Bilateral cochlear-implant (CI) users struggle to understand speech in noisy environments despite receiving some spatial-hearing benefits. One potential solution is to provide acoustic beamforming. A ...headphone-based experiment was conducted to compare speech understanding under natural CI listening conditions and for two non-adaptive beamformers, one single beam and one binaural, called "triple beam," which provides an improved signal-to-noise ratio (beamforming benefit) and usable spatial cues by reintroducing interaural level differences. Speech reception thresholds (SRTs) for speech-on-speech masking were measured with target speech presented in front and two maskers in co-located or narrow/wide separations. Numerosity judgments and sound-localization performance also were measured. Natural spatial cues, single-beam, and triple-beam conditions were compared. For CI listeners, there was a negligible change in SRTs when comparing co-located to separated maskers for natural listening conditions. In contrast, there were 4.9- and 16.9-dB improvements in SRTs for the beamformer and 3.5- and 12.3-dB improvements for triple beam (narrow and wide separations). Similar results were found for normal-hearing listeners presented with vocoded stimuli. Single beam improved speech-on-speech masking performance but yielded poor sound localization. Triple beam improved speech-on-speech masking performance, albeit less than the single beam, and sound localization. Thus, triple beam was the most versatile across multiple spatial-hearing domains.
How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell ...differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partition into discrete states. Key developmental gene sets are actively repressed outside of the appropriate organ without obvious bivalency. Candidate enhancers, functional in zebrafish, allow imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allows correlation to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for investigating normal and abnormal human development.
Bacterial biofilms present a significant medical challenge because they are recalcitrant to current therapeutic regimes. A key component of biofilm formation in the opportunistic human pathogen ...Pseudomonas aeruginosa is the biosynthesis of the exopolysaccharides Pel and Psl, which are involved in the formation and maintenance of the structural biofilm scaffold and protection against antimicrobials and host defenses. Given that the glycoside hydrolases PelAh and PslGh encoded in the pel and psl biosynthetic operons, respectively, are utilized for in vivo exopolysaccharide processing, we reasoned that these would provide specificity to target P. aeruginosa biofilms. Evaluating these enzymes as potential therapeutics, we demonstrate that these glycoside hydrolases selectively target and degrade the exopolysaccharide component of the biofilm matrix. PelAh and PslGh inhibit biofilm formation over a 24-hour period with a half maximal effective concentration (EC50) of 69.3 ± 1.2 and 4.1 ± 1.1 nM, respectively, and are capable of disrupting preexisting biofilms in 1 hour with EC50 of 35.7 ± 1.1 and 12.9 ± 1.1 nM, respectively. This treatment was effective against clinical and environmental P. aeruginosa isolates and reduced biofilm biomass by 58 to 94%. These noncytotoxic enzymes potentiated antibiotics because the addition of either enzyme to a sublethal concentration of colistin reduced viable bacterial counts by 2.5 orders of magnitude when used either prophylactically or on established 24-hour biofilms. In addition, PelAh was able to increase neutrophil killing by ~50%. This work illustrates the feasibility and benefits of using bacterial exopolysaccharide biosynthetic glycoside hydrolases to develop novel antibiofilm therapeutics.
Administrators often assume new teachers come prepared with the foundational skills required to be effective teachers. Not only is this frequently a false assumption, but some of these skills do also ...not fully make sense until a teacher has responsibility for a classroom. To assist in the transition process, many teachers will attend orientation and be assigned a mentor. However, they will not receive professional development designed to establish the foundational skills of classroom management, direct instruction, classroom assessment and professionalism. These are the bedrock skills necessary for both short and long-term success as a professional educator. Through concise, research-based explanations and practical application activities, this book is designed to fill this void. Whether it is read alone, in concert with a mentor, or as part of a systematic district induction program, teachers that master the content of this text will become effective with their students.
We report that polymerization‐induced self‐assembly (PISA) can be used to prepare lyotropic phases comprising diblock copolymer nano‐objects in non‐polar media. RAFT dispersion polymerization of ...benzyl methacrylate (BzMA) at 90 °C using a trithiocarbonate‐capped hydrogenated polybutadiene (PhBD) steric stabilizer block in n‐dodecane produces either spheres or worms that exhibit long‐range order at 40 % w/w solids. NMR studies enable calculation of instantaneous copolymer compositions for each phase during the BzMA polymerization. As the PBzMA chains grow longer when targeting PhBD80–PBzMA40, time‐resolved small‐angle X‐ray scattering reveals intermediate body‐centered cubic (BCC) and hexagonally close‐packed (HCP) sphere phases prior to formation of a final hexagonal cylinder phase (HEX). The HEX phase is lost on serial dilution and the aligned cylinders eventually form disordered flexible worms. The HEX phase undergoes an order–disorder transition on heating to 150 °C and a pure HCP phase forms on cooling to 20 °C.
Polymerization‐induced self‐assembly (PISA) can produce lyotropic phases of block copolymer nano‐objects. Time‐resolved SAXS studies confirm that reversible addition–fragmentation chain transfer (RAFT) dispersion polymerization of benzyl methacrylate in n‐dodecane initially produces spheres exhibiting long‐range order that subsequently evolve to form hexagonally packed worms. Serial dilution leads to disordered worms.
Hereditary peripheral neuropathies are inherited disorders affecting the peripheral nervous system, including Charcot-Marie-Tooth disease, familial amyloid polyneuropathy and hereditary sensory and ...motor neuropathies. While the molecular basis of hereditary peripheral neuropathies has been extensively researched, interventional trials of pharmacological therapies are lacking.
We collated evidence for the effectiveness of pharmacological and gene-based treatments for hereditary peripheral neuropathies.
We searched several databases for randomised controlled trials (RCT), observational studies and case reports of therapies in hereditary peripheral neuropathies. Two investigators extracted and analysed the data independently, assessing study quality using the Oxford Centre for Evidence Based Medicine 2011 Levels of Evidence in conjunction with the Jadad scale.
Of the 2046 studies initially identified, 119 trials met our inclusion criteria, of which only 34 were carried over into our final analysis. Ascorbic acid was shown to have no therapeutic benefit in CMT1A, while a combination of baclofen, naltrexone and sorbitol (PXT3003) demonstrated some efficacy, but phase III data are incomplete. In TTR-related amyloid polyneuropathy tafamidis, patisiran, inotersen and revusiran showed significant benefit in high quality RCTs. Smaller studies showed the efficacy of L-serine for SPTLC1-related hereditary sensory neuropathy, riboflavin for Brown-Vialetto-Van Laere syndrome (SLC52A2/3) and phytanic acid-poor diet in Refsum disease (PHYH).
The 'treatable' variants highlighted in this project will be flagged in the treatabolome database to alert clinicians at the time of the diagnosis and enable timely treatment of patients with hereditary peripheral neuropathies.
Molecular markers scalable for clinical use are critical for the development of effective treatments and the design of clinical trials. Here, we identify proteins in sera of patients and mouse models ...with Charcot-Marie-Tooth disease (CMT) with characteristics that make them suitable as biomarkers in clinical practice and therapeutic trials. We collected serum from mouse models of CMT1A (C61 het), CMT2D (GarsC201R, GarsP278KY), CMT1X (Gjb1-null), CMT2L (Hspb8K141N) and from CMT patients with genotypes including CMT1A (PMP22d), CMT2D (GARS), CMT2N (AARS) and other rare genetic forms of CMT. The severity of neuropathy in the patients was assessed by the CMT Neuropathy Examination Score (CMTES). We performed multitargeted proteomics on both sample sets to identify proteins elevated across multiple mouse models and CMT patients. Selected proteins and additional potential biomarkers, such as growth differentiation factor 15 (GDF15) and cell free mitochondrial DNA, were validated by ELISA and quantitative PCR, respectively. We propose that neural cell adhesion molecule 1 (NCAM1) is a candidate biomarker for CMT, as it was elevated in Gjb1-null, Hspb8K141N, GarsC201R and GarsP278KY mice as well as in patients with both demyelinating (CMT1A) and axonal (CMT2D, CMT2N) forms of CMT. We show that NCAM1 may reflect disease severity, demonstrated by a progressive increase in mouse models with time and a significant positive correlation with CMTES neuropathy severity in patients. The increase in NCAM1 may reflect muscle regeneration triggered by denervation, which could potentially track disease progression or the effect of treatments. We found that member proteins of the complement system were elevated in Gjb1-null and Hspb8K141N mouse models as well as in patients with both demyelinating and axonal CMT, indicating possible complement activation at the impaired nerve terminals. However, complement proteins did not correlate with the severity of neuropathy measured on the CMTES scale. Although the complement system does not seem to be a prognostic biomarker, we do show complement elevation to be a common disease feature of CMT, which may be of interest as a therapeutic target. We also identify serum GDF15 as a highly sensitive diagnostic biomarker, which was elevated in all CMT genotypes as well as in Hspb8K141N, Gjb1-null, GarsC201R and GarsP278KY mouse models. Although we cannot fully explain its origin, it may reflect increased stress response or metabolic disturbances in CMT. Further large and longitudinal patient studies should be performed to establish the value of these proteins as diagnostic and prognostic molecular biomarkers for CMT.
Mast cell activation syndrome (MCAS) is a term applied to several clinical entities which have gained increased attention from patients and medical providers. While several descriptive publications ...about MCAS exist, there are many gaps in knowledge resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell (MC) activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to MC activation in MCAS patients remain to be elucidated.
The purpose of this manuscript is to summarize the known literature, identify gaps in knowledge, and highlight research needs. Several topics are covered: 1) Contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; 2) Mechanistic research; 3) Management of typical and refractory symptoms, and 4) MCAS-specific education for patients and healthcare providers.
Polymerization‐induced self‐assembly (PISA) enables the scalable synthesis of functional block copolymer nanoparticles with various morphologies. Herein we exploit this versatile technique to produce ...so‐called “high χ–low N” diblock copolymers that undergo nanoscale phase separation in the solid state to produce sub‐10 nm surface features. By varying the degree of polymerization of the stabilizer and core‐forming blocks, PISA provides rapid access to a wide range of diblock copolymers, and enables fundamental thermodynamic parameters to be determined. In addition, the pre‐organization of copolymer chains within sterically‐stabilized nanoparticles that occurs during PISA leads to enhanced phase separation relative to that achieved using solution‐cast molecularly‐dissolved copolymer chains.
Polymerization‐induced self‐assembly enables the scalable synthesis of functional block copolymer nanoparticles with various morphologies. This versatile technique is exploited to prepare so‐called “high χ–low N” diblock copolymers that undergo nanoscale phase separation in the solid state to produce sub‐10 nm domains.
IntroductionExercise, support and advice are considered core components of management for most musculoskeletal conditions and are typically provided by physiotherapists through regular face-to-face ...treatments. However, exercise can be provided remotely as part of a home exercise programme, while support and advice can be provided over the telephone. There is initial evidence from trials and systematic reviews to suggest that remotely provided physiotherapy can be used to manage a variety of musculoskeletal conditions safely and effectively.Methods and analysisThe aim of this single-blind randomised controlled non-inferiority trial is to determine whether a supported home exercise programme is as good as or better than face-to-face physiotherapy for the treatment of musculoskeletal conditions. Two hundred and ten participants will be recruited from five public hospitals in Sydney, Australia. Participants will be randomised to either the supported home exercise group or the face-to-face physiotherapy group. Participants allocated to the supported home exercise group will initially receive one face-to-face session with the trial physiotherapist and will then be managed remotely for the next 6 weeks. Participants allocated to the face-to-face physiotherapy group will receive a course of physiotherapy as typically provided in Sydney government hospitals. The primary outcome is function measured by the Patient Specific Functional Scale at 6 weeks. There will be nine secondary outcomes measured at 6 and 26 weeks. Separate analyses will be conducted on each outcome, and all analyses will be conducted on an intention-to-treat basis. A health economic evaluation will be conducted from a health funder plus patient perspective.Ethics and disseminationEthical approval was obtained on the 17 March 2017 from the Northern Sydney Local Health District HREC, trial number HREC/16HAWKE/431-RESP/16/287. The results of this study will be submitted for publication to peer-reviewed journals and be presented at national and international conferences. Recruitment commenced in March 2019, and it is anticipated that the trial will be completed by December 2021. This trial will investigate two different models of physiotherapy care for people with musculoskeletal conditions.Trial registration numberCPMP/ICH-135/95.Protocol versionThe most recent version of the protocol is V.1.2 dated November 2019.
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