Applying item-response theory to the development of a screening adaptation of the Goldman-Fristoe Test of Articulation-2

PURPOSE: Item Response Theory (IRT) is a psychometric approach to measurement that uses latent trait abilities (e.g., speech sound production skills) to model performance on individual items that vary by difficulty and discrimination. An IRT analysis was applied to preschooler’s productions of the words on the Goldman-Fristoe Test of Articulation-2 (GFTA-2) to identify candidates for a screening measure of speech sound production skills. METHOD: The phoneme accuracies from 154 preschoolers, with speech skills on the GFTA-2 ranging from the 1st to above the 90th percentile, were analyzed with a two-parameter logistic model. RESULTS: A total of 108 of the 232 phonemes from stimuli in the sounds-in-words subtest fit the IRT model. These phonemes, and subgroups of the most difficult of these phonemes, correlated significantly with the children’s overall percentile scores on the GFTA-2. Regression equations calculated for the five and ten most difficult phonemes predicted overall percentile score at levels commensurate with other screening measures. CONCLUSIONS: These results suggest that speech production accuracy can be screened effectively with a small number of sounds. They motivate further research towards the development of a screening measure of children’s speech sound production skills whose stimuli consist of a limited number of difficult phonemes

Epithelial arginase-1 is a key mediator of age-associated delayed healing in vaginal injury

Pelvic organ prolapse is a disorder that substantially affects the quality of life of millions of women worldwide. The greatest risk factors for prolapse are increased parity and older age, with the largest group requiring surgical intervention being post-menopausal women over 65. Due to ineffective healing in the elderly, prolapse recurrence rates following surgery remain high. Therefore, there is an urgent need to elucidate the cellular and molecular drivers of poor healing in pelvic floor dysfunction to allow effective management and even prevention. Recent studies have uncovered the importance of Arginase 1 for modulating effective healing in the skin. We thus employed novel in vitro and in vivo vaginal injury models to determine the specific role of Arginase 1 in age-related vaginal repair. Here we show, for the first time, that aged rat vaginal wounds have reduced Arginase 1 expression and delayed healing. Moreover, direct inhibition of Arginase 1 in human vaginal epithelial cells also led to delayed scratch-wound closure. By contrast, activation of Arginase 1 significantly accelerated healing in aged vaginal wounds in vivo, to rates comparable to those in young animals. Collectively, these findings reveal a new and important role for Arginase 1 in mediating effective vaginal repair. Targeting age-related Arginase 1 deficiency is a potential viable therapeutic strategy to promote vaginal healing and reduce recurrence rate after surgical repair of pelvic organ prolapse

Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers1-3, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse4-7. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels8,9. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies10,11. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro12-15. Similar to Alzheimer's disease12,14,16-18, all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases

Complaint risk among mental health practitioners compared with physical health practitioners::A retrospective cohort study of complaints to health regulators in Australia

Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. To understand complaint risk among mental health practitioners compared with physical health practitioners. Design Retrospective cohort study, using incidence rate ratios (IRRs) to analyse complaint risk and a multivariate regression model to identify predictors of complaints. Setting National study using complaints data from health regulators in Australia. Participants All psychiatrists and psychologists (a € mental health practitioners\u27) and all physicians, optometrists, physiotherapists, osteopaths and chiropractors (a € physical health practitioners\u27) registered to practice in Australia between 2011 and 2016. Outcome measures Incidence rates, source and nature of complaints to regulators. Results In total, 7903 complaints were lodged with regulators over the 6-year period. Most complaints were lodged by patients and their families. Mental health practitioners had a complaint rate that was more than twice that of physical health practitioners (complaints per 1000 practice years: psychiatrists 119.1 vs physicians 48.0, p\u3c0.001; psychologists 21.9 vs other allied health 7.5, p\u3c0.001). Their risk of complaints was especially high in relation to reports, records, confidentiality, interpersonal behaviour, sexual boundary breaches and the mental health of the practitioner. Among mental health practitioners, male practitioners (psychiatrists IRR: 1.61, 95% CI 1.39 to 1.85; psychologists IRR: 1.85, 95% CI 1.65 to 2.07) and older practitioners (≥65 years compared with 36-45 years: psychiatrists IRR 2.37, 95% CI 1.95 to 2.89; psychologists IRR 1.78, 95% CI 1.47 to 2.14) were at increased risk of complaints. Conclusions Mental health practitioners were more likely to be the subject of complaints than physical health practitioners. Areas of increased risk are related to professional ethics, communication skills and the health of mental health practitioners themselves. Further research could usefully explore whether addressing these risk factors through training, professional development and practitioner health initiatives may reduce the risk of complaints about mental health practitioners

Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold.

The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer's disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau filaments vary within, or between, the brains of individuals with AD. We used a combination of electron cryo-microscopy (cryo-EM) and immuno-gold negative-stain electron microscopy (immuno-EM) to determine the structures of paired helical filaments (PHFs) and straight filaments (SFs) from the frontal cortex of 17 cases of AD (15 sporadic and 2 inherited) and 2 cases of atypical AD (posterior cortical atrophy). The high-resolution structures of PHFs and SFs from the frontal cortex of 3 cases of AD, 2 sporadic and 1 inherited, were determined by cryo-EM. We also used immuno-EM to study the PHFs and SFs from a number of cortical and subcortical brain regions. PHFs outnumbered SFs in all AD cases. By cryo-EM, PHFs and SFs were made of two C-shaped protofilaments with a combined cross-β/β-helix structure, as described previously for one case of AD. The higher resolution structures obtained here showed two additional amino acids at each end of the protofilament. The immuno-EM findings, which indicated the presence of repeats 3 and 4, but not of the N-terminal regions of repeats 1 and 2, of tau in the filament cores of all AD cases, were consistent with the cryo-EM results. These findings show that there is no significant variation in tau filament structures between individuals with AD. This knowledge will be crucial for understanding the mechanisms that underlie tau filament formation and for developing novel diagnostics and therapies

Plug-and-play genetic access to drosophila cell types using exchangeable exon cassettes.

Genetically encoded effectors are important tools for probing cellular function in living animals, but improved methods for directing their expression to specific cell types are required. Here, we introduce a simple, versatile method for achieving cell-type-specific expression of transgenes that leverages the untapped potential of "coding introns" (i.e., introns between coding exons). Our method couples the expression of a transgene to that of a native gene expressed in the cells of interest using intronically inserted "plug-and-play" cassettes (called "Trojan exons") that carry a splice acceptor site followed by the coding sequences of T2A peptide and an effector transgene. We demonstrate the efficacy of this approach in Drosophila using lines containing suitable MiMIC (Minos-mediated integration cassette) transposons and a palette of Trojan exons capable of expressing a range of commonly used transcription factors. We also introduce an exchangeable, MiMIC-like Trojan exon construct that can be targeted to coding introns using the Crispr/Cas system.This work was supported by the Intramural Research Program of the National Institute of Mental Health (B.H.W.) and by grants from the Whitehall Foundation (C.J.P.), NIH (R01DC013070, C.J.P.), the Wellcome Trust (H.I. and M.L.), and the Sir Isaac Newton Trust, Cambridge (M.L.). J.E. was supported by FONDECYT #1141278 and the CINV, which is supported by the Millennium Scientific Initiative of the Ministerio de Economía, Fomento y Turismo. We thank the Bellen laboratory and the Drosophila Gene Disruption Project at Baylor College of Medicine, the Bloomington Stock Center (NIH P40OD018537), and Julie Simpson for fly lines. Thanks also to Aaron DiAntonio, Aaron Hsueh, and John Reinitz for antibodies and the NINDS Sequencing Core Facility for DNA sequencing. Finally, thanks to Sarah Naylor for technical help and Grace Gray, Herman Dierick, Koen Venken, and Hugo Bellen for comments on the manuscript and productive discussions.This is the final published version. It first appeared at http://www.ncbi.nlm.nih.gov/pubmed/25732830

Ultrasound capsule endoscopy:sounding out the future

Video capsule endoscopy (VCE) has been of immense benefit in the diagnosis and management of gastrointestinal (GI) disorders since its introduction in 2001. However, it suffers from a number of well recognized deficiencies. Amongst these is the limited capability of white light imaging, which is restricted to analysis of the mucosal surface. Current capsule endoscopes are dependent on visual manifestation of disease and limited in regards to transmural imaging and detection of deeper pathology. Ultrasound capsule endoscopy (USCE) has the potential to overcome surface only imaging and provide transmural scans of the GI tract. The integration of high frequency microultrasound (µUS) into capsule endoscopy would allow high resolution transmural images and provide a means of both qualitative and quantitative assessment of the bowel wall. Quantitative ultrasound (QUS) can provide data in an objective and measurable manner, potentially reducing lengthy interpretation times by incorporation into an automated diagnostic process. The research described here is focused on the development of USCE and other complementary diagnostic and therapeutic modalities. Presently investigations have entered a preclinical phase with laboratory investigations running concurrently

Structures of filaments from Pick's disease reveal a novel tau protein fold

The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases1. Tau assemblies seem to spread through specific neural networks in each disease2, with short filaments having the greatest seeding activity3. The abundance of tau inclusions strongly correlates with disease symptoms4. Six tau isoforms are expressed in the normal adult human brain-three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau)1. In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions5, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations6,7. Such conformers may give rise to different neuropathological phenotypes8,9, reminiscent of prion strains10. However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer's disease, which contain both 3R and 4R tau11. Here we determine the structures of tau filaments from patients with Pick's disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254-Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer's disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick's disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer's disease. Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers

On the Other Side: Manipulating the Immune Checkpoint Landscape of Dendritic Cells to Enhance Cancer Immunotherapy

Monoclonal antibodies targeting co-inhibitory immune checkpoint molecules have been successful in clinical trials of both solid and hematological malignancies as acknowledged by the 2018 Nobel Prize in Medicine, however improving clinical response rates is now key to expanding their efficacy in areas of unmet medical need. Antibodies to checkpoint inhibitors target molecules on either T cells or tumor cells to stimulate T cells or remove tumor mediated immunosuppression, respectively. However, many of the well-characterized T cell immune checkpoint receptors have their ligands on antigen presenting cells or exert direct effects on those cells. Dendritic cells are the most powerful antigen presenting cells; they possess the ability to elicit antigen-specific responses and have important roles in regulation of immune tolerance. Despite their theoretical benefits in cancer immunotherapy, the translation of DC therapies into the clinic is yet to be fully realized and combining DC-based immunotherapy with immune checkpoint inhibitors is an attractive strategy. This combination takes advantage of the antigen presenting capability of DC to maximize specific immune responses to tumor antigens whilst removing tumor-associated immune inhibitory mechanisms with immune checkpoint inhibition. Here we review the expression and functional effects of immune checkpoint molecules on DC and identify rational combinations for DC vaccination to enhance antigen-specific T cell responses, cytokine production, and promotion of long-lasting immunological memory

Cryo-EM structures of tau filaments from Alzheimer's disease

Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases