Chromosome banding analysis and genomic microarrays are both useful but not equivalent methods for genomic complexity risk stratification in chronic lymphocytic leukemia patients.

Genome complexity has been associated with poor outcome in patients with chronic lymphocytic leukemia (CLL). Previous cooperative studies established five abnormalities as the cut-off that best predicts an adverse evolution by chromosome banding analysis (CBA) and genomic microarrays (GM). However, data comparing risk stratification by both methods are scarce. Herein, we assessed a cohort of 340 untreated CLL patients highly enriched in cases with complex karyotype (CK) (46.5%) with parallel CBA and GM studies. Abnormalities found by both techniques were compared. Prognostic stratification in three risk groups based on genomic complexity (0-2, 3- 4 and ≥5 abnormalities) was also analyzed. No significant differences in the percentage of patients in each group were detected, but only a moderate agreement was observed between methods when focusing on individual cases (κ=0.507; P<0.001). Discordant classification was obtained in 100 patients (29.4%), including 3% classified in opposite risk groups. Most discrepancies were technique-dependent and no greater correlation in the number of abnormalities was achieved when different filtering strategies were applied for GM. Nonetheless, both methods showed a similar concordance index for prediction of time to first treatment (TTFT) (CBA: 0.67 vs. GM: 0.65) and overall survival (CBA: 0.55 vs. GM: 0.57). High complexity maintained its significance in the multivariate analysis for TTFT including TP53 and IGHV status when defined by CBA (hazard ratio [HR] 3.23; P<0.001) and GM (HR 2.74; P<0.001). Our findings suggest that both methods are useful but not equivalent for risk stratification of CLL patients. Validation studies are needed to establish the prognostic value of genome complexity based on GM data in future prospective studies.

Innate Immunity in Mucopolysaccharide Diseases.

Mucopolysaccharidoses are rare paediatric lysosomal storage disorders, characterised by accumulation of glycosaminoglycans within lysosomes. This is caused by deficiencies in lysosomal enzymes involved in degradation of these molecules. Dependent on disease, progressive build-up of sugars may lead to musculoskeletal abnormalities and multi-organ failure, and in others, to cognitive decline, which is still a challenge for current therapies. The worsening of neuropathology, observed in patients following recovery from flu-like infections, suggests that inflammation is highly implicated in disease progression. This review provides an overview of the pathological features associated with the mucopolysaccharidoses and summarises current knowledge regarding the inflammatory responses observed in the central nervous system and periphery. We propose a model whereby progressive accumulation of glycosaminoglycans elicits an innate immune response, initiated by the Toll-like receptor 4 pathway, but also precipitated by secondary storage components. Its activation induces cells of the immune system to release pro-inflammatory cytokines, such as TNF-α and IL-1, which induce progression through chronic neuroinflammation. While TNF-α is mostly associated with bone and joint disease in mucopolysaccharidoses, increasing evidence implicates IL-1 as a main effector of innate immunity in the central nervous system. The (NOD)-like receptor protein 3 inflammasome is therefore implicated in chronic neuroinflammation and should be investigated further to identify novel anti-inflammatory treatments.

Genomic arrays identify high-risk chronic lymphocytic leukemia with genomic complexity: a multi-center study.

Complex karyotype (CK) identified by chromosome-banding analysis (CBA) has shown prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genome-wide detection of copy-number alterations (CNAs) and could therefore be well equipped to detect the presence of a CK. Current knowledge on genomic arrays in CLL is based on outcomes of single center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2293 arrays from 13 diagnostic laboratories according to established standards. CNAs were found outside regions captured by CLL FISH probes in 34% of patients, and several of them including gains of 8q, deletions of 9p and 18p (p<0.01) were linked to poor outcome after correction for multiple testing. Patients (n=972) could be divided in three distinct prognostic subgroups based on the number of CNAs. Only high genomic complexity (high-GC), defined as ≥5 CNAs emerged as an independent adverse prognosticator on multivariable analysis for time to first treatment (Hazard ratio: 2.15, 95% CI: 1.36-3.41; p=0.001) and overall survival (Hazard ratio: 2.54, 95% CI: 1.54-4.17; p<0.001; n=528). Lowering the size cutoff to 1 Mb in 647 patients did not significantly improve risk assessment. Genomic arrays detected more chromosomal abnormalities and performed at least as well in terms of risk stratification compared to simultaneous chromosome banding analysis as determined in 122 patients. Our findings highlight genomic array as an accurate tool for CLL risk stratification.

Molecular detection of Gram-positive bacteria in the human lung through an optical fiber-based endoscope.

PURPOSE: The relentless rise in antimicrobial resistance is a major societal challenge and requires, as part of its solution, a better understanding of bacterial colonization and infection. To facilitate this, we developed a highly efficient no-wash red optical molecular imaging agent that enables the rapid, selective, and specific visualization of Gram-positive bacteria through a bespoke optical fiber-based delivery/imaging endoscopic device. METHODS: We rationally designed a no-wash, red, Gram-positive-specific molecular imaging agent (Merocy-Van) based on vancomycin and an environmental merocyanine dye. We demonstrated the specificity and utility of the imaging agent in escalating in vitro and ex vivo whole human lung models (n = 3), utilizing a bespoke fiber-based delivery and imaging device, coupled to a wide-field, two-color endomicroscopy system. RESULTS: The imaging agent (Merocy-Van) was specific to Gram-positive bacteria and enabled no-wash imaging of S. aureus within the alveolar space of whole ex vivo human lungs within 60 s of delivery into the field-of-view, using the novel imaging/delivery endomicroscopy device. CONCLUSION: This platform enables the rapid and specific detection of Gram-positive bacteria in the human lung.

High dose genistein in Sanfilippo syndrome: A randomised controlled trial.

The aim of this study was to evaluate the efficacy of high dose genistein aglycone in Sanfilippo syndrome (mucopolysaccharidosis type III). High doses of genistein aglycone have been shown to correct neuropathology and hyperactive behaviour in mice, but efficacy in humans is uncertain. This was a single centre, double-blinded, randomised, placebo-controlled study with open-label extension phase. Randomised participants received either 160 mg/kg/day genistein aglycone or placebo for 12 months; subsequently all participants received genistein for 12 months. The primary outcome measure was the change in heparan sulfate concentration in cerebrospinal fluid (CSF), with secondary outcome measures including heparan sulfate in plasma and urine, total glycosaminoglycans in urine, cognitive and adaptive behaviour scores, quality of life measures and actigraphy. Twenty-one participants were randomised and 20 completed the placebo-controlled phase. After 12 months of treatment, the CSF heparan sulfate concentration was 5.5% lower in the genistein group (adjusted for baseline values), but this was not statistically significant (P = .26), and CSF heparan sulfate increased in both groups during the open-label extension phase. Reduction of urinary glycosaminoglycans was significantly greater in the genistein group (32.1% lower than placebo after 12 months, P = .0495). Other biochemical and clinical parameters showed no significant differences between groups. High dose genistein aglycone (160 mg/kg/day) was not associated with clinically meaningful reductions in CSF heparan sulfate and no evidence of clinical efficacy was detected. However, there was a statistically significant reduction in urine glycosaminoglycans. These data do not support the use of genistein aglycone therapy in mucopolysaccharidosis type III. High dose genistein aglycone does not lead to clinically meaningful reductions in biomarkers or improvement in neuropsychological outcomes in mucopolysaccharidosis type III.

Training for difficult conversations and breaking bad news over the phone in the emergency department.

Due to the COVID-19 pandemic, there have been strict limits on visitors to hospitals. This has led to clinicians having an increasing number of difficult conversations with patients and their relatives over the phone. There is a lack of published literature examining how to do this well, but it is recognised that phone communication does differ from face to face interactions, and requires specific training. What is most important to patients and their families when receiving bad news is privacy, adequate time without interruptions, clarity and honesty when delivering the information, and an empathetic and caring attitude. Much of the work done on breaking bad news has been done in oncology and focusses on face to face interaction; there has been an assumption that this is transferrable to the emergency department, and more recently that this is applicable to conversations over the phone. Multiple educational interventions to improve the delivery of bad news have been developed, with differing frameworks to help clinicians carry out this stressful task. Simulation is widely used to train clinicians to break bad news, and has solid theoretical foundations for its use. The psychological safety of participants must be considered, especially with emotive subjects such as breaking bad news. We believe there is a need for specific training in breaking bad news over the phone, and developed an innovative simulation-based session to address this. The training has been well received, and has also highlighted the need for a space where clinicians feel able to discuss the emotional impact of the difficult conversations they are having.

Gamified applications for secondary prevention in patients with high cardiovascular disease risk: A systematic review of effectiveness and acceptability.

INTRODUCTION: Gamified health mobile applications (apps) are promoted as innovative approaches to self-management and risk factor reduction. However, information is lacking on effectiveness or feasibility in older patients at high risk for cardiovascular diseases (CVD), which limits uptake and recommendations by nurses. This study aimed to evaluate the effectiveness and acceptability of gamified apps for CVD secondary prevention. METHODS: EQUATOR PRISMA checklist was used to guide the systematic review. PubMed, Embase and SCOPUS were searched from inception to January 2020 for studies evaluating app interventions incorporating ≥2 game tactics and targeting secondary prevention in patients diagnosed with heart disease, hypertension, stroke or type 2 diabetes. Narrative summaries of results were used as meta-analysis were not possible. The PROSPERO ID number was CRD42020209791. RESULTS: Seven studies involving 657 patients were included. Gamified apps resulted in more improvement in physical activity, HbA1C and diabetes self-management empowerment compared to multiple different comparators, and more physical activity motivation compared to a neutral content control app. Heart failure knowledge also improved significantly. However, no benefits above usual care were evident for blood pressure or body mass index, or from app use for heart failure self-management, medication adherence or atrial fibrillation knowledge. App acceptability in terms of usage declined with time but was high for the game components of challenges, medication monitoring, viewing of leader boards and badges and walking training participation. Enjoyment was highest for elements that featured surprise/novelty, having teammates, challenges, good graphic design and clarity. CONCLUSIONS: Gamified mobile apps show the potential to improve secondary prevention in high CVD risk patients. Indications for acceptability were evident, with higher adherence than clinic-based secondary prevention programmes. However, further well-designed randomised controlled trials, which track app usage are needed to confirm this potential and encourage nurses to recommend these types of apps.

Guidance about age-friendly outdoor exercise equipment and associated strategies to maximise usability for older people.

Outdoor exercise equipment has become popular as important environmental infrastructure to provide opportunities for physical activity and social connectedness in public settings. With higher sedentary behaviour and physical inactivity reported among older people, infrastructure changes and safe environments that promote older peoples' health and mobility are required. Due to ageing-related functional decline and health conditions associated with ageing, older adults may have special physical needs that require careful consideration when choosing outdoor equipment. However, limited information is available regarding the suitability of the types of exercise equipment for older people. This commentary provides further information on the type of equipment available, its functionality and suitability for older age populations and key considerations for the decision-maker involved in selecting, installing and supporting community use of outdoor exercise equipment. Recommendations on what is required to maximise usability from a system or organisational-based approach using research evidence is also discussed. Older people are more susceptible to the negative influences of their local environment and outdoor neighbourhood conditions. Consequently, the age-friendliness and suitability of the outdoor exercise equipment characteristics, location and settings may facilitate older adults' engagement in physical and social activities.

Core crosstalk in ordered imaging fiber bundles.

Coherent fiber bundles are used widely for imaging. Commonly, disordered arrays of randomly sized fiber cores avoid proximity between like-cores, which would otherwise result in increased core crosstalk and a negative impact on imaging. Recently, stack-and-draw fiber manufacture techniques have been used to produce fibers with a controlled core layout to minimize core crosstalk. However, one must take manufacturing considerations into account during stack-and-draw fiber design in order to avoid impractical or unachievable fabrication. This comes with a set of practical compromises, such as using only a small number of different core sizes. Through characterization of core crosstalk patterns, this Letter aims to aid the understanding of crosstalk limitations imposed by such compromises in the core layout made for ease of fabrication.

Demonstrating the Use of Optical Fibres in Biomedical Sensing: A Collaborative Approach for Engagement and Education.

This paper demonstrates how research at the intersection of physics, engineering, biology and medicine can be presented in an interactive and educational way to a non-scientific audience. Interdisciplinary research with a focus on prevalent diseases provides a relatable context that can be used to engage with the public. Respiratory diseases are significant contributors to avoidable morbidity and mortality and have a growing social and economic impact. With the aim of improving lung disease understanding, new techniques in fibre-based optical endomicroscopy have been recently developed. Here, we present a novel engagement activity that resembles a bench-to-bedside pathway. The activity comprises an inexpensive educational tool (<$70) adapted from a clinical optical endomicroscopy system and tutorials that cover state-of-the-art research. The activity was co-created by high school science teachers and researchers in a collaborative way that can be implemented into any engagement development process.

Target Audience and Preferences Related to an Australian Coronary Heart Disease Specific Mobile App: A Mixed Methods Study.

BACKGROUND: Widespread availability of mobile technologies offers the opportunity to support secondary prevention of coronary heart disease (CHD) via mobile apps, however, the target audience and their app preferences are unknown. This study aims to identify the potential audience for an Australian CHD specific app and their recommendations and preferences. METHODS: A two-phase mixed methods study: Phase 1: CHD patients (n=282) were surveyed on mobile app engagement. Phase 2: Four focus groups with regular app users (n=12) identified preferences and recommendations generated after using a CHD-specific publicly available app (MyHeartMyLife) for 2 weeks. Data were thematically analysed. RESULTS: Survey participants were aged ≥56 years (238/282, 84.4%) and male (204/282, 72.3%). More than one third (108/282, 38.3%) were regular app users, of whom 83/108, (76.9%) used health apps. Regular app users were more likely to be <56 years (versus ≥70 years; OR 4.70, 95% CI 1.92, 11.51), employed (OR 3.07, 95% CI 1.63, 5.77) and had completed high school education (OR 2.37, 95% CI 1.30, 4.34). Focus group participants using the CHD-specific app were aged 41-79 years (mean 62.2 SD 5.3 years) and 10/12 were male. Coronary heart disease specific app preferences generated included: immediate access to relevant and practical health information and records; behaviour change motivation; more experienced app users located and used app features readily and provided support for less experienced users. In addition, ensuring ease of reading and interpreting data, adding physical activity tracking, the ability to integrate and synchronise with other apps and devices, and capacity to store additional personal medical records were also recommended. CONCLUSIONS: The target audience for CHD-specific apps is aged <56 years, employed, has completed high school and is an experienced app user. User preferences and recommendations identified features present in publicly available apps, but many features need development.

What do young women with obesity want from a weight management program?

PURPOSE: Early adulthood is a high-risk time for weight gain; however, young women with obesity are difficult to recruit to weight management programs. To encourage participation and retention, it is important to understand what young women want from these programs. The purpose of the study was to explore participants' perspectives on the features of an ideal weight management program. METHODS: Semi-structured interview schedules were used to elicit information from eight focus groups [27 women; mean age of 29.1 (± 5.1) years, mean body mass index (BMI; kg/m2) of 35.8 (± 2.9)]. The focus groups were transcribed, coded and analyzed qualitatively. RESULTS: The themes that emerged were program content, format, program characteristics, program name, location and duration. A major finding from the study is that participants value a program that includes nutritional, psychological and lifestyle interventions, and includes components that are not traditionally part of weight management programs such as body acceptance, sexual health and dressing and grooming. A program name that conveys wellness and body positivity was valued. Participants highlighted the importance of individualized programs that are also tailored to the needs of young adults, and delivered by credible and approachable staff who provide accountability. Cost-effectiveness, flexibility, accessibility, time-commitment were important considerations and the use of a combination of virtual and in-person methods (including group interventions) appealed to this cohort. CONCLUSION: Knowledge of program features which resonate with young women facilitates development of innovative ways to engage and support evidence-based weight management in this vulnerable group. LEVEL OF EVIDENCE: V.

The role of innate immunity in mucopolysaccharide diseases.

Mucopolysaccharidoses are lysosomal storage disorders characterised by accumulation of abnormal pathological glycosaminoglycans, cellular dysfunction and widespread inflammation, resulting in progressive cognitive and motor decline. Lysosomes are important mediators of immune cell function, and therefore accumulation of glycosaminoglycans (GAGs) and other abnormal substrates could affect immune function and directly impact on disease pathogenesis. This review summarises current knowledge with regard to inflammation in mucopolysaccharidosis, with an emphasis on the brain and outlines a potential role for GAGs in induction of inflammation. We propose a model by which the accumulation of GAGs and other factors may impact on innate immune signalling with particular focus on the Toll-like receptor 4 pathway. Innate immunity appears to have a dominating role in mucopolysaccharidosis; however, furthering understanding of innate immune signalling would have significant impact on highlighting novel anti-inflammatory therapeutics for use in mucopolysaccharide diseases. This article is part of the Special Issue "Lysosomal Storage Disorders".

Non-myeloablative busulfan chimeric mouse models are less pro-inflammatory than head-shielded irradiation for studying immune cell interactions in brain tumours.

BACKGROUND: Chimeric mouse models generated via adoptive bone marrow transfer are the foundation for immune cell tracking in neuroinflammation. Chimeras that exhibit low chimerism levels, blood-brain barrier disruption and pro-inflammatory effects prior to the progression of the pathological phenotype, make it difficult to distinguish the role of immune cells in neuroinflammatory conditions. Head-shielded irradiation overcomes many of the issues described and replaces the recipient bone marrow system with donor haematopoietic cells expressing a reporter gene or different pan-leukocyte antigen, whilst leaving the blood-brain barrier intact. However, our previous work with full body irradiation suggests that this may generate a pro-inflammatory peripheral environment which could impact on the brain's immune microenvironment. Our aim was to compare non-myeloablative busulfan conditioning against head-shielded irradiation bone marrow chimeras prior to implantation of glioblastoma, a malignant brain tumour with a pro-inflammatory phenotype. METHODS: Recipient wild-type/CD45.1 mice received non-myeloablative busulfan conditioning (25 mg/kg), full intensity head-shielded irradiation, full intensity busulfan conditioning (125 mg/kg) prior to transplant with whole bone marrow from CD45.2 donors and were compared against untransplanted controls. Half the mice from each group were orthotopically implanted with syngeneic GL-261 glioblastoma cells. We assessed peripheral blood, bone marrow and spleen chimerism, multi-organ pro-inflammatory cytokine profiles at 12 weeks and brain chimerism and immune cell infiltration by whole brain flow cytometry before and after implantation of glioblastoma at 12 and 14 weeks respectively. RESULTS: Both non-myeloablative conditioning and head-shielded irradiation achieve equivalent blood and spleen chimerism of approximately 80%, although bone marrow engraftment is higher in the head-shielded irradiation group and highest in the fully conditioned group. Head-shielded irradiation stimulated pro-inflammatory cytokines in the blood and spleen but not in the brain, suggesting a systemic response to irradiation, whilst non-myeloablative conditioning showed no cytokine elevation. Non-myeloablative conditioning achieved higher donor chimerism in the brain after glioblastoma implantation than head-shielded irradiation with an altered immune cell profile. CONCLUSION: Our data suggest that non-myeloablative conditioning generates a more homeostatic peripheral inflammatory environment than head-shielded irradiation to allow a more consistent evaluation of immune cells in glioblastoma and can be used to investigate the roles of peripheral immune cells and bone marrow-derived subsets in other neurological diseases.

Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinico-biological differences. Considering this, we assessed prognosis separately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet A M-CLL patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to-first-treatment and a treatment probability at five and ten years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet A U-CLL patients, besides TP53 abnormalities, del(11q) and/or SF3B1 mutations were associated with the shortest time-to-first-treatment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage CLL patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in CLL.

An evidence-based approach to developing low-carbohydrate diets for type 2 diabetes management: A systematic review of interventions and methods.

AIM: To identify core diet and delivery components of low-carbohydrate (CHO) diets that have demonstrated efficacy for type 2 diabetes (T2D) management. MATERIALS AND METHODS: MEDLINE, Pre-MEDLINE, EMBASE, CINAHL and the Cochrane Library of Controlled Trials databases were systematically searched from inception until August 18, 2018. Primary intervention studies of low-CHO diets (≤130 g/d or 26% total energy intake [TEI]) were included. Content analysis was performed on the low-CHO diet protocols classified as safe and effective for T2D management. RESULTS: A total of 41 studies published between 1963 and 2018 were included, of which 40 were classified as safe and effective for inclusion in the primary analysis. Thirteen studies (13/40) were on very-low-CHO diets (<50 g/d), 14/40 included low-CHO diets (≤130 g/d or 26% TEI), and 13/40 were adapted according to participant progress. Thirty-one studies reported a total energy prescription, of which 18/31 encouraged ad libitum intakes. Twenty studies reported a prescribed dietary fat amount, of which 18/20 were unrestricted or high-fat (>35% TEI). Twenty-six studies reported a prescribed dietary protein amount, of which 22 were unrestricted or were high-protein (>25% TEI). The types of dietary CHO, fat and protein recommended were predominantly whole foods. Common delivery methods reported were dietician and/or physician involvement, moderate to high frequency of contact (≥1 session/month) and use of participant self-monitoring. CONCLUSIONS: Multiple approaches for developing and delivering a low-CHO diet intervention for T2D management are safe and effective. A comprehensive set of core dietary components to consider in the formulation of low-CHO diet protocols were identified for use in clinical practice and to inform evidence-based guidelines for T2D management.

Macrophage enzyme and reduced inflammation drive brain correction of mucopolysaccharidosis IIIB by stem cell gene therapy.

Mucopolysaccharidosis IIIB is a paediatric lysosomal storage disease caused by deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU), involved in the degradation of the glycosaminoglycan heparan sulphate. Absence of NAGLU leads to accumulation of partially degraded heparan sulphate within lysosomes and the extracellular matrix, giving rise to severe CNS degeneration with progressive cognitive impairment and behavioural problems. There are no therapies. Haematopoietic stem cell transplant shows great efficacy in the related disease mucopolysaccharidosis I, where donor-derived monocytes can transmigrate into the brain following bone marrow engraftment, secrete the missing enzyme and cross-correct neighbouring cells. However, little neurological correction is achieved in patients with mucopolysaccharidosis IIIB. We have therefore developed an ex vivo haematopoietic stem cell gene therapy approach in a mouse model of mucopolysaccharidosis IIIB, using a high-titre lentiviral vector and the myeloid-specific CD11b promoter, driving the expression of NAGLU (LV.NAGLU). To understand the mechanism of correction we also compared this with a poorly secreted version of NAGLU containing a C-terminal fusion to IGFII (LV.NAGLU-IGFII). Mucopolysaccharidosis IIIB haematopoietic stem cells were transduced with vector, transplanted into myeloablated mucopolysaccharidosis IIIB mice and compared at 8 months of age with mice receiving a wild-type transplant. As the disease is characterized by increased inflammation, we also tested the anti-inflammatory steroidal agent prednisolone alone, or in combination with LV.NAGLU, to understand the importance of inflammation on behaviour. NAGLU enzyme was substantially increased in the brain of LV.NAGLU and LV.NAGLU-IGFII-treated mice, with little expression in wild-type bone marrow transplanted mice. LV.NAGLU treatment led to behavioural correction, normalization of heparan sulphate and sulphation patterning, reduced inflammatory cytokine expression and correction of astrocytosis, microgliosis and lysosomal compartment size throughout the brain. The addition of prednisolone improved inflammatory aspects further. Substantial correction of lysosomal storage in neurons and astrocytes was also achieved in LV.NAGLU-IGFII-treated mice, despite limited enzyme secretion from engrafted macrophages in the brain. Interestingly both wild-type bone marrow transplant and prednisolone treatment alone corrected behaviour, despite having little effect on brain neuropathology. This was attributed to a decrease in peripheral inflammatory cytokines. Here we show significant neurological disease correction is achieved using haematopoietic stem cell gene therapy, suggesting this therapy alone or in combination with anti-inflammatories may improve neurological function in patients.

A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency.

Recombinant adeno-associated viruses (AAVs) are popular in vivo gene transfer vehicles. However, vector doses needed to achieve therapeutic effect are high and some target tissues in the central nervous system remain difficult to transduce. Gene therapy trials using AAV for the treatment of neurological disorders have seldom led to demonstrated clinical efficacy. Important contributing factors are low transduction rates and inefficient distribution of the vector. To overcome these hurdles, a variety of capsid engineering methods have been utilized to generate capsids with improved transduction properties. Here we describe an alternative approach to capsid engineering, which draws on the natural evolution of the virus and aims to yield capsids that are better suited to infect human tissues. We generated an AAV capsid to include amino acids that are conserved among natural AAV2 isolates and tested its biodistribution properties in mice and rats. Intriguingly, this novel variant, AAV-TT, demonstrates strong neurotropism in rodents and displays significantly improved distribution throughout the central nervous system as compared to AAV2. Additionally, sub-retinal injections in mice revealed markedly enhanced transduction of photoreceptor cells when compared to AAV2. Importantly, AAV-TT exceeds the distribution abilities of benchmark neurotropic serotypes AAV9 and AAVrh10 in the central nervous system of mice, and is the only virus, when administered at low dose, that is able to correct the neurological phenotype in a mouse model of mucopolysaccharidosis IIIC, a transmembrane enzyme lysosomal storage disease, which requires delivery to every cell for biochemical correction. These data represent unprecedented correction of a lysosomal transmembrane enzyme deficiency in mice and suggest that AAV-TT-based gene therapies may be suitable for treatment of human neurological diseases such as mucopolysaccharidosis IIIC, which is characterized by global neuropathology.

Omega-3 polyunsaturated fatty acids status and cognitive function in young women.

BACKGROUND: Research indicates that low omega-3 polyunsaturated fatty acid (n-3 PUFA) may be associated with decreased cognitive function. This study examined the association between n-3 PUFA status and cognitive function in young Australian women. METHODS: This was a secondary outcome analysis of a cross-sectional study that recruited 300 healthy women (18-35 y) of normal weight (NW: BMI 18.5-24.9 kg/m2) or obese weight (OB: BMI ≥30.0 kg/m2). Participants completed a computer-based cognition testing battery (IntegNeuro™) evaluating the domains of impulsivity, attention, information processing, memory and executive function. The Omega-3 Index (O3I) was used to determine n-3 PUFA status (percentage of EPA (20:5n-3) plus DHA (22:6n3) in the red cell membrane) and the participants were divided into O3I tertile groups: T1 < 5.47%, T2 = 5.47-6.75%, T3 > 6.75%. Potential confounding factors of BMI, inflammatory status (C-reactive Protein), physical activity (total MET-min/wk), alpha1-acid glycoprotein, serum ferritin and hemoglobin, were assessed. Data reported as z-scores (mean ± SD), analyses via ANOVA and ANCOVA. RESULTS: Two hundred ninety-nine women (26.9 ± 5.4 y) completed the study (O3I data, n = 288). The ANOVA showed no overall group differences but a significant group × cognition domain interaction (p < 0.01). Post hoc tests showed that participants in the low O3I tertile group scored significantly lower on attention than the middle group (p = 0.01; ES = 0.45 [0.15-0.74]), while the difference with the high group was borderline significant (p = 0.052; ES = 0.38 [0.09-0.68]). After confounder adjustments, the low group had lower attention scores than both the middle (p = 0.01) and high (p = 0.048) groups. These findings were supported by univariate analyses which found significant group differences for the attention domain only (p = 0.004). CONCLUSIONS: Cognitive function in the attention domain was lower in women with lower O3I, but still within normal range. This reduced but normal level of cognition potentially provides a lower baseline from which cognition would decline with age. Further investigation of individuals with low n-3 PUFA status is warranted.

Actual competence, rather than perceived competence, is a better predictor of physical activity in children aged 6-9 years.

There is a limited understanding about the relative importance of perceived and actual competence on emergent physical activity levels in children and whether there is a difference in their development and strength between boys and girls. This study used a single-cohort, multiple age group design to monitor physical activity, actual motor competence (AMC) and perceived competence (PC) on four occasions over 18 months in 6-to 9-year-old boys and girls (N = 201). Physical activity was measured by 7-day daily step counts (pedometer) and activity diary. AMC was assessed by mastery of skill criteria for 4 motor skills; run, overhand throw, standing broad jump, and line walk. PC was measured with the Self Description Questionnaire-I. Linear Mixed Model analysis revealed that AMC, Gender and School significantly impacted physical activity levels longitudinally in these children. AMC made a greater contribution (9-30%) to physical activity levels than PC (0-5%), and at an earlier age in boys (7 years) than girls (9 years). The need to acknowledge these developing distinctions in considering emergent physical activity levels has important implications for childhood learning environments and physical activity interventions.