta protein production was significantly lower in Hemin-treated animals. Conclusion: Treatment with Hemin was able both to prevent the progression of fibrosis and to reverse an established renal scar. Modulation of inflammation appears to be the major mechanism behind HO-1 cytoprotection.Fundacao de Amparo Pesquisa do Estado de Sao Paulo-FAPESP[07/07139-3]Coordenaco de Aperfeioamento de Pessoal de Nivel Superior-CAPESInstituto Nacional de Ciencia e Tecnologia de Complexos Fluidos (INCT)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNP

Update on current views and advances on RSV infection (Review).

Respiratory syncytial virus (RSV) infection represents an excellent paradigm of precision medicine in modern paediatrics and several clinical trials are currently performed in the prevention and management of RSV infection. A new taxonomic terminology for RSV was recently adopted, while the diagnostic and omics techniques have revealed new modalities in the early identification of RSV infections and for better understanding of the disease pathogenesis. Coordinated clinical and research efforts constitute an important step in limiting RSV global predominance, improving epidemiological surveillance, and advancing neonatal and paediatric care. This review article presents the key messages of the plenary lectures, oral presentations and posters of the '5th workshop on paediatric virology' (Sparta, Greece, 12th October 2019) organized by the Paediatric Virology Study Group, focusing on recent advances in the epidemiology, pathogenesis, diagnosis, prognosis, clinical management and prevention of RSV infection in childhood

Healthy aging and disease: role for telomere biology?

Aging is a biological process that affects most cells, organisms and species. Human aging is associated with increased susceptibility to a variety of chronic diseases, including cardiovascular disease, Type 2 diabetes, neurological diseases and cancer. Despite the remarkable progress made during the last two decades, our understanding of the biology of aging remains incomplete. Telomere biology has recently emerged as an important player in the aging and disease process