Remodeling of the ICF:A commentary

Since its publication in 2001 the International Classification of Functioning, Disability and Health (ICF) has attracted debate about the content and the model presented. After almost 20 years use, regular updating since 2008 and with the prospect of a new edition in 2020 there is increasing interest in the ICF as a tool to meet contemporary information requirements. Information on functioning is important across not only health systems, but all areas where change in functioning is important: education, employment, and social welfare for example. This commentary responds to the issues raised in a commentary by Mitra & Shakespeare in 2019 and supports review of the ICF in the current context by informing users and providers of data on human functioning how they might engage in the maintenance, updating, and modernisation of the ICF

5α-TETRAHYDROCORTICOSTERONE: A TOPICAL ANTI-INFLAMMATORY GLUCOCORTICOID WITH AN IMPROVED THERAPEUTIC INDEX IN A MURINE MODEL OF DERMATITIS

Background and PurposeGlucocorticoids are powerful anti-inflammatory drugs, but are associated with many side-effects. Topical application in atopic dermatitis leads to skin thinning, metabolic changes, and adrenal suppression. 5α-Tetrahydrocorticosterone (5αTHB) is a potential selective anti-inflammatory with reduced metabolic effects. Here, the efficacy and side-effect profile of 5αTHB were compared with hydrocortisone in preclinical models of irritant dermatitis.Experimental ApproachAcute irritant dermatitis was invoked in ear skin of male C57BL/6 mice with a single topical application of croton oil. Inflammation was assessed as oedema via ear weight following treatment with 5αTHB and hydrocortisone. Side-effects of 5αTHB and hydrocortisone were assessed following chronic topical steroid treatment (28 days) to non-irritated skin. Skin thinning was quantified longitudinally by caliper measurements and summarily by qPCR for transcripts for genes involved in extracellular matrix homeostasis; systemic effects of topical steroid administration also were assessed. Clearance of 5αTHB and hydrocortisone were measured following intravenous and oral administration.Key Results5αTHB suppressed ear swelling in mice, with ED50 similar to hydrocortisone (23 μg vs. 13 μg). Chronic application of 5αTHB did not cause skin thinning, adrenal atrophy, weight loss, thymic involution, or raised insulin levels, all of which were observed with topical hydrocortisone. Transcripts for genes involved in collagen synthesis and stability were adversely affected by all doses of hydrocortisone, but only by the highest dose of 5αTHB (8× ED50). 5αTHB was rapidly cleared from the systemic circulation.Conclusions and ImplicationsTopical 5αTHB has potential to treat inflammatory skin conditions, particularly in areas of delicate skin

Re-evaluating pretomanid analogues for Chagas disease:Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class

Resolving the ancestry of Austronesian-speaking populations

There are two very different interpretations of the prehistory of Island Southeast Asia (ISEA), with genetic evidence invoked in support of both. The “out-of-Taiwan” model proposes a major Late Holocene expansion of Neolithic Austronesian speakers from Taiwan. An alternative, proposing that Late Glacial/postglacial sea-level rises triggered largely autochthonous dispersals, accounts for some otherwise enigmatic genetic patterns, but fails to explain the Austronesian language dispersal. Combining mitochondrial DNA (mtDNA), Y-chromosome and genome-wide data, we performed the most comprehensive analysis of the region to date, obtaining highly consistent results across all three systems and allowing us to reconcile the models. We infer a primarily common ancestry for Taiwan/ISEA populations established before the Neolithic, but also detected clear signals of two minor Late Holocene migrations, probably representing Neolithic input from both Mainland Southeast Asia and South China, via Taiwan. This latter may therefore have mediated the Austronesian language dispersal, implying small-scale migration and language shift rather than large-scale expansion

Interventions to increase engagement with rehabilitation in adults with acquired brain injury: A systematic review

Rehabilitation in adults with acquired brain injury is often hampered by a lack of client engagement with the rehabilitation process, leading to frustration, withdrawal of services and poorer recovery. Motivation, apathy and awareness are potential mechanisms underlying engagement, but few studies have suggested potential intervention techniques. A systematic review of the literature was carried out to identify and evaluate interventions designed to increase rehabilitation engagement in adults with acquired brain injury. Database searches used the following terms: rehabilitation, brain injury, and compliance/engagement/adherence in PsychInfo, Medline, Cinahl, Embase, AMED, Web of Knowledge, PsycBite, Cochrane clinical trials, and clinicaltrials.org. Hand searches were conducted of reference lists and relevant journals. Fifteen studies were included in the review. Intervention techniques fell into two broad categories: behavioural modification techniques and cognitive/meta-cognitive skills. Contingent reward techniques were most effective at increasing adherence and compliance, while interventions enabling clients' active participation in rehabilitation appeared to increase engagement and motivation. The review highlighted methodological and measurement inconsistencies in the field and suggested that interventions should be tailored to clients' abilities and circumstances

Horse grimace scale does not detect pain in horses with equine gastric ulcer syndrome

Equine gastric ulcer syndrome (EGUS) is a highly prevalent and presumptively painful condition, although the amount of pain horses might experience is currently unknown. The aims of this study were to determine if the Horse Grimace Scale (HGS) could identify pain behaviours in horses with and without EGUS and if severity would be positively associated with the HGS score. Horse grimace scale scores were assessed blindly using facial photographs by seven observers and involved evaluation of 6 facial action units as 0 (not present), 1 (moderately present) and 2 (obviously present). Lameness examination, serum amyloid A (SAA) measurement and gastroscopy evaluation were performed on all horses. Horses (n = 61) were divided into two and three groups based on the presence (yes, no) and severity (none, mild, moderate-severe) of EGUS, respectively. Presence of lameness and elevated SAA (≥50 µg/mL) were used as exclusion criteria. Inter-observer reliability was analyzed by intra-class correlation coefficients (ICC). HGS scores between groups were compared using Welch’s and Brown Forsythe tests (p < 0.05). Overall, HGS ICC was “excellent” (0.75). No significant differences (p = 0.566) were observed in HGS scores between horses with and without gastric lesions (mean, 95% CI; 3.36, 2.76–3.95 and 3, 1.79–4.20, respectively). HGS was not influenced by the presence or severity of EGUS in this current study. Further studies investigating the use of different pain scales in horses with EGUS are needed

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest