Egr1 Expression Is Correlated With Synaptic Activity but Not Intrinsic Membrane Properties in Mouse Adult-Born Dentate Granule Cells.

The discovery of adult-born granule cells (aDGCs) in the dentate gyrus of the hippocampus has raised questions regarding how they develop, incorporate into the hippocampal circuitry, and contribute to learning and memory. Here, we used patch-clamp electrophysiology to investigate the intrinsic and synaptic excitability of mouse aDGCs as they matured, enabled by using a tamoxifen-induced genetic label to birth date the aDGCs at different animal ages. Importantly, we also undertook immunofluorescence studies of the expression of the immediate early gene Egr1 and compared these findings with the electrophysiology data in the same animals. We examined two groups of animals, with aDGC birthdating when the mice were 2 months and at 7-9 months of age. In both groups, cells 4 weeks old had lower thresholds for current-evoked action potentials than older cells but fired fewer spikes during long current pulses and responded more poorly to synaptic activation. aDGCs born in both 2 and 7-9-month-old mice matured in their intrinsic excitability and synaptic properties from 4-12 weeks postgenesis, but this occurred more slowly for the older age animals. Interestingly, this pattern of intrinsic excitability changes did not correlate with the pattern of Egr1 expression. Instead, the development of Egr1 expression was correlated with the frequency of spontaneous excitatory postsynaptic currents. These results suggest that in order for aDGCs to fully participate in hippocampal circuitry, as indicated by Egr1 expression, they must have developed enough synaptic input, in spite of the greater input resistance and reduced firing threshold that characterizes young aDGCs.

The diabetes annual review in a postal box: A qualitative study exploring the views of people living with diabetes (DiaBox-Qual).

AIM: The diabetes annual review is an important part of clinical care. Non-attendance is increasingly common and associated with poor health outcomes. At-home self-collection of blood tests, urine samples and anthropometric data through a postal box may facilitate engagement. We aimed to explore the views of people living with diabetes on the use of a postal box as an alternative to usual care for self-collecting blood samples, urine samples and anthropometric data and to understand whether the availability of a postal box would facilitate the uptake of the diabetes annual review. METHODS: We conducted semi-structured interviews and focus groups with adults who have type 1 or type 2 diabetes. Purposive sampling was used to obtain a high representation of infrequent attendees of annual review appointments within the study population. Transcripts were collated and analysed thematically. RESULTS: Twenty participants took part including eight infrequent attendees. All infrequent attendees and most regular attendees responded positively to a postal box, with convenience being the most prominent value described. Concerns raised related to capability of self-collection and the accuracy of results. Participants were asked for suggestions to improve the postal box. The most common themes related to communication; needing clearer information about each test in the postal box; feedback of results; and utilising the box to communicate priorities for discussion at future consultations. CONCLUSION: Postal boxes for annual reviews were well-received by those living with diabetes. Designed well, they have the potential to overcome more than just the physical barriers to annual review attendance.

The experiences of men on active surveillance for prostate cancer and their significant others: A qualitative synthesis.

BACKGROUND: Active surveillance (AS) for prostate cancer (PCa) is a monitoring pathway for men with low-grade, slow growing PCa and aims to delay or avoid active treatment by treating only in the case of disease progression. Experiences of this pathway vary but living with an untreated cancer can have a negative psychological impact on both the patient and their significant other (SO). Literature suggests partners are the primary source of support for men on AS, and therefore it is important to consider SO experiences alongside those of the patient. To the best of our knowledge this is the first UK-based qualitative review looking specifically at experiences of AS for both men with PCa and their SOs. METHODS: MEDLINE (Ovid), EMBASE, PsychINFO, CINAHL and Cochrane Library were searched for literature reporting qualitative experiences of AS for PCa for either men on AS or SOs (or both). 2769 records were identified and screened, with 28 meeting the eligibility criteria. Qualitative data were synthesised and included men on AS (n = 428), and SOs (n = 51). RESULTS: Experiences of the AS pathway vary but reports of uncertainty and anxiety were present in the accounts of both men on AS and SOs. SOs are intertwined throughout every part of the PCa journey, and couples presented as a unit that were on AS together. Both patients and SOs expressed a need for more support, and highly valued peer support. Despite this finding, men expressed a dislike towards 'support groups'. CONCLUSIONS: Increased recognition in clinical practice of SO involvement in AS is needed. Further research is required to explore the specific types of support that would be most acceptable to this population to address the unmet support needs uncovered in this review.

Mothers' and fathers' attitudes toward stuttering in the Middle East compared to Europe and North America.

BACKGROUND: Parents play a central role in the treatment of childhood stuttering. Addressing parental attitudes toward stuttering is helpful therapeutically. The extent to which differences in attitudes toward stuttering exist on the basis of sex, geographical region and parental status (e.g., parent of a stuttering child, parent of a nonstuttering child, nonparent) is unclear. Many studies investigating such factors have used the Public Opinion Survey of Human Attributes-Stuttering (POSHA-S) questionnaire. A large POSHA-S database has collected responses from over 20 000 people from 49 countries. AIMS: The aim of this study was to use the POSHA-S database to examine the extent to which the following variables influence attitudes toward stuttering: (a) parents' sex (mothers vs. fathers), (b) geographic region (Middle East vs. Europe and North America), (c) parents' children (stuttering vs. nonstuttering) and (d) parental status (parents versus nonparents). METHODS & PROCEDURES: Data used in this study were extracted from selected, relevant studies that administered the POSHA-S to respondents. The Overall Stuttering Scores were compared on the basis of sex and parent status (i.e., mothers and fathers; nonparent women and men) and were then compared within and across the two geographical areas. Group comparisons were performed using analysis of variance followed by independent t tests, and Cohen's d was calculated to determine effect sizes. OUTCOMES & RESULTS: Statistically significant differences were observed upon the basis of geographical region. In general, male parents and nonparents tend to have more positive stuttering attitudes among the Middle Eastern samples while female parents and nonparents tend to show more positive attitudes in European and North American samples in the POSHA-S database. Effect sizes were small for all comparisons. CONCLUSIONS & IMPLICATIONS: The effect of geographic region and culture may predict sex-based differences among mothers' and fathers' attitudes toward stuttering; however, the clinical significance is unclear. Additional research is needed to better understand how children who stutter are affected by their parents' attitudes toward stuttering. WHAT THIS PAPER ADDS: What is already known on this subject The research clearly indicates that attitudes toward stuttering vary according to geographical region. Less clear is whether mothers and fathers from geographically diverse backgrounds hold different attitudes toward stuttering and the extent to which parental status (being a parent, parent of a child who stutters or nonparent) affects attitudes toward stuttering. What this study adds This study's findings confirm that geographical differences do influence attitudes toward stuttering. Male parents and nonparents tend to have equal or more positive attitudes toward stuttering in Middle Eastern samples, whereas non-Middle Eastern female parents and nonparents tend to show hold more positive attitudes. What are the clinical implications of this work? In addition to being culturally sensitive when working with parents of children who stutter, clinicians should also consider that mothers and fathers may have some differences in attitudes and behaviours toward their child's stuttering. These differences should be considered when designing treatment plans. It should also be noted that, despite statistical significance, the effect sizes in this study were low, suggesting that further research as well as close collaboration with parents of children who stutter is warranted.

Active surveillance for prostate cancer is a shared journey: the dyadic perspective.

Active surveillance for prostate cancer monitors disease progression, with a view to actively treat only if progression is evident. Living with an untreated cancer can negatively impact psychological wellbeing. Partners can influence decisions to convert to active treatment in the absence of disease progression, it is, therefore, important to consider partner reactions and responses to prostate cancer treatment options. We explored the experiences of men on active surveillance and their partners and the impact partner feelings, responses and reactions to active surveillance have on the patient. Semi-structured personal communication were conducted with nine male-female couples (n = 18). All male participants were on active surveillance for prostate cancer. Data was analysed using an adapted version of the Collaco et al. (2021) Framework Method for dyadic data analysis. Dyads function as an interconnected unit with interlinked emotional responses. Differing feelings about active surveillance within the couple were common; men prioritised avoidance of active treatment side effects, partners prioritised minimising the chance of disease progression. Partner inclusion is important, but they sometimes felt excluded by their partners and/or health care professionals. More support is needed for this population. Dyadic support is bidirectional and complex with partners often less comfortable with active surveillance than their partners. More research is needed to explore how partners can be better included and supported.

Secreted Amyloid Precursor Protein Alpha (sAPPα) Regulates the Cellular Proteome and Secretome of Mouse Primary Astrocytes.

Secreted amyloid precursor protein alpha (sAPPα), processed from a parent mammalian brain protein, amyloid precursor protein, can modulate learning and memory. Recently it has been shown to modulate the transcriptome and proteome of human neurons, including proteins with neurological functions. Here, we analysed whether the acute administration of sAPPα facilitated changes in the proteome and secretome of mouse primary astrocytes in culture. Astrocytes contribute to the neuronal processes of neurogenesis, synaptogenesis and synaptic plasticity. Cortical mouse astrocytes in culture were exposed to 1 nM sAPPα, and changes in both the whole-cell proteome (2 h) and the secretome (6 h) were identified with Sequential Window Acquisition of All Theoretical Fragment Ion Spectra-Mass Spectrometry (SWATH-MS). Differentially regulated proteins were identified in both the cellular proteome and secretome that are involved with neurologically related functions of the normal physiology of the brain and central nervous system. Groups of proteins have a relationship to APP and have roles in the modulation of cell morphology, vesicle dynamics and the myelin sheath. Some are related to pathways containing proteins whose genes have been previously implicated in Alzheimer's disease (AD). The secretome is also enriched in proteins related to Insulin Growth Factor 2 (IGF2) signaling and the extracellular matrix (ECM). There is the promise that a more specific investigation of these proteins will help to understand the mechanisms of how sAPPα signaling affects memory formation.

Assessing Disparities in Medicaid Home- and Community-Based Services: A Systematic Review.

In recent years, expansion of home and community-based services (HCBS) for older adults and persons with disabilities has become a national priority in the U.S. In addition, lawmakers and health-care providers are pursuing opportunities to minimize disparities in healthcare service delivery. Marrying these priorities will require policymakers to identify existing Medicaid HCBS disparities toward development of new, more equitable policies. This study provides a systematic literature review using an adapted theoretical framework to describe disparities in Medicaid HCBS. Key findings are organized into four domains: availability, accessibility, accommodation, and acceptability. We found a lack of concerted research effort targeting Medicaid HCBS disparities in the context of all four domains, with an especially notable dearth of content related to acceptability. We also identified very few articles that focused on specific marginalized groups, suggesting a need for more research into whether Medicaid HCBS are available, accessible, accommodating, and acceptable for a variety of diverse populations. Our findings underscore the need for researchers and policymakers to conceptualize and evaluate existing Medicaid HCBS policy toward development of a more equitable Medicaid HCBS program design in the future.

In Elimination Settings, Measles Antibodies Wane After Vaccination but Not After Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: We conducted a systematic review to assess whether measles humoral immunity wanes in previously infected or vaccinated populations in measles elimination settings. METHODS: After screening 16 822 citations, we identified 9 articles from populations exposed to wild-type measles and 16 articles from vaccinated populations that met our inclusion criteria. RESULTS: Using linear regression, we found that geometric mean titers (GMTs) decreased significantly in individuals who received 2 doses of measles-containing vaccine (MCV) by 121.8 mIU/mL (95% confidence interval [CI], -212.4 to -31.1) per year since vaccination over 1 to 5 years, 53.7 mIU/mL (95% CI, -95.3 to -12.2) 5 to 10 years, 33.2 mIU/mL (95% CI, -62.6 to -3.9), 10 to 15 years, and 24.1 mIU/mL (95% CI, -51.5 to 3.3) 15 to 20 years since vaccination. Decreases in GMT over time were not significant after 1 dose of MCV or after infection. Decreases in the proportion of seropositive individuals over time were not significant after 1 or 2 doses of MCV or after infection. CONCLUSIONS: Measles antibody waning in vaccinated populations should be considered in planning for measles elimination.

An altered secretome is an early marker of the pathogenesis of CLN6 Batten disease.

Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited childhood neurodegenerative disorders. In addition to the accumulation of auto-fluorescent storage material in lysosomes, NCLs are largely characterised by region-specific neuroinflammation that can predict neuron loss. These phenotypes suggest alterations in the extracellular environment-making the secretome an area of significant interest. This study investigated the secretome in the CLN6 (ceroid-lipofuscinosis neuronal protein 6) variant of NCL. To investigate the CLN6 secretome, we co-cultured neurons and glia isolated from Cln6nclf or Cln6± mice, and utilised mass spectrometry to compare protein constituents of conditioned media. The significant changes noted in cathepsin enzymes, were investigated further via western blotting and enzyme activity assays. Viral-mediated gene therapy was used to try and rescue the wild-type phenotype and restore the secretome-both in vitro in co-cultures and in vivo in mouse plasma. In Cln6nclf cells, proteomics revealed a marked increase in catabolic and cytoskeletal-associated proteins-revealing new similarities between the pathogenic signatures of NCLs with other neurodegenerative disorders. These changes were, in part, corrected by gene therapy intervention, suggesting these proteins as candidate in vitro biomarkers. Importantly, these in vitro changes show promise for in vivo translation, with Cathepsin L (CTSL) activity reduced in both co-cultures and Cln6nclf plasma samples post gene-therapy. This work suggests the secretome plays a role in CLN6 pathogenesis and highlights its potential use as an in vitro model. Proteomic changes present a list of candidate biomarkers for monitoring disease and assessing potential therapeutics in future studies.

Chain conformation of polymers adsorbed to clay particles: effects of charge and concentration.

High molecular weight polymers are used in industrially important applications where the polymers adsorb onto surfaces of inorganic particles and facilitate dispersion, stabilization or flocculation of formulations. The surface conformation of these adsorbed polymers is key to their performance, yet an understanding of the effects of polymer charge, concentration and molecular weight on polymer conformation is incomplete. Here the adsorption behavior of high molecular weight, non-ionic, polyethylene oxide (PEO) and anionic partially hydrolyzed polyacrylamide (HPAM) polymers to a model clay, LAPONITE® (a trademark of BYK Additives, Inc.), was studied by small angle neutron scattering over a range of polymer concentrations. The adsorption of PEO was dependent on polymer concentration at all molecular weights, first adsorbing onto the radial edge of the clay particles and then to the clay faces as polymer concentration increased. While similar behavior was observed at low concentrations of HPAM, above a critical concentration, HPAM desorption results in large clay aggregates, which decrease in size at higher polymer loadings. The difference in adsorption properties as a function of polymer charge and concentration is interpreted in terms of conformational differences of adsorbed polymer at the clay surface. Changes in the volume fraction of adsorbed PEO with polymer concentration indicate changes in the relative amounts of adsorbed chain segments in trains, loops and tails, with no clay aggregation. In contrast, a constant volume fraction of adsorbed HPAM at low concentrations gives way to desorption at higher concentration due to charge repulsion, and depletion aggregation of the clay.

Cost effectiveness of therapist delivered cognitive behavioural therapy and web-based self-management in irritable bowel syndrome: the ACTIB randomised trial.

BACKGROUND: Telephone therapist delivered CBT (TCBT) and web-based CBT (WCBT) have been shown to be significantly more clinically effective than treatment as usual (TAU) at reducing IBS symptom severity and impact at 12 months in adults with refractory IBS. In this paper we assess the cost-effectiveness of the interventions. METHODS: Participants were recruited from 74 general practices and three gastroenterology centres in England. Interventions costs were calculated, and other service use and lost employment measured and costed for one-year post randomisation. Quality-adjusted life years (QALYs) were combined with costs to determine cost-effectiveness of TCBT and WCBT compared to TAU. RESULTS: TCBT cost £956 more than TAU (95% CI, £601-£1435) and generated 0.0429 more QALYs. WCBT cost £224 more than TAU (95% CI, - £11 to £448) and produced 0.029 more QALYs. Compared to TAU, TCBT had an incremental cost per QALY of £22,284 while the figure for WCBT was £7724. After multiple imputation these ratios increased to £27,436 and £17,388 respectively. Including lost employment and informal care, TCBT had costs that were on average £866 lower than TAU (95% CI, - £1133 to £2957), and WCBT had costs that were £1028 lower than TAU (95% CI, - £448 to £2580). CONCLUSIONS: TCBT and WCBT resulted in more QALYs and higher costs than TAU. Complete case analysis suggests both therapies are cost-effective from a healthcare perspective. Imputation for missing data reduces cost-effectiveness but WCTB remained cost-effective. If the reduced societal costs are included both interventions are likely to be more cost-effective. Trial registration ISRCTN44427879 (registered 18.11.13).

What Is the Evidence to Support a Correlate of Protection for Measles? A Systematic Review.

BACKGROUND: Many studies assume that the serologic correlate of protection from measles disease is 120 mIU/mL. We systematically reviewed the literature to examine the evidence supporting this correlate of protection. METHODS: We searched peer-reviewed and gray literature for articles reporting a measles correlate of protection. We excluded studies focusing on special populations, infants aged <9 months, and those using animal models or nonstandard vaccines or administration routes. We extracted and synthesized data from full-text articles that met inclusion criteria. RESULTS: We screened 14 778 articles and included 5 studies in our review. The studies reported either preexposure antibody concentrations of individuals along with a description of symptoms postexposure, or the proportion of measles cases that had preexposure antibody concentrations above a threshold of immunity specified by the authors. Some studies also described secondary antibody responses upon exposure. The variation in laboratory methods between studies made comparisons difficult. Some of the studies that assumed 120 mIU/mL as a correlate of protection identified symptomatic individuals with preexposure titers exceeding this threshold. CONCLUSIONS: Our findings underscore the scant data upon which the commonly used 120 mIU/mL measles threshold of protection is based, suggesting that further work is required to characterize the measles immunity threshold.

Improving Empathy in Healthcare Consultations-a Secondary Analysis of Interventions.

A recent systematic review of randomised trials suggested that empathic communication improves patient health outcomes. However, the methods for training healthcare practitioners (medical professionals; HCPs) in empathy and the empathic behaviours demonstrated within the trials were heterogeneous, making the evidence difficult to implement in routine clinical practice. In this secondary analysis of seven trials in the review, we aimed to identify (1) the methods used to train HCPs, (2) the empathy behaviours they were trained to perform and (3) behaviour change techniques (BCTs) used to encourage the adoption of those behaviours. This detailed understanding of interventions is necessary to inform implementation in clinical practice. We conducted a content analysis of intervention descriptions, using an inductive approach to identify training methods and empathy behaviours and a deductive approach to describe the BCTs used. The most commonly used methods to train HCPs to enhance empathy were face-to-face training (n = 5), role-playing (n = 3) and videos (self or model; n = 3). Duration of training was varied, with both long and short training having high effect sizes. The most frequently targeted empathy behaviours were providing explanations of treatment (n = 5), providing non-specific empathic responses (e.g. expressing understanding) and displaying a friendly manner and using non-verbal behaviours (e.g. nodding, leaning forward, n = 4). The BCT most used to encourage HCPs to adopt empathy behaviours was "Instruction on how to perform behaviour" (e.g. a video demonstration, n = 5), followed by "Credible source" (e.g. delivered by a psychologist, n = 4) and "Behavioural practice" (n = 3 e.g. role-playing). We compared the effect sizes of studies but could not extrapolate meaningful conclusions due to high levels of variation in training methods, empathy skills and BCTs. Moreover, the methods used to train HCPs were often poorly described which limits study replication and clinical implementation. This analysis of empathy training can inform future research, intervention reporting standards and clinical practice.

Gene Therapy Corrects Brain and Behavioral Pathologies in CLN6-Batten Disease.

CLN6-Batten disease, a form of neuronal ceroid lipofuscinosis is a rare lysosomal storage disorder presenting with gradual declines in motor, visual, and cognitive abilities and early death by 12-15 years of age. We developed a self-complementary adeno-associated virus serotype 9 (scAAV9) vector expressing the human CLN6 gene under the control of a chicken ß-actin (CB) hybrid promoter. Intrathecal delivery of scAAV9.CB.hCLN6 into the cerebrospinal fluid (CSF) of the lumbar spinal cord of 4-year-old non-human primates was safe, well tolerated, and led to efficient targeting throughout the brain and spinal cord. A single intracerebroventricular (i.c.v.) injection at post-natal day 1 in Cln6 mutant mice delivered scAAV9.CB.CLN6 directly into the CSF, and it prevented or drastically reduced all of the pathological hallmarks of Batten disease. Moreover, there were significant improvements in motor performance, learning and memory deficits, and survival in treated Cln6 mutant mice, extending survival from 15 months of age (untreated) to beyond 21 months of age (treated). Additionally, many parameters were similar to wild-type counterparts throughout the lifespan of the treated mice.

An Exploration of How Individuals with an Ostomy Communicatively Manage Uncertainty.

Individuals with an ostomy (a surgical diversion of part of the digestive tract through the abdomen) face a variety of uncertainties, due to the chronic and anatomy-altering nature of living with an ostomy, as well as the perceived stigma attached to having one. However, little is known about how these individuals negotiate uncertainty, and more specifically, how they manage the information they receive and disclose in the uncertainty management process. Thus, through 21 semi-structured interviews of individuals with an ostomy and the use of Uncertainty Management Theory as a theoretical framework, the current study found individuals with an ostomy attempted to negotiate uncertainty by managing information received and disclosed and by adapting to chronic uncertainty. This investigation recommends practical applications for medical professionals, supportive others, patients with an ostomy, as well as future surgical candidates to help manage uncertainty.

Patients' Experiences of Telephone-Based and Web-Based Cognitive Behavioral Therapy for Irritable Bowel Syndrome: Longitudinal Qualitative Study.

BACKGROUND: Cognitive behavioral therapy (CBT) is recommended in guidelines for people with refractory irritable bowel syndrome (IBS). However, the availability of CBT is limited, and poor adherence has been reported in face-to-face CBT. OBJECTIVE: Nested within a randomized controlled trial of telephone- and web-delivered CBT for refractory IBS, this qualitative study aims to identify barriers to and facilitators of engagement over time with the interventions, identify social and psychological processes of change, and provide insight into trial results. METHODS: A longitudinal qualitative study was nested in a randomized controlled trial. Repeated semistructured interviews were conducted at 3 (n=34) and 12 months (n=25) post baseline. Participants received telephone-based CBT (TCBT; n=17 at 3 months and n=13 at 12 months) or web-based CBT (WCBT; n=17 at 3 months and n=12 at 12 months). Inductive thematic analysis was used to analyze the data. RESULTS: Participants viewed CBT as credible for IBS, perceived their therapists as knowledgeable and supportive, and liked the flexibility of web-based and telephone-based delivery; these factors facilitated engagement. Potential barriers to engagement in both groups (mostly overcome by our participants) included initial skepticism and concerns about the biopsychosocial nature of CBT, initial concerns about telephone-delivered talking therapy, challenges of maintaining motivation and self-discipline given already busy lives, and finding nothing new in the WCBT (WCBT group only). Participants described helpful changes in their understanding of IBS, attitudes toward IBS, ability to recognize IBS patterns, and IBS-related behaviors. Consistent with the trial results, participants described lasting positive effects on their symptoms, work, and social lives. Reasons and remedies for some attenuation of effects were identified. CONCLUSIONS: Both TCBT and WCBT for IBS were positively received and had lasting positive impacts on participants' understanding of IBS, IBS-related behaviors, symptoms, and quality of life. These forms of CBT may broaden access to CBT for IBS.

Assessing telephone-delivered cognitive-behavioural therapy (CBT) and web-delivered CBT versus treatment as usual in irritable bowel syndrome (ACTIB): a multicentre randomised trial.

OBJECTIVE: To evaluate the clinical effectiveness of two modes of cognitive-behavioural therapy (CBT) for IBS compared with treatment as usual (TAU) in refractory IBS. DESIGN: A three-arm randomised controlled trial assessing telephone-delivered CBT (TCBT), web-based CBT (WCBT) with minimal therapist support, and TAU. Blinding participants and therapists was not possible. Chief investigator, assessors and statisticians were blinded. Participants were adults with refractory IBS (clinically significant symptoms for ≥12 months despite first-line therapies), recruited by letter and opportunistically from 74 general practices and three gastroenterology centres in London and South of England between May 2014 to March 2016. Co-primary outcomes were IBS Symptom Severity Score (IBS-SSS) and Work and Social Adjustment Scale (WSAS) at 12 months. RESULTS: 558/1452 (38.4%) patients screened for eligibility were randomised: 76% female: 91% white: mean age 43 years. (391/558) 70.1% completed 12 months of follow-up. Primary outcomes: Compared with TAU (IBS-SSS 205.6 at 12 months), IBS-SSS was 61.6 (95% CI 33.8 to 89.5) points lower (p<0.001) in TCBT and 35.2 (95% CI 12.6 to 57.8) points lower (p=0.002) in WCBT at 12 months. Compared with TAU (WSAS score 10.8 at 12 months) WSAS was 3.5 (95% CI 1.9 to 5.1) points lower (p<0.001) in TCBT and 3.0 (95% CI 1.3 to 4.6) points lower (p=0.001) in WCBT. All secondary outcomes showed significantly greater improvement (p≤0.002) in CBT arms compared with TAU. There were no serious adverse reactions to treatment. CONCLUSION: Both CBT interventions were superior to TAU up to 12 months of follow-up. TRIAL REGISTRATION NUMBER: ISRCTN44427879.

Longitudinal In Vivo Monitoring of the CNS Demonstrates the Efficacy of Gene Therapy in a Sheep Model of CLN5 Batten Disease.

Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are neurodegenerative lysosomal storage diseases predominantly affecting children. Single administration of brain-directed lentiviral or recombinant single-stranded adeno-associated virus 9 (ssAAV9) vectors expressing ovine CLN5 into six pre-clinically affected sheep with a naturally occurring CLN5 NCL resulted in long-term disease attenuation. Treatment efficacy was demonstrated by non-invasive longitudinal in vivo monitoring developed to align with assessments used in human medicine. The treated sheep retained neurological and cognitive function, and one ssAAV9-treated animal has been retained and is now 57 months old, almost triple the lifespan of untreated CLN5-affected sheep. The onset of visual deficits was much delayed. Computed tomography and MRI showed that brain structures and volumes remained stable. Because gene therapy in humans is more likely to begin after clinical diagnosis, self-complementary AAV9-CLN5 was injected into the brain ventricles of four 7-month-old affected sheep already showing early clinical signs in a second trial. This also halted disease progression beyond their natural lifespan. These findings demonstrate the efficacy of CLN5 gene therapy, using three different vector platforms, in a large animal model and, thus, the prognosis for human translation.

A Systematic Review of Cognitive Outcomes in Angiographically Negative Subarachnoid Haemorrhage.

Clinical outcomes, including performance on cognitive assessment, in patients with angiographically negative subarachnoid haemorrhage (anSAH) are often interpreted as benign with a good prognostic trajectory. However, diffuse cognitive deficits have been reported within this patient cohort resulting from anSAH, albeit to a lesser extent when compared to other neurovascular events. We consider cognitive outcomes in relation to anSAH to systematically review reported deficits, with a view to quantify and categorise cognitive impairment in this cohort. Anxiety and depression were also included within this review, provided they were assessed alongside cognitive function. Performance deficits in attention and executive function are commonly reported, with set-shifting and interference tasks most commonly impaired in patients. Non-executive cognitive functions are negatively implicated also. Clinical implications and hypotheses relating to the source of these deficits are discussed. This review was formally registered with PROSPERO (CRD42017075294).

Characterisation of early changes in ovine CLN5 and CLN6 Batten disease neural cultures for the rapid screening of therapeutics.

Batten disease (neuronal ceroid lipofuscinosis) refers to a group of neurodegenerative lysosomal storage diseases predominantly affecting children. There are currently no effective treatments, and the functions of many of the associated gene products are unknown. Here we characterise fetal neural cultures from two genetically distinct sheep forms of Batten disease, with mutations in the lysosomal protein encoding gene CLN5 and endoplasmic reticulum membrane protein encoding gene CLN6, respectively. We found similar reductions in autophagy, acidic organelles and synaptic recycling in both forms compared to unaffected cells. We then developed a high-throughput screen and tested for correction of deficient cells with lentiviral-mediated CLN5 or CLN6 gene transfer and fibrate drugs, gemfibrozil and fenofibrate in CLN6 deficient neural cultures. These assays provide a simple system to rapidly screen candidate therapies or libraries of drugs prior to in vivo testing.