Restoration of Vision with Ectopic Expression of Human Rod Opsin

SummaryMany retinal dystrophies result in photoreceptor loss, but the inner retinal neurons can survive, making them potentially amenable to emerging optogenetic therapies. Here, we show that ectopically expressed human rod opsin, driven by either a non-selective or ON-bipolar cell-specific promoter, can function outside native photoreceptors and restore visual function in a mouse model of advanced retinal degeneration. Electrophysiological recordings from retinal explants and the visual thalamus revealed changes in firing (increases and decreases) induced by simple light pulses, luminance increases, and naturalistic movies in treated mice. These responses could be elicited at light intensities within the physiological range and substantially below those required by other optogenetic strategies. Mice with rod opsin expression driven by the ON-bipolar specific promoter displayed behavioral responses to increases in luminance, flicker, coarse spatial patterns, and elements of a natural movie at levels of contrast and illuminance (≈50–100 lux) typical of natural indoor environments. These data reveal that virally mediated ectopic expression of human rod opsin can restore vision under natural viewing conditions and at moderate light intensities. Given the inherent advantages in employing a human protein, the simplicity of this intervention, and the quality of vision restored, we suggest that rod opsin merits consideration as an optogenetic actuator for treating patients with advanced retinal degeneration

The development of metaphorical language comprehension in typical development and in Williams syndrome

The domain of figurative language comprehension was used to probe the developmental relation between language and cognition in typically developing individuals and individuals with Williams syndrome. Extending the work of Vosniadou and Ortony, the emergence of nonliteral similarity and category knowledge was investigated in 117 typically developing children between 4 and 12 years of age, 19 typically developing adults, 15 children with Williams syndrome between 5 and 12 years of age, and 8 adults with Williams syndrome. Participants were required to complete similarity and categorization statements by selecting one of two words (e.g., either “The sun is like ___” or “The sun is the same kind of thing as ___”) with word pairs formed from items that were literally, perceptually, or functionally similar to the target word or else anomalous (e.g., moon, orange, oven, or chair, respectively). Results indicated that individuals with Williams syndrome may access different, less abstract knowledge in figurative language comparisons despite the relatively strong verbal abilities found in this disorder

Effectiveness of PhysioDirect telephone assessment and advice services for patients with musculoskeletal problems: pragmatic randomised controlled trial.

OBJECTIVES: To assess the clinical effectiveness, effect on waiting times, and patient acceptability of PhysioDirect services in patients with musculoskeletal problems, compared with usual care. DESIGN: Pragmatic randomised controlled trial to assess equivalence in clinical effectiveness. Patients were individually randomised in a 2:1 ratio to PhysioDirect or usual care. SETTING: Four physiotherapy services in England. PARTICIPANTS: Adults (aged ≥ 18 years) referred by general practitioners or self referred for musculoskeletal physiotherapy. INTERVENTIONS: PhysioDirect services invited patients to telephone a physiotherapist for initial assessment and advice, followed by face-to-face physiotherapy if necessary. Usual care involved patients joining a waiting list for face-to-face treatment. MAIN OUTCOME MEASURES: Numbers of appointments, waiting time for treatment, and non-attendance rates. Primary outcome was physical health (SF-36v2 physical component score) at six months. Secondary outcomes included four other measures of health outcome, mental component score and scales from the SF-36v2, time lost from work, and patient satisfaction and preference. Participants were not blind to allocation, but outcome data were collected blind to allocation. RESULTS: Of 1506 patients allocated to PhysioDirect and 743 to usual care, 85% provided primary outcome data at six months (1283 and 629 patients, respectively). PhysioDirect patients had fewer face-to-face appointments than usual care patients (mean 1.91 v 3.11; incidence rate ratio 0.59 (95% confidence interval 0.53 to 0.65)), a shorter waiting time (median 7 days v 34 days; arm time ratio 0.32 (0.29 to 0.35)), and lower rates of non-attendance (incidence rate ratio 0.55 (0.41 to 0.73)). After six months' follow-up, the SF-36v2 physical component score was equivalent between groups (adjusted difference in means -0.01 (-0.80 to 0.79)). Health outcome measures suggested a trend towards slightly greater improvement in the PhysioDirect arm at six week follow-up and no difference at six months. There was no difference in time lost from work. PhysioDirect patients were no more satisfied with access to physiotherapy than usual care patients, but had slightly lower satisfaction overall at six months (difference in satisfaction -3.8% (-7.3% to -0.3%); P=0.031). PhysioDirect patients were more likely than usual care patients to prefer PhysioDirect in future. No adverse events were detected. CONCLUSIONS: PhysioDirect is equally clinically effective compared with usual care, provides faster access to physiotherapy, and seems to be safe. However, it could be associated with slightly lower patient satisfaction. TRIAL REGISTRATION: Current Controlled Trials ISRCTN55666618

'PhysioDirect' telephone assessment and advice services for physiotherapy: protocol for a pragmatic randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Providing timely access to physiotherapy has long been a problem for the National Health Service in the United Kingdom. In an attempt to improve access some physiotherapy services have introduced a new treatment pathway known as PhysioDirect. Physiotherapists offer initial assessment and advice by telephone, supported by computerised algorithms, and patients are sent written self-management and exercise advice by post. They are invited for face-to-face treatment only when necessary. Although several such services have been developed, there is no robust evidence regarding clinical and cost-effectiveness, nor the acceptability of PhysioDirect.</p> <p>Methods/Design</p> <p>This protocol describes a multi-centre pragmatic individually randomised trial, with nested qualitative research. The aim is to determine the effectiveness, cost-effectiveness, and acceptability of PhysioDirect compared with usual models of physiotherapy based on patients going onto a waiting list and receiving face-to-face care. PhysioDirect services will be established in four areas in England. Adult patients in these areas with musculoskeletal problems who refer themselves or are referred by a primary care practitioner for physiotherapy will be invited to participate in the trial. About 1875 consenting patients will be randomised in a 2:1 ratio to PhysioDirect or usual care. Data about outcome measures will be collected at baseline and 6 weeks and 6 months after randomisation. The primary outcome is clinical improvement at 6 months; secondary outcomes include cost, waiting times, time lost from work and usual activities, patient satisfaction and preference. The impact of PhysioDirect on patients in different age-groups and with different conditions will also be examined.</p> <p>Incremental cost-effectiveness will be assessed in terms of quality adjusted life years in relation to cost.</p> <p>Qualitative methods will be used to explore factors associated with the success or failure of the service, the acceptability of PhysioDirect to patients and staff, and ways in which the service could be improved.</p> <p>Discussion</p> <p>It is still relatively unusual to evaluate new forms of service delivery using randomised controlled trials. By combining rigorous trial methods with economic analysis of cost-effectiveness and qualitative research this study will provide robust evidence to inform decisions about the widespread introduction of PhysioDirect services.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN55666618</p

Evaluating acupuncture and standard care for pregnant women with back pain:the EASE Back pilot randomised controlled trial (ISRCTN49955124)

Background Low back pain (LBP) and pelvic girdle pain (PGP) during pregnancy are common and often accepted as a ‘normal’ part of pregnancy. Many women receive little in the way of treatment, and yet pain interferes with sleep, daily activities and work and leads to increasing requests for induction of labour or elective caesarean section. The aim of this study was to assess the feasibility of a full RCT evaluating the benefit of acupuncture for pregnancy-related back pain. Methods This study is a single-centre, three-arm pilot RCT in one large maternity unit and associated antenatal and physiotherapy clinics. Women were eligible if they had pregnancy-related LBP with or without PGP. Exclusions included a history of miscarriage, high risk of early labour or pre-eclampsia, PGP only and previous acupuncture. Interventions were standard care (SC): a self-management booklet with physiotherapy if needed. SC+TA: the booklet and physiotherapy comprising true (penetrating) acupuncture, advice and exercise. SC+NPA: the booklet and physiotherapy comprising non-penetrating acupuncture, advice and exercise. Remote telephone randomisation used a 1:1:1 allocation ratio stratified by gestational weeks. Three measures of pain/function were compared to inform the primary outcome measure in a full RCT: the Pelvic Girdle Questionnaire (PGQ), Oswestry Disability Index (ODI) and 11-point 0–10 numerical rating scale for pain. Analysis focused on process evaluation of recruitment, retention, descriptive information on outcomes, adherence to treatment, occurrence of adverse events and impact of physiotherapist training. Results One hundred twenty-five women were randomised (45% of those eligible) between April and October 2013; 73% (n = 91) provided 8-week follow-up data. Three of six recruitment methods accounted for 82% of total uptake: screening questionnaire at the 20-week scan, community midwives issuing study cards, and self-referral following local awareness initiatives. Physiotherapists’ self-confidence on managing pregnancy-related LBP improved post training. The PGQ is suitable as the primary outcome in a full trial. The average number of treatment sessions in both SC+TA and SC+NPA was six (in line with treatment protocols). No serious adverse events attributable to the trial treatments were reported. Conclusions A full RCT is feasible and would provide evidence about the effectiveness of acupuncture and inform treatment choices for women with pregnancy-related LBP

The development of sentence-interpretation strategies in monolingual German-learning children with and without specific language impairment

Previous research on sentence comprehension conducted with German-learning children has concentrated on the role of case marking and word order in typically developing children. This paper compares, the performance of German-learning children with language impairment (age 4-6 years) and without language impairment (aged 2-6, 8-9 years) in two experiments that systematically vary the cues animacy, case marking; word-order, and subject-verb agreement. The two experiments differ with regard to the choice of case marking: in the first it is distinct but in the second it is neutralized. The theoretical framework is the competition model developed by Bates and Mac Whinney and their collaborators, a variant of the parallel distributed processing models. It is hypothesized that children of either population first appreciate the cue animacy that can be processed locally, that is, "on the spot," before they turn to more distributed cues leading ultimately up to subject-verb agreement, which presupposes the comparison of various constituents before an interpretation can be established. Thus agreement is more "costly" in processing than animacy or the (more) local cue initial NP. In experiment I with unambiguous case markers it is shown that the typically developing children proceed from animacy to the nominative (predominantly in coalition with the initial NP) to agreement, while in the second experiment with ambiguous case markers these children turn from animacy to the initial NP and then to agreement. The impaired children also progress from local to distributed cues. Yet, in contrast to the control group, they do not acknowledge the nominative in coalition with the initial NP in the first experiment but only in support of agreement. However, although they do not seem to appreciate distinct case markers to any large extent in the first experiment, they are irritated if such distinctions are lacking: in experiment II all impaired children turn to. animacy (some in coalition with the initial NP and/or particular word orders). In the discussion, the relationship between short-term memory and processing as well as the relationship between production and comprehension of case markers and agreement are addressed. Further research is needed to explore in more detail "cue costs" in sentence comprehension

Comprehensive analysis of the chromatin landscape in Drosophila melanogaster.

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function

Defining national net zero goals is critical for food and land use policy

The identification of agriculture and land use configurations that achieve net zero (NZ) greenhouse gas emissions is critical to inform appropriate land use and food policy, yet national NZ targets lack consistent definitions. Here, 3000 randomised scenarios projecting future agricultural production and compatible land use combinations in Ireland were screened using ten NZ definitions. When aggregating carbon dioxide, methane, and nitrous oxide emissions using various methods, 1–85% of scenarios met NZ criteria. Despite considerable variation, common actions emerged across definitions, including high rates of afforestation, organic soil re-wetting, and cattle destocking. Ambitious technical abatement of agricultural emissions moderated, but could not substitute, these actions. With abatement, 95th percentile milk output varied from 11–91% of 2021 output, but was associated with reductions of up to 98% in suckler-beef production, and a 47–387% increase in forest cover. Achieving NZ will thus require transformation of Ireland’s land sector. Lagging land use change effects require urgent action, but sustaining a just transition will require visioning of future NZ land use combinations supporting a sustainable and resilient food system, alongside an expanding circular bioeconomy. We provide new insight into the sensitivity of such visioning to NZ definitions, pointing to an urgent need for international consensus on the accounting of methane emissions in NZ targets