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There is not a welfare protocol for horses reared for meat production in semi-extensive systems. The aims of the study were to develop a specific welfare protocol suitable to be applied at pasture and on stable; and to evaluate whether the welfare items were influenced by the farming system (pasture vs stable). 52 non-animal-based measures (N-ABMs) and 14 animal-based measures (ABMs), classified into 6 thematic areas (training, feeding, facilities, ABMs, biosecurity, health management) were selected by a focus group. The protocol was applied on a total of 429 Catria horses located across 26 pastures during the warm seasons and on 7 stables during the cold seasons. Differences obtained within each horse-unit were calculated by using the diversity index (VARNC) and the distance from the ideal (dfi) index. Chi-square test was used for comparing the relative frequencies (%) of the answers (pasture vs stable). Most the welfare items were classified as adequate in both pasture and stable, yet differences were found within ‘training’ (p = 0.02) and ‘feeding’ (p

This contribution deals with effect measures for covariates in ordinal data models to address the interpretation of the results on the extreme categories of the scales, evaluate possible response styles, and motivate collapsing of extreme categories. It provides a simpler interpretation of the influence of the covariates on the probability of the response categories both in standard cumulative link models under the proportional odds assumption and in the recent extension of the Combination of Uncertainty and Preference of the respondents models, the mixture models introduced to account for uncertainty in rating systems. The article shows by means of marginal effect measures that the effects of the covariates are underestimated when the uncertainty component is neglected. Visualization tools for the effect of covariates are proposed, and measures of relative size and partial effect based on rates of change are evaluated by the use of real data sets.

Abstract Early access programs (EAPs) generally refer to patient access to medicines/indications before marketing authorization, possibly extended to price and reimbursement approval. These programs include compassionate use, which is usually covered by pharmaceutical companies, and EAPs reimbursed by third-party payers. This paper aims at comparing EAPs in four European countries (France, Italy, Spain, UK) and providing empirical evidence on EAPs in Italy. The comparative analysis was conducted through a literature review (including scientific and grey literature), complemented by 30-min semi-structured interviews with local experts. The Italian empirical analysis employed data available on the National Medicines Agency website. Although EAPs are very different across countries, they exhibit some common features: (i) eligibility criteria refer to the absence of valid therapeutic alternatives and a presumed favourable risk–benefit profile; (ii) payers do not allocate a pre-determined budget to these programs; (iii) total spending on EAPs is unknown. The French EAPs seem to be the most structured, financed through social insurance, covering pre-marketing, post-marketing and pre-reimbursement phases and providing for data collection. Italy’s approach to EAPs has been varied, with several programs covered by different payers, including the cohort-based 648 List (for both early access and off-label use), the nominal-based 5% Fund, and Compassionate Use. Most applications to EAPs are from the Antineoplastic and immunomodulating drug class (ATC L). Some 62% of indications in the 648 List are either not under clinical development or have never been approved (pure off-label use). For those subsequently approved, most approved indications coincide with those covered through EAPs. Only the 5% Fund provides data on economic impact (€ 81.2 million in 2021; average cost per patient € 61.5K). Diverse EAPs are a possible source of inequalities in access to medicines across Europe. A harmonization of these programs, though difficult to achieve, could be modelled on the French EAPs and provide key advantages, not least of which a common effort to collect real-world data in parallel with clinical trials and clear separation between EAPs and off-label use programs.

Cell-substrate adhesion of the social amoeba Dictyostelium discoideum, a model organism often used for the study of chemotaxis, is non-specific and does not involve focal adhesion complexes. Therefore, micropatterned substrates where adherent Dictyostelium cells are constrained to designated microscopic regions are difficult to make. Here we present a micropatterning technique for Dictyostelium cells that relies on coating the substrate with an ∼1μm thick layer of polyethylene glycol (PEG) gel. We show that, when plated on a substrate with narrow parallel stripes of PEG-gel and glass, Dictyostelium cells nearly exclusive adhere to and migrate along the glass stripes, thus providing a model system to study one-dimensional migration of amoeboid cells. Surprisingly, we find substantial differences in the adhesion to PEG-gel and glass stripes between vegetative and developed cells and between two different axenic laboratory strains of Dictyostelium, AX2 and AX4. Even more surprisingly, we find that the distribution of Dictyostelium cells between PEG-gel and glass stripes is significantly affected by the expression of several fluorescent protein markers of the cytoskeleton. We carry out atomic force microscopy based single cell force spectroscopy measurements that confirm that the force of adhesion to PEG-gel substrate can be significantly different between vegetative and developed cells, AX2 and AX4 cells, and cells with and without fluorescent markers. Thus, the choice of parental background, the degree of development, and the expression of fluorescent protein markers can all have a profound effect on cell-substrate adhesion and should be considered when comparing migration of cells and when designing micropatterned substrates.

We report the case of a paediatric female patient affected by Bannayan-Riley-Ruvalcaba syndrome (BRRS) and congenital hypothyroidism (CH) with homozygous mutation of the TPO gene. She underwent total thyroidectomy at the age of seven years because of the development of a multinodular goiter. BRRS patients present an increased risk of benign and malignant thyroid disease since childhood because of inactivating mutation of PTEN, an onco-suppressor gene. Instead, homozygous mutations in the TPO gene can be associated with severe forms of hypothyroidism with goiter; previous studies have described cases of follicular and papillary thyroid cancer in CH patients with TPO mutation despite a perfectly controlled thyroid function with Levothyroxine therapy. To our knowledge, this is the first case that describes the possible synergic role of coexisting mutation of both TPO and PTEN in the development of multinodular goiter underlining the importance of a tailored surveillance program in these patients, especially during childhood.

We investigated dengue virus (DENV) and asymptomatic DENV infections in rural villages of Kampong Cham Province, Cambodia, during 2012 and 2013. We conducted perifocal investigations in and around households for 149 DENV index cases identified through hospital and village surveillance. We tested participants 0.5-30 years of age by using nonstructural 1 rapid tests and confirmed DENV infections using quantitative reverse transcription PCR or nonstructural 1-capture ELISA. We used multivariable Poisson regressions to explore links between participants' DENV infection status and household characteristics. Of 7,960 study participants, 346 (4.4%) were infected with DENV, among whom 302 (87.3%) were

Objective: Our objective was to develop and validate cutoff values in the systemic Juvenile Arthritis Disease Activity Score 10 (sJADAS10) that distinguish the states of inactive disease (ID), minimal disease activity (MDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with systemic juvenile idiopathic arthritis, based on subjective disease state assessment by the treating pediatric rheumatologist. Methods: The cutoff definition cohort was composed of 400 patients enrolled at 30 pediatric rheumatology centers in 11 countries. Using the subjective physician rating as an external criterion, six methods were applied to identify the cutoffs: mapping, calculation of percentiles of cumulative score distribution, the Youden index, 90% specificity, maximum agreement, and receiver operating characteristic curve analysis. Sixty percent of the patients were assigned to the definition cohort, and 40% were assigned to the validation cohort. Cutoff validation was conducted by assessing discriminative ability. Results: The sJADAS10 cutoffs that separated ID from MDA, MDA from MoDA, and MoDA from HDA were ≤2.9, ≤10, and >20.6, respectively. The cutoffs discriminated strongly among different levels of pain, between patients with and without morning stiffness, and among patients whose parents judged their disease status as remission or persistent activity or flare or were satisfied or not satisfied with current illness outcome. Conclusion: The sJADAS cutoffs revealed good metrologic properties in both definition and validation cohorts and are therefore suitable for use in clinical trials and routine practice. [ABSTRACT FROM AUTHOR]

Summary: Background: Encephalitis is a worldwide public health issue, with a substantially high burden among children in southeast Asia. We aimed to determine the causes of encephalitis in children admitted to hospitals across the Greater Mekong region by implementing a comprehensive state-of-the-art diagnostic procedure harmonised across all centres, and identifying clinical characteristics related to patients’ conditions. Methods: In this multicentre, observational, prospective study of childhood encephalitis, four referral hospitals in Cambodia, Vietnam, Laos, and Myanmar recruited children (aged 28 days to 16 years) who presented with altered mental status lasting more than 24 h and two of the following minor criteria: fever (within the 72 h before or after presentation), one or more generalised or partial seizures (excluding febrile seizures), a new-onset focal neurological deficit, cerebrospinal fluid (CSF) white blood cell count of 5 per mL or higher, or brain imaging (CT or MRI) suggestive of lesions of encephalitis. Comprehensive diagnostic procedures were harmonised across all centres, with first-line testing was done on samples taken at inclusion and results delivered within 24 h of inclusion for main treatable causes of disease and second-line testing was done thereafter for mostly non-treatable causes. An independent expert medical panel reviewed the charts and attribution of causes of all the included children. Using multivariate analyses, we assessed risk factors associated with unfavourable outcomes (ie, severe neurological sequelae and death) at discharge using data from baseline and day 2 after inclusion. This study is registered with ClinicalTrials.gov, NCT04089436, and is now complete. Findings: Between July 28, 2014, and Dec 31, 2017, 664 children with encephalitis were enrolled. Median age was 4·3 years (1·8–8·8), 295 (44%) children were female, and 369 (56%) were male. A confirmed or probable cause of encephalitis was identified in 425 (64%) patients: 216 (33%) of 664 cases were due to Japanese encephalitis virus, 27 (4%) were due to dengue virus, 26 (4%) were due to influenza virus, 24 (4%) were due to herpes simplex virus 1, 18 (3%) were due to Mycobacterium tuberculosis, 17 (3%) were due to Streptococcus pneumoniae, 17 (3%) were due to enterovirus A71, 74 (9%) were due to other pathogens, and six (1%) were due to autoimmune encephalitis. Diagnosis was made within 24 h of admission to hospital for 83 (13%) of 664 children. 119 (18%) children had treatable conditions and 276 (42%) had conditions that could have been preventable by vaccination. At time of discharge, 153 (23%) of 664 children had severe neurological sequelae and 83 (13%) had died. In multivariate analyses, risk factors for unfavourable outcome were diagnosis of M tuberculosis infection upon admission (odds ratio 3·23 [95% CI 1·04–10·03]), coma on day 2 (2·90 [1·78–4·72]), supplementary oxygen requirement (1·89 [1·25–2·86]), and more than 1 week duration between symptom onset and admission to hospital (3·03 [1·68–5·48]). At 1 year after inclusion, of 432 children who were discharged alive from hospital with follow-up data, 24 (5%) had died, 129 (30%) had neurological sequelae, and 279 (65%) had completely recovered. Interpretation: In southeast Asia, most causes of childhood encephalitis are either preventable or treatable, with Japanese encephalitis virus being the most common cause. We provide crucial information that could guide public health policy to improve diagnostic, vaccination, and early therapeutic guidelines on childhood encephalitis in the Greater Mekong region. Funding: Institut Pasteur, Institut Pasteur International Network, Fondation Merieux, Aviesan Sud, INSERM, Wellcome Trust, Institut de Recherche pour le Développement (IRD), and Fondation Total.