Advanced Systemic Mastocytosis with associated haematological neoplasm: Treatment with avapritinib can facilitate successful bridge to allogeneic haematopoietic cell transplant.

Advanced systemic mastocytosis (AdvSM) is a rare, life-limiting mast cell (MC) neoplasm, with approximately 70% patients having an associated haematological neoplasm (AHN). Avapritinib, a selective tyrosine kinase inhibitor targeting KIT D816V, has shown potent activity translating clinically into durable responses in the phase 1 EXPLORER (NCT02561988) and phase 2 PATHFINDER (NCT03580655) studies. We report three patients with AdvSM-AHN on avapritinib who achieved complete remission (CR) of SM and were successfully bridged to allogeneic haematopoietic cell transplant (allo-HCT). Two cases additionally highlight the risk of clonal evolution within the AHN component and requirement for close monitoring while on targeted therapy.

Using genomic prediction to detect microevolutionary change of a quantitative trait.

Detecting microevolutionary responses to natural selection by observing temporal changes in individual breeding values is challenging. The collection of suitable datasets can take many years and disentangling the contributions of the environment and genetics to phenotypic change is not trivial. Furthermore, pedigree-based methods of obtaining individual breeding values have known biases. Here, we apply a genomic prediction approach to estimate breeding values of adult weight in a 35-year dataset of Soay sheep (Ovis aries). Comparisons are made with a traditional pedigree-based approach. During the study period, adult body weight decreased, but the underlying genetic component of body weight increased, at a rate that is unlikely to be attributable to genetic drift. Thus cryptic microevolution of greater adult body weight has probably occurred. Genomic and pedigree-based approaches gave largely consistent results. Thus, using genomic prediction to study microevolution in wild populations can remove the requirement for pedigree data, potentially opening up new study systems for similar research.

Excellent medium-term survival of an all-inside tensionable knotted suture device justifies repair of most meniscal tears encountered during reconstructive knee ligament surgery.

PURPOSE: All-inside meniscal repair devices have evolved to allow surgeons to undertake complex repairs in a timely and efficient manner. This is advantageous in active patients, where meniscus preservation is critical in preserving joint function and stability. The aim of the study was to evaluate the failure rate of all-inside meniscal repair performed in patients undergoing reconstructive ligament surgery using a particular meniscal repair device. METHODS: Patients were identified using a single-site prospectively maintained patient registry. Primary outcome was failure, defined as return to surgery with documented failure of repair. Complication rates and functional scores were also recorded. Patients in whom meniscal repair failure was identified were further assessed, to identify any common features. RESULTS: Over an 8-year period, 323 patients underwent meniscal repair at the time of ligament reconstruction, compared to 244 meniscectomies. Of these, 286 patients underwent repair using an all-inside suture device. One-hundred and twenty-seven repairs were to the medial meniscus only, 124 were lateral, and in 35 patients both menisci were repaired. Follow-up was to a median of 51.5 months. There were 31 (9.7%) failures reported at a median of 22 months post-operatively (IQR 13.5-41.5). Medial repair failures were seen more frequently than lateral (13.6% versus 5.6% OR 2.62 95% CI 1.17-5.88 p = 0.022). Failure of ACL reconstruction was associated with meniscal repair failure (OR 5.83 95% CI 1.55-21.95 p = 0.0039). Multi-ligament reconstruction was undertaken in 70/286 patients receiving meniscal repair and was not associated with failure (OR 1.3 95% CI 0.57-2.98 p = 0.51). Mode number of all-inside sutures used was 3 in both medial and lateral repairs (Range 1-9 lateral; 1-7 medial). CONCLUSIONS: All-inside repair is a safe and versatile technique which can be used in the majority of meniscal tears encountered during ligament reconstruction with excellent mid-term success. Failure is seen more commonly in medial sided repairs and with failure of ACL reconstruction. LEVEL OF EVIDENCE: IV.

Habituation and individual variation in the endocrine stress response in the Trinidadian guppy (Poecilia reticulata).

The vertebrate stress response enables individuals to react to and cope with environmental challenges. A crucial aspect of the stress response is the elevation of circulating glucocorticoids. However, continued activation of the stress response under repeated exposure to stressors can be damaging to fitness. Under certain circumstances it may therefore be adaptive to habituate to repeated exposures to a particular stressor by reducing the magnitude of any associated release of glucocorticoids. Here, we investigate whether Trinidadian guppies (Poecilia reticulata) habituate to repeated exposure to a mild stressor, using a waterborne hormone sampling approach that has previously been shown to elicit a stress response in small fish. We also test for individual variation in the extent of habituation to this stressor. Concentrating on freely circulating cortisol, we found that the first exposure to the assay induced high cortisol release rates but that guppies tended to habituate quickly to subsequent exposures. There were consistent differences among individuals in their average cortisol release rate (after accounting for effects of variables such as body size) over repeated exposures. Our analyses did not find evidence of individual differences in habituation rate, although limitations in statistical power could account for this finding. We repeated the analysis for free 11-ketotestosterone, which can also respond to stressors, but found no obvious habituation pattern and no among-individual variation. We also present data on conjugated forms of both hormones, which were repeatable but did not show the expected time-lagged habituation effect. We discuss consistent individual differences around the general pattern of habituation in the flexible stress response, and highlight the potential for individual variation in habituation to facilitate selection against the deleterious effects of chronic stress.

Spatial relationship between bone formation and mechanical stimulus within cortical bone: Combining 3D fluorochrome mapping and poroelastic finite element modelling.

Bone is a dynamic tissue and adapts its architecture in response to biological and mechanical factors. Here we investigate how cortical bone formation is spatially controlled by the local mechanical environment in the murine tibia axial loading model (C57BL/6). We obtained 3D locations of new bone formation by performing 'slice and view' 3D fluorochrome mapping of the entire bone and compared these sites with the regions of high fluid velocity or strain energy density estimated using a finite element model, validated with ex-vivo bone surface strain map acquired ex-vivo using digital image correlation. For the comparison, 2D maps of the average bone formation and peak mechanical stimulus on the tibial endosteal and periosteal surface across the entire cortical surface were created. Results showed that bone formed on the periosteal and endosteal surface in regions of high fluid flow. Peak strain energy density predicted only the formation of bone periosteally. Understanding how the mechanical stimuli spatially relates with regions of cortical bone formation in response to loading will eventually guide loading regime therapies to maintain or restore bone mass in specific sites in skeletal pathologies.

Towards using a focussed phased array of millimetre length scale elements for ultrasound imaging.

Sparse phased array ultrasound transducers with millimetre length scale elements have previously been proposed for generating hyperthermia but not for imaging. Numerical simulation with a pseudospectral solver was used to investigate: (a) how the position of the maximum pressure in the focal region changed with element diameter and frequency; (b) how the size and position of the focal region changed with focal distance under steering; and (c) the imaging performance of 15 element random arrays. These analyses were performed for both piston-like and non piston-like millimetre diameter elements since previous work has shown a shift in the distance to the maximum pressure in the focal region with the latter. The results for these elements were compared with elements where the diameter was <λ/2. The distance from the array to the position of maximum pressure in the focal region diverged from the value with element diameter <λ/2; values for piston-like elements increased positively whilst values for non piston-like elements increased negatively. With distances expressed in λ, no difference was found for arrays at 1 MHz and 2.5 MHz. For piston-like elements, but not for non piston-like elements, two peaks were found in the focal region which were in-line with the direction of propagation for a focus on the central axis but which rotated to become parallel with the direction of propagation when steering exceeded 20°. The size and position of the focal region under steering was similar for the non piston-like elements and elements with diameter <λ/2. Little difference was found in image quality or the size of the point spread function (PSF) between images at 2.5 MHz with piston-like and non piston-like behaviour for steering angles less than 20° when compared with a linear array of similar size. These results suggest that imaging with random arrays of millimetre length scale elements is possible.

Paediatric physeal sparing posterior cruciate ligament (PCL) reconstruction with parental donation allograft: Rationale and operative approach.

BACKGROUND: Paediatric PCL injuries are rare but constitute a significant management challenge. We describe a novel approach to the surgical management of an 11-year-old boy who presented with persisting symptomatic instability following 18months of failed conservative therapy. METHODS: PCL reconstruction was performed using a physeal sparing, all-inside technique under fluoroscopic control. This avoids the potential for iatrogenic growth injury. A parentally donated hamstrings allograft was used to ensure adequate graft size, and reinforced using a non-elastic two millimetre braided suture. Graft reinforcement safeguards against stretching during the early healing phase, but must be removed thereafter to avoid creating a physeal tether. RESULTS: At three months, clinical examination under anaesthesia showed equivalent PCL laxity in the operated knee compared to the normal contralateral knee. The graft reinforcement tape was incised as planned with no change in laxity assessment. Arthroscopic evaluation demonstrated a quiet joint with a well healed graft and no synovitis. Postoperative long leg radiographs showed no growth deformity against preoperative status. CONCLUSION: In paediatric patients with persisting symptomatic instability despite appropriate conservative management, surgical reconstruction of the PCL should be considered. Standard treatment has higher complication rates and poorer graft survival than in an adult cohort. Specific problems include iatrogenic growth plate injury causing growth arrest or angular deformity, inadequate graft size if using hamstrings autograft, and the additional technical challenge of small patient size. Early results from extra-physeal, all-inside PCL reconstruction using a parentally donated allograft are promising and may provide an alternative solution to traditional surgical management.

Imaging out-of-plane polarized emission patterns on gap mode SERS substrates: from high molecular coverage to the single molecule regime.

Gap mode surface-enhanced Raman scattering (SERS) substrates are created when a single nanoparticle is deposited on a thin metal film, creating a region of significant electromagnetic field enhancement in the gap between the nanoparticle and the film due to excitation of a vertically-oriented, out-of-plane dipole plasmon mode, e.g. the gap plasmon. When molecules are located in the gap and couple to the gap plasmon mode, the resulting emission is polarized perpendicular to the thin film, generating SERS emission patterns that have a characteristic donut shape. We analyze these SERS emission patterns using a dipole emission model and extract out-of-plane and in-plane emission angles associated with the gap plasmon mode. Fluctuations in both of these angles reveal dynamic heterogeneity due to molecular motion within the hot spot that changes as a function of molecular coverage. We also reveal static heterogeneity associated with structural defects in the thin film component of the gap mode substrates, indicating that even nanometer-scale surface roughness can impact the quality of gap mode emission.

Blood-feeding patterns of native mosquitoes and insights into their potential role as pathogen vectors in the Thames estuary region of the United Kingdom.

BACKGROUND: The range of vertebrate hosts on which species of mosquito blood-feed is an important parameter for identifying potential vectors and in assessing the risk of incursion and establishment of vector-borne pathogens. In the United Kingdom, studies of mosquito host range have collected relatively few specimens and used techniques that could only broadly identify host species. This study conducted intensive collection and analysis of mosquitoes from a grazing marsh environment in southeast England. This site provides extensive wetland habitat for resident and migratory birds and has abundant human nuisance biting mosquitoes. The aim was to identify the blood-feeding patterns of mosquito species present at the site which could contribute to the transmission of pathogens. METHODS: Twice-weekly collections of mosquitoes were made from Elmley Nature Reserve, Kent, between June and October 2014. Mosquitoes were collected using resting boxes, by aspiration from man-made structures and using a Mosquito Magnet Pro baited with 1-octen-3-ol. Blood-fed specimens were classified according to the degree of blood meal digestion using the Sella scale and vertebrate origin determined using sequencing of a fragment of the mitochondrial cytochrome C oxidase subunit I gene. Mosquitoes that were morphologically cryptic were identified to species level using multiplex PCR and sequencing methods. RESULTS: A total of 20,666 mosquitoes of 11 species were collected, and 2,159 (10.4%) were blood-fed (Sella scale II-VI); of these 1,341 blood-fed specimens were selected for blood meal analysis. Vertebrate origin was successfully identified in 964 specimens (72%). Collections of blood-fed individuals were dominated by Anopheles maculipennis complex (73.5%), Culiseta annulata (21.2%) and Culex pipiens form pipiens (10.4%). Nineteen vertebrate hosts comprising five mammals and 14 birds were identified as hosts for mosquitoes, including two migratory bird species. Feeding on birds by Culex modestus and Anopheles atroparvus populations in England was demonstrated. CONCLUSIONS: This study expands the vertebrate host range of mosquitoes in the Thames estuary region of the UK. Feeding on both resident and migratory bird species by potential arbovirus vectors including Cx. pipiens f. pipiens and Cx. modestus indicates the potential for enzootic transmission of an introduced arbovirus between migratory and local bird species by native mosquito species.

Accounting for female space sharing in St. Kilda Soay sheep (Ovis aries) results in little change in heritability estimates.

When estimating heritability in free-living populations, it is common practice to account for common environment effects, because of their potential to generate phenotypic covariance among relatives thereby biasing heritability estimates. In quantitative genetic studies of natural populations, however, philopatry, which results in relatives being clustered in space, is rarely accounted for. The two studies that have been carried out so far suggest absolute declines in heritability estimates of up to 43% when accounting for space sharing by relatives. However, due to methodological limitations these estimates may not be representative. We used data from the St. Kilda Soay sheep population to estimate heritabilities with and without accounting for space sharing for five traits for which there is evidence for additive genetic variance (birthweight, birth date, lamb August weight, and female post-mortem jaw and metacarpal length). We accounted for space sharing by related females by separately incorporating spatial autocorrelation, and a home range similarity matrix. Although these terms accounted for up to 18% of the variance in these traits, heritability estimates were only reduced by up to 7%. Our results suggest that the bias caused by not accounting for space sharing may be lower than previously thought. This suggests that philopatry does not inevitably lead to a large bias if space sharing by relatives is not accounted for. We hope our work stimulates researchers to model shared space when relatives in their study population share space, as doing so will enable us to better understand when bias may be of particular concern.

Constrained evolution of the sex comb in Drosophila simulans.

Male fitness is dependent on sexual traits that influence mate acquisition (precopulatory sexual selection) and paternity (post-copulatory sexual selection), and although many studies have documented the form of selection in one or the other of these arenas, fewer have done it for both. Nonetheless, it appears that the dominant form of sexual selection is directional, although theoretically, populations should converge on peaks in the fitness surface, where selection is stabilizing. Many factors, however, can prevent populations from reaching adaptive peaks. Genetic constraints can be important if they prevent the development of highest fitness phenotypes, as can the direction of selection if it reverses across episodes of selection. In this study, we examine the evidence that these processes influence the evolution of the multivariate sex comb morphology of male Drosophila simulans. To do this, we conduct a quantitative genetic study together with a multivariate selection analysis to infer how the genetic architecture and selection interact. We find abundant genetic variance and covariance in elements of the sex comb. However, there was little evidence for directional selection in either arena. Significant nonlinear selection was detected prior to copulation when males were mated to nonvirgin females, and post-copulation during sperm offence (again with males mated to nonvirgins). Thus, contrary to our predictions, the evolution of the D. simulans sex comb is limited neither by genetic constraints nor by antagonistic selection between pre- and post-copulatory arenas, but nonlinear selection on the multivariate phenotype may prevent sex combs from evolving to reach some fitness maximizing optima.

Fisher's sons' effect in sexual selection: absent, intermittent or just low experimental power?

The Fisherian sexual selection paradigm has been called the null model of sexual selection. At its heart is the expectation of a genetic correlation (rG ) between female preference and male trait. However, recent meta-analysis has shown estimated correlations are often extremely weak and not statistically significant. We show here that systematic failure of studies to reject the null hypothesis that rG  = 0 is almost certainly due to the low power of most experimental designs used. We provide an easy way to assess experimental power a priori and suggest that current data make it difficult to definitively test a key component of the Fisher effect.

Measurement and modelling the sensitivity of tetrapolar transfer impedance measurements.

Finite element method (FEM) modelling of a small disk in a homogeneous saline medium showed that the sensitivity distribution for tetrapolar transfer impedance measurements was dependant on the ratio, σdisk/σsaline, and not absolute conductivity values. In addition, the amplitude of the negative sensitivity regions between the drive and receive electrodes decreased non-linearly with σdisk/σsaline for σdisk/σsaline < 1, eventually becoming zero. This non-linear behaviour determined the limit of the assumption of a small change in conductivity in Geselowitz's lead theorem with 0.5 <σdisk/σsaline <1.5 for the measurements reported. The modelling supported the design of a sensitivity measurement system using an insulating support and a metal disk in a saline filled tank. Measurements were shown to give good agreement with sensitivity predictions from Geselowitz's lead theorem. Replacing the homogeneous medium in the FEM model with layers of different conductivity parallel to the plane of the electrodes changed the sensitivity distribution when the thickness of the layers adjacent to the electrodes were less than ½ the electrode spacing. A layer of greater conductivity over a layer of lesser conductivity next to the electrodes gave a peak in the sensitivity distribution and extended regions of negative sensitivity further into the tissue.

Sex-specific plasticity and genotype × sex interactions for age and size of maturity in the sheepshead swordtail, Xiphophorus birchmanni.

Responses to sexually antagonistic selection are thought to be constrained by the shared genetic architecture of homologous male and female traits. Accordingly, adaptive sexual dimorphism depends on mechanisms such as genotype-by-sex interaction (G×S) and sex-specific plasticity to alleviate this constraint. We tested these mechanisms in a population of Xiphophorus birchmanni (sheepshead swordtail), where the intensity of male competition is expected to mediate intersexual conflict over age and size at maturity. Combining quantitative genetics with density manipulations and analysis of sex ratio variation, we confirm that maturation traits are dimorphic and heritable, but also subject to large G×S. Although cross-sex genetic correlations are close to zero, suggesting sex-linked genes with important effects on growth and maturation are likely segregating in this population, we found less evidence of sex-specific adaptive plasticity. At high density, there was a weak trend towards later and smaller maturation in both sexes. Effects of sex ratio were stronger and putatively adaptive in males but not in females. Males delay maturation in the presence of mature rivals, resulting in larger adult size with subsequent benefit to competitive ability. However, females also delay maturation in male-biased groups, incurring a loss of reproductive lifespan without apparent benefit. Thus, in highly competitive environments, female fitness may be limited by the lack of sex-specific plasticity. More generally, assuming that selection does act antagonistically on male and female maturation traits in the wild, our results demonstrate that genetic architecture of homologous traits can ease a major constraint on the evolution of adaptive dimorphism.

Piezo2 is the major transducer of mechanical forces for touch sensation in mice.

The sense of touch provides critical information about our physical environment by transforming mechanical energy into electrical signals. It is postulated that mechanically activated cation channels initiate touch sensation, but the identity of these molecules in mammals has been elusive. Piezo2 is a rapidly adapting, mechanically activated ion channel expressed in a subset of sensory neurons of the dorsal root ganglion and in cutaneous mechanoreceptors known as Merkel-cell-neurite complexes. It has been demonstrated that Merkel cells have a role in vertebrate mechanosensation using Piezo2, particularly in shaping the type of current sent by the innervating sensory neuron; however, major aspects of touch sensation remain intact without Merkel cell activity. Here we show that mice lacking Piezo2 in both adult sensory neurons and Merkel cells exhibit a profound loss of touch sensation. We precisely localize Piezo2 to the peripheral endings of a broad range of low-threshold mechanoreceptors that innervate both hairy and glabrous skin. Most rapidly adapting, mechanically activated currents in dorsal root ganglion neuronal cultures are absent in Piezo2 conditional knockout mice, and ex vivo skin nerve preparation studies show that the mechanosensitivity of low-threshold mechanoreceptors strongly depends on Piezo2. This cellular phenotype correlates with an unprecedented behavioural phenotype: an almost complete deficit in light-touch sensation in multiple behavioural assays, without affecting other somatosensory functions. Our results highlight that a single ion channel that displays rapidly adapting, mechanically activated currents in vitro is responsible for the mechanosensitivity of most low-threshold mechanoreceptor subtypes involved in innocuous touch sensation. Notably, we find that touch and pain sensation are separable, suggesting that as-yet-unknown mechanically activated ion channel(s) must account for noxious (painful) mechanosensation.

Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a costimulatory molecule that negatively regulates T-cell activation. Originally identified in murine CD8(+) T cells, it has been found to be rapidly induced on human T cells. Furthermore, CTLA-4 is expressed on regulatory T cells. Clinically, targeting CTLA-4 has clinical utility in the treatment of melanoma. Whether the expression of CTLA-4 is differentially regulated in CD8(+) vs CD4(+) human T cells is unclear. Here, we analyzed CTLA-4 in normal human CD4(+) and CD8(+) T-cell subsets and show for the first time that CTLA-4 is expressed significantly higher in the CD4(+) T cells than in CD8(+) T cells. CTLA-4 is higher at the protein and the transcriptional levels in CD4(+) T cells. This increase is due to the activation of the CTLA-4 promoter, which undergoes acetylation at the proximal promoter. Furthermore, we show that blocking CTLA-4 on CD4(+) T cells permits greater proliferation in CD4(+) vs CD8(+) cells. These findings demonstrate a differential regulation of CTLA-4 on CD4(+) and CD8(+) T-cell subsets, which is likely important to the clinical efficacy for anti-CTLA-4 therapies. The findings hint to strategies to modulate CTLA-4 expression by targeting epigenetic transcription to alter the immune response.

Transformational teaching and adolescent physical activity: multilevel and mediational effects.

BACKGROUND: Regular physical activity is associated with a range of physical and psychological health benefits. In North America the majority of adolescents are insufficiently active. PURPOSE: The purpose of this study was to examine the prospective relationship between adolescents' perceptions of transformational leadership displayed by their school physical education teachers and their own physical activity behaviors, both with respect to within-class physical activity (WCPA) and also leisure time physical activity (LTPA). METHOD: The study used a prospective observational design. Using multilevel structural equation modeling (MSEM), we examined the extent to which adolescents' affective attitudes mediated the effects of teachers' behaviors on adolescents' physical activity responses. Two thousand nine hundred and forty-eight adolescents (M age = 14.33, SD = 1.00, N female = 1,641, 55.7 %) from 133 Grade 8-10 classes in British Columbia (Canada) provided ratings of their physical education teachers' behaviors midway through the school year. Two months later, students completed measures of affective attitudes, WCPA, and LTPA. RESULTS: The results indicated that adolescents' perceptions of transformational teaching explained significant variance in both WCPA and LTPA, and these effects were fully mediated by adolescents' affective attitudes (total indirect effect: b = 0.581, p < 0.001). CONCLUSION: The findings suggest that transformational leadership behaviors displayed by physical education teachers may be an important source of adolescent enjoyment of physical education as well as health-enhancing physical activity involvement within school and outside of school.

Competition as a source of constraint on life history evolution in natural populations.

Competition among individuals is central to our understanding of ecology and population dynamics. However, it could also have major implications for the evolution of resource-dependent life history traits (for example, growth, fecundity) that are important determinants of fitness in natural populations. This is because when competition occurs, the phenotype of each individual will be causally influenced by the phenotypes, and so the genotypes, of competitors. Theory tells us that indirect genetic effects arising from competitive interactions will give rise to the phenomenon of 'evolutionary environmental deterioration', and act as a source of evolutionary constraint on resource-dependent traits under natural selection. However, just how important this constraint is remains an unanswered question. This article seeks to stimulate empirical research in this area, first highlighting some patterns emerging from life history studies that are consistent with a competition-based model of evolutionary constraint, before describing several quantitative modelling strategies that could be usefully applied. A recurrent theme is that rigorous quantification of a competition's impact on life history evolution will require an understanding of the causal pathways and behavioural processes by which genetic (co)variance structures arise. Knowledge of the G-matrix among life history traits is not, in and of itself, sufficient to identify the constraints caused by competition.

Osteotomy around the knee: evolution, principles and results.

PURPOSE: This article summarises the history and evolution of osteotomy around the knee, examining the changes in principles, operative technique and results over three distinct periods: Historical (pre 1940), Modern Early Years (1940-2000) and Modern Later Years (2000-Present). We aim to place the technique in historical context and to demonstrate its evolution into a validated procedure with beneficial outcomes whose use can be justified for specific indications. MATERIALS AND METHODS: A thorough literature review was performed to identify the important steps in the development of osteotomy around the knee. RESULTS: The indications and surgical technique for knee osteotomy have never been standardised, and historically, the results were unpredictable and at times poor. These factors, combined with the success of knee arthroplasty from the 1980s onward, led to knee osteotomy being regarded as an irrelevant surgical option by many surgeons. Despite its fluctuating reputation, this article demonstrates the reasons for the enduring practice of osteotomy, not least because achieving the appropriate alignment is now recognised as the foundation step when planning any surgical intervention. CONCLUSIONS: With appropriate patient selection, accurate pre-operative planning, modern surgical fixation techniques and rapid rehabilitation, osteotomy around the knee is now an effective biological treatment for degenerative disease, deformity, knee instability and also as an adjunct to other complex joint surface and meniscal cartilage surgery. LEVEL OF EVIDENCE: V.

Scaling from challenge experiments to the field: Quantifying the impact of vaccination on the transmission of bluetongue virus serotype 8.

Bluetongue (BT) is an economically important disease of ruminants caused by bluetongue virus (BTV) and transmitted by Culicoides biting midges. The most practical and effective way to protect susceptible animals against BTV is by vaccination. Data from challenge studies in calves and sheep conducted by Intervet International b.v., in particular, presence of viral RNA in the blood of challenged animals, were used to estimate vaccine efficacy. The results of the challenge studies for calves indicated that vaccination is likely to reduce the basic reproduction number (R(0)) for BTV in cattle to below one (i.e. prevent major outbreaks within a holding) and that this reduction is robust to uncertainty in the model parameters. Sensitivity analysis showed that the whether or not vaccination is predicted to reduce R(0) to below one depended on the following assumptions: (i) whether "doubtful" results from the challenge studies are treated as negative or positive; (ii) whether or not the probability of transmission from host to vector is reduced by vaccination; and (iii) whether the extrinsic incubation period follows a realistic gamma distribution or the more commonly used exponential distribution. For sheep, all but one of the vaccinated animals were protected and, consequently, vaccination will consistently reduce R(0) in sheep to below one. Using a stochastic spatial model for the spread of BTV in Great Britain (GB), vaccination was predicted to reduce both the incidence of disease and spatial spread in simulated BTV outbreaks in GB, in both reactive vaccination strategies and when an incursion occurred into a previously vaccinated population.