ObjectiveAs gene-based therapies may soon arise for patients with spinocerebellar ataxia (SCA), there is a critical need to identify biomarkers of disease progression with effect sizes greater than clinical scores, enabling trials with smaller sample sizes.MethodsWe enrolled a unique cohort of patients with SCA1 (n = 15), SCA2 (n = 12), SCA3 (n = 20) and SCA7 (n = 10) and 24 healthy controls of similar age, sex and body mass index. We collected longitudinal clinical and imaging data at baseline and follow-up (mean interval of 24 months). We performed both manual and automated volumetric analyses. Diffusion tensor imaging (DTI) and a novel tractography method, called fixel-based analysis (FBA), were assessed at follow-up. Effect sizes were calculated for clinical scores and imaging parameters.ResultsClinical scores worsened as atrophy increased over time (p < 0.05). However, atrophy of cerebellum and pons showed very large effect sizes (>1.2) compared to clinical scores (<0.8). FBA, applied for the first time to SCA, was sensitive to microstructural cross-sectional differences that were not captured by conventional DTI metrics, especially in the less studied SCA7 group. FBA also showed larger effect sizes than DTI metrics.ConclusionThis study showed that volumetry outperformed clinical scores to measure disease progression in SCA1, SCA2, SCA3 and SCA7. Therefore, we advocate the use of volumetric biomarkers in therapeutic trials of autosomal dominant ataxias. In addition, FBA showed larger effect size than DTI to detect cross-sectional microstructural alterations in patients relative to controls.

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The hereditary spastic paraplegias are an expanding and heterogeneous group of disorders characterized by spasticity in the lower limbs. Plasma biomarkers are needed to guide the genetic testing of spastic paraplegia. Spastic paraplegia type 5 (SPG5) is an autosomal recessive spastic paraplegia due to mutations in CYP7B1, which encodes a cytochrome P450 7α-hydroxylase implicated in cholesterol and bile acids metabolism. We developed a method based on ultra-performance liquid chromatography electrospray tandem mass spectrometry to validate two plasma 25-hydroxycholesterol (25-OHC) and 27-hydroxycholesterol (27-OHC) as diagnostic biomarkers in a cohort of 21 patients with SPG5. For 14 patients, SPG5 was initially suspected on the basis of genetic analysis, and then confirmed by increased plasma 25-OHC, 27-OHC and their ratio to total cholesterol. For seven patients, the diagnosis was initially based on elevated plasma oxysterol levels and confirmed by the identification of two causal CYP7B1 mutations. The receiver operating characteristic curves analysis showed that 25-OHC, 27-OHC and their ratio to total cholesterol discriminated between SPG5 patients and healthy controls with 100% sensitivity and specificity. Taking advantage of the robustness of these plasma oxysterols, we then conducted a phase II therapeutic trial in 12 patients and tested whether candidate molecules (atorvastatin, chenodeoxycholic acid and resveratrol) can lower plasma oxysterols and improve bile acids profile. The trial consisted of a three-period, three-treatment crossover study and the six different sequences of three treatments were randomized. Using a linear mixed effect regression model with a random intercept, we observed that atorvastatin decreased moderately plasma 27-OHC (∼30%, P < 0.001) but did not change 27-OHC to total cholesterol ratio or 25-OHC levels. We also found an abnormal bile acids profile in SPG5 patients, with significantly decreased total serum bile acids associated with a relative decrease of ursodeoxycholic and lithocholic acids compared to deoxycholic acid. Treatment with chenodeoxycholic acid restored bile acids profile in SPG5 patients. Therefore, the combination of atorvastatin and chenodeoxycholic acid may be worth considering for the treatment of SPG5 patients but the neurological benefit of these metabolic interventions remains to be evaluated in phase III therapeutic trials using clinical, imaging and/or electrophysiological outcome measures with sufficient effect sizes. Overall, our study indicates that plasma 25-OHC and 27-OHC are robust diagnostic biomarkers of SPG5 and shall be used as first-line investigations in any patient with unexplained spastic paraplegia.

The timing of birth has a predominant influence on both the reproductive success of the mother and the life‐history trajectory of her offspring. Because early growth and survival are key drivers of population dynamics, there is an urgent need to understand how global change is affecting reproductive phenology and performance. However, identifying when and where birth occurs is often difficult in the wild due to the cryptic behaviour of females around parturition, although this information may also help managers to protect reproductive females and newborn against human disturbance. While several approaches to identify parturition based on movement metrics derived from GPS monitoring have previously been proposed, their performance has not been evaluated over a range of species with contrasted movement characteristics. Here, we present a novel approach to detect parturition by combining data on animal movements, activity rate and habitat use. Using machine learning approaches, we evaluated the relative and combined performance of each category of metrics in predicting parturition for three large herbivores with contrasted life histories: a hider‐type species, the roe deer Capreolus capreolus and two follower‐type species, the Mediterranean mouflon Ovis gmelini musimon × Ovis sp. and the Alpine ibex Capra ibex. We first showed that detection of parturition was much improved when birth‐related modifications in the habitat use and activity rate of the mother were considered, rather than relying on movement metrics only. We then demonstrated that our approach was highly successful (76%–100% of events correctly identified) in detecting parturition in both follower and hider species. Furthermore, our approach generated estimates for peak birth date and the proportion of parturient females that were comparable with those based on direct observations at the population scale. Finally, our approach outperformed the most commonly employed methods in the literature which generally failed to identify non‐reproductive females for the three studied species, and provided birth timing estimates that only poorly match the true parturition date. We suggest that by combining sources of information, we have developed a standardised methodological approach for inferring parturition in the wild, not only for large herbivores but also for any species where parturition induces marked behavioural changes in the mother.

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Wildlife reservoirs of infectious diseases raise major management issues. In Europe, brucellosis has been eradicated in domestic ruminants from most countries and wild ruminants have not been considered important reservoirs so far. However, a high prevalence of Brucella melitensis infection has been recently identified in a French population of Alpine ibex (Capra ibex), after the emergence of brucellosis was confirmed in a dairy cattle farm and two human cases. This situation raised the need to identify the factors driving the persistence of Brucella infection at high prevalence levels in this ibex population. In the present paper, we studied the shedding pattern of B. melitensis in ibex from Bargy Massif, French Alps. Bacteriological examinations (1–15 tissues/samples per individual) were performed on 88 seropositive, supposedly infected and euthanized individuals. Among them, 51 (58%) showed at least one positive culture, including 45 ibex with at least one Brucella isolation from a urogenital sample or a lymph node in the pelvic area (active infection in organs in the pelvic area). Among these 45 ibex, 26 (30% of the total number of necropsied animals) showed at least one positive culture for a urogenital organ and were considered as being at risk of shedding the bacteria at the time of capture. We observed significant heterogeneity between sex-and-age classes: seropositive females were most at risk to excrete Brucella before the age of 5 years, possibly corresponding to abortion during the first pregnancy following infection such as reported in the domestic ruminants. The high shedding potential observed in young females may have contributed to the self-sustained maintenance of infection in this population, whereas males are supposed to play a role of transmission between spatial units through venereal transmission during mating. This heterogeneity in the shedding potential of seropositive individuals should be considered in the future to better evaluate management scenarios in this system as well as in others.

France attained 'Officially Tuberculosis-Free' status in 2000. However, the Côte d'Or department (a French administrative unit) has since seen an increase in bovine tuberculosis (bTB) cases, with 35% of cases attributed to neighbourhood contamination. The aim of this study was to investigate the characteristics of neighbourhood contacts in an area affected by bTB in 2010, through the use of social network methods. We carried out a survey to determine the frequency and distribution of between-herd contacts in an area containing 22 farms. Contacts were weighted, as not all types of contact carried the same risk of bTB transmission. Cattle movement was considered to be associated with the highest risk, but was not observed within the studied area during the study period. Contact with wild boars was the most frequent type of contact, but was associated with a very low risk. Direct cattle-to-cattle contacts in pasture and contacts with badger latrines were less frequent, but entailed a greater risk of M. bovis transmission. Centrality values were heterogeneous in these two networks. This would enable the disease to spread more rapidly at the start of epidemics than in a perfect randomly mixed population. However, this situation should also result in the total number of infected herds being smaller. We attributed 95% of the contacts to direct contact in pasture or contact with wild boars or badger latrines. Other kinds of contact occurred less frequently (equipment sharing, cattle straying) or did not occur at all (attendance at a show). Most of the contact types were correlated, but none was sufficient in itself to account for all contacts between one particular farm and its neighbours. Contacts with neighbours therefore represent a challenge for the implementation or improvement of control measures.

While it is now broadly accepted that inter-individual variation in the outcomes of host–pathogen interactions is at least partially genetically controlled, host immunogenetic characteristics are rarely investigated in wildlife epidemiological studies. Furthermore, most immunogenetic studies in the wild focused solely on the major histocompatibility complex (MHC) diversity despite it accounts for only a fraction of the genetic variation in pathogen resistance. Here, we investigated immunogenetic diversity of the Alpine ibex (Capra ibex) population of the Bargy massif, reservoir of a virulent outbreak of brucellosis. We analysed the polymorphism and associations with disease resistance of the MHC Class II Drb gene and several non-MHC genes (Toll-like receptor genes, Slc11A1) involved in the innate immune response to Brucella in domestic ungulates. We found a very low neutral genetic diversity and a unique MHC Drb haplotype in this population founded few decades ago from a small number of individuals. By contrast, other immunity-related genes have maintained polymorphism and some showed significant associations with the brucellosis infection status hence suggesting a predominant role of pathogen-mediated selection in their recent evolutionary trajectory. Our results highlight the need to monitor immunogenetic variation in wildlife epidemiological studies and to look beyond the MHC.