Epidemiological Characteristics of Classical Scrapie Outbreaks in 30 Sheep Flocks in the United Kingdom

Most previous analyses of scrapie outbreaks have focused on flocks run by research institutes, which may not reflect the field situation. Within this study, we attempt to rectify this deficit by describing the epidemiological characteristics of 30 sheep flocks naturally-infected with classical scrapie, and by exploring possible underlying causes of variation in the characteristics between flocks, including flock-level prion protein (PrP) genotype profile. In total, the study involved PrP genotype data for nearly 8600 animals and over 400 scrapie cases.We found that most scrapie cases were restricted to just two PrP genotypes (ARQ/VRQ and VRQ/VRQ), though two flocks had markedly different affected genotypes, despite having similar underlying genotype profiles to other flocks of the same breed; we identified differences amongst flocks in the age of cases of certain PrP genotypes; we found that the age-at-onset of clinical signs depended on peak incidence and flock type; we found evidence that purchasing infected animals is an important means of introducing scrapie to a flock; we found some evidence that flock-level PrP genotype profile and flock size account for variation in outbreak characteristics; identified seasonality in cases associated with lambing time in certain flocks; and we identified one case that was homozygous for phenylalanine at codon 141, a polymorphism associated with a very high risk of atypical scrapie, and 28 cases that were heterozygous at this codon.This paper presents the largest study to date on commercially-run sheep flocks naturally-infected with classical scrapie, involving 30 study flocks, more than 400 scrapie cases and over 8500 PrP genotypes. We show that some of the observed variation in epidemiological characteristics between farms is related to differences in their PrP genotype profile; although much remains unexplained and may instead be attributed to the stochastic nature of scrapie dynamics

Epidemiological Characteristics of Classical Scrapie Outbreaks in 30 Sheep Flocks in the United Kingdom

Most previous analyses of scrapie outbreaks have focused on flocks run by research institutes, which may not reflect the field situation. Within this study, we attempt to rectify this deficit by describing the epidemiological characteristics of 30 sheep flocks naturally-infected with classical scrapie, and by exploring possible underlying causes of variation in the characteristics between flocks, including flock-level prion protein (PrP) genotype profile. In total, the study involved PrP genotype data for nearly 8600 animals and over 400 scrapie cases.We found that most scrapie cases were restricted to just two PrP genotypes (ARQ/VRQ and VRQ/VRQ), though two flocks had markedly different affected genotypes, despite having similar underlying genotype profiles to other flocks of the same breed; we identified differences amongst flocks in the age of cases of certain PrP genotypes; we found that the age-at-onset of clinical signs depended on peak incidence and flock type; we found evidence that purchasing infected animals is an important means of introducing scrapie to a flock; we found some evidence that flock-level PrP genotype profile and flock size account for variation in outbreak characteristics; identified seasonality in cases associated with lambing time in certain flocks; and we identified one case that was homozygous for phenylalanine at codon 141, a polymorphism associated with a very high risk of atypical scrapie, and 28 cases that were heterozygous at this codon.This paper presents the largest study to date on commercially-run sheep flocks naturally-infected with classical scrapie, involving 30 study flocks, more than 400 scrapie cases and over 8500 PrP genotypes. We show that some of the observed variation in epidemiological characteristics between farms is related to differences in their PrP genotype profile; although much remains unexplained and may instead be attributed to the stochastic nature of scrapie dynamics

Identification of modifiable factors associated with owner-reported equine laminitis in Britain using a web-based cohort study approach

Equine laminitis is a complex disease that manifests as pain and lameness in the feet, often with debilitating consequences. There is a paucity of data that accounts for the multifactorial nature of laminitis and considers time-varying covariates that may be associated with disease development; particularly those that are modifiable and present potential interventions. A previous case-control study identified a number of novel, modifiable factors associated with laminitis which warranted further investigation and corroboration. The aim of this study was to identify factors associated with equine laminitis in horses/ponies in Great Britain (GB) using a prospective, web-based cohort study design, with particular interest in evaluating modifiable factors previously identified in the case-control study

Successful Cognitive Aging in Rats: A Role for mGluR5 Glutamate Receptors, Homer 1 Proteins and Downstream Signaling Pathways

Normal aging is associated with impairments in cognition, especially learning and memory. However, major individual differences are known to exist. Using the classical Morris Water Maze (MWM) task, we discriminated a population of 24-months old Long Evans aged rats in two groups - memory-impaired (AI) and memory-unimpaired (AU) in comparison with 6-months old adult animals. AI rats presented deficits in learning, reverse memory and retention. At the molecular level, an increase in metabotropic glutamate receptors 5 (mGluR5) was observed in post-synaptic densities (PSD) in the hippocampus of AU rats after training. Scaffolding Homer 1b/c proteins binding to group 1 mGluR facilitate coupling with its signaling effectors while Homer 1a reduces it. Both Homer 1a and 1b/c levels were up-regulated in the hippocampus PSD of AU animals following MWM task. Using immunohistochemistry we further demonstrated that mGluR5 as well as Homer 1b/c stainings were enhanced in the CA1 hippocampus sub-field of AU animals. In fact mGluR5 and Homer 1 isoforms were more abundant and co-localized in the hippocampal dendrites in AU rats. However, the ratio of Homer 1a/Homer 1b/c bound to mGluR5 in the PSD was four times lower for AU animals compared to AI rats. Consequently, AU animals presented higher PKCγ, ERK, p70S6K, mTOR and CREB activation. Finally the expression of immediate early gene Arc/Arg3.1 was shown to be higher in AU rats in accordance with its role in spatial memory consolidation. On the basis of these results, a model of successful cognitive aging with a critical role for mGluR5, Homer 1 proteins and downstream signalling pathways is proposed here

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment

Korkeakoulutettujen asumispreferenssit osana pääkaupunkiseudun alueellista eriytymistä

Tässä tutkielmassa tarkastellaan työssäkäyvien ylemmän korkeakoulutkinnon suorittaneiden asumispreferenssejä sellaisilla asuinalueilla, jotka ovat sosioekonomisesti tarkasteltuna hyväosaisia. Useat tutkimukset osoittavat pääkaupunkiseudun eriytyneen alueellisesti siten, että korkeakoulutetut ovat sijoittuneet asumaan Helsinginniemelle ja länsipainotteisesti merenrannoille. Matalan tulo- ja koulutustason, korkean työttömyyden ja etnisen heterogeenisyyden alueet painottuvat lähinnä Helsingin itäiseen suurpiiriin ja pääkaupunkiseudun radanvarsialueille. Tutkielmassa pureudutaan alueelliseen, sosioekonomiseen ja etniseen eriytymiseen korkeakoulutettujen asumispreferenssien lisäksi myös tutkittavien omien eriytymistä koskevien pohdintojen kautta. Tutkielman näkökulma on kulttuurisosiologinen. Teoreettisena taustana käytetään Bourdieun distinktioteoriaa erityisesti painottaen kulttuurisen pääoman merkitystä asumisvalintojen ja alueellista eriytymistä koskevien käsitysten mahdollistajana ja selittäjänä. Tutkielman fokuksessa on pääkaupunkiseudun alueellinen kehitys, mitä taustoitetaan ottamalla huomioon myös suomalaisen yhteiskunnan historialliset ja kulttuuriset erityispiirteet, kuten suomalaisten yhteneväiset asumistoiveet ja sosiaaliseen sekoittamiseen perustuva asunto- ja kaavoituspolitiikka. Tutkielman aineisto koostuu kymmenestä puolistrukturoidusta teemahaastattelusta. Haastateltavat olivat iältään 30 – 55-vuotiaita ylemmän korkeakoulututkinnon suorittaneita naisia ja miehiä. Kuusi heistä asui Helsinginniemellä ja neljä muilla pääkaupunkiseudun kerrostalovaltaisilla alueilla. Aineiston analyysimenetelmä on abduktiivinen sisällönanalyysi. Analyysin pohjana käytetään aiempaa tutkimustietoa alueellisesta eriytymisestä ja asumispreferensseistä. Tuloksena esitetään korkeakoulutettujen asumispreferenssien ilmentävän urbaania asumisen elämäntyyliä. Asumisessa arvostetaan helppoutta: kerrostaloasumista, hyviä liikenneyhteyksiä ja palveluita. Kulttuuriset arvostukset liittyvät alueen historiallisuuteen, esteettisyyteen, suvaitsevaisuuteen ja sosiaalisten suhteiden myötä korostuvaan asukkaiden samankaltaisuuteen sekä turvallisuudentunteeseen. Alueellinen eriytyminen tulee ymmärrettäväksi tuntemattomiin ihmisiin liittyvien turvattomuuskokemusten ja uhkien kautta. Käytännössä tämä tapahtuu muille kuin omalle asuinalueelle paikantuvien turvallisuusuhkien ja vaarojen alueellisesti paikannettavana välttelemisenä. Eriytyminen on myös etäisyyden kautta määrittynyttä, korkeasti koulutetut ovat eriytyneet alueellisesti asuinalueidensa ja työpaikkojensa mukaisesti. Muut alueet asukkaineen jäävät konkreettisesti etäisiksi. Sosioekonominen, etninen ja alueellinen eriytyminen on haastateltavien käsitysten perusteella hyvin tunnistettua ja tiedostettua. Johtopäätöksenä todetaan erontekojen noudattavan toisenlaista logiikkaa kuin Bourdieun Ranskaa koskevissa tutkimuksissa. Suomalaisessa yhteiskunnassa distinktioita tehdään ennen kaikkea häivyttämällä sosioekonomisia eroja; puheessa korostetaan tasa-arvoa ja omaa ylempää asemaa tuodaan alaspäin tavallisuuspuheen kautta. Oma asuinalue nähdään tavallisena sosioekonomisesta eriytymisestä huolimatta. Puheet ja käsitykset tuotetaan kulttuurisen pääoman kautta yhteiskunnallisesti sopiviksi ja hyväksytyiksi. Tällainen puhe on hyvin harkittua, varovaista ja refleksiivistä. Sosiaalisiin suhteisiin ja turvallisuuteen perustuva samankaltaisten ihmisten pariin hakeutuminen kuitenkin on olennainen osa pääkaupunkiseudun alueellista eriytymistä

Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials

Background Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. Methods We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Findings Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5–14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4–8·6]; rate ratio 1·37 [95% CI 1·17–1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92–1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95–1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94–1·15]; p=0·45). Interpretation Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered—eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy