A Chromosomal Deletion and New Frameshift Mutation Cause ARSACS in an African-American

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare, progressive, neurodegenerative disease characterized by ataxia, spasticity and polyneuropathy. First described in the French-Canadian population of Quebec in 1978, ARSACS has since been identified in multiple patients worldwide. In this clinical case report, we describe the evaluation of an 11-years-old African-American male who presented to neuromuscular clinic for assessment of a gait abnormality. He had a history of gross motor delay since early childhood, frequent falls and a below average IQ. Chromosomal microarray revealed a 1.422 megabase loss in the 13q12.12 region, which includes the SACS gene. Next Generation Sequencing then showed a novel, predicted to be pathogenic missense mutation (c.11824dup) of this gene. His clinical presentation and neurological imaging further confirmed the diagnosis of ARSACS. To our knowledge, this is the first reported case of this disease in the African-American population of the United States. This case report further highlights the growing trend of identifying genetic diseases previously restricted to single, ethnically isolated regions in many different ethnic groups worldwide

Ultrasonic locating devices for central venous cannulation: meta-analysis

OBJECTIVES: To assess the evidence for the clinical effectiveness of ultrasound guided central venous cannulation. DATA SOURCES: 15 electronic bibliographic databases, covering biomedical, science, social science, health economics, and grey literature. DESIGN: Systematic review and meta-analysis of randomised controlled trials. POPULATIONS: Patients scheduled for central venous access. INTERVENTION REVIEWED: Guidance using real time two dimensional ultrasonography or Doppler needles and probes compared with the anatomical landmark method of cannulation. DATA EXTRACTION: Risk of failed catheter placement (primary outcome), risk of complications from placement, risk of failure on first attempt at placement, number of attempts to successful catheterisation, and time (seconds) to successful catheterisation. DATA SYNTHESIS: 18 trials (1646 participants) were identified. Compared with the landmark method, real time two dimensional ultrasound guidance for cannulating the internal jugular vein in adults was associated with a significantly lower failure rate both overall (relative risk 0.14, 95% confidence interval 0.06 to 0.33) and on the first attempt (0.59, 0.39 to 0.88). Limited evidence favoured two dimensional ultrasound guidance for subclavian vein and femoral vein procedures in adults (0.14, 0.04 to 0.57 and 0.29, 0.07 to 1.21, respectively). Three studies in infants confirmed a higher success rate with two dimensional ultrasonography for internal jugular procedures (0.15, 0.03 to 0.64). Doppler guided cannulation of the internal jugular vein in adults was more successful than the landmark method (0.39, 0.17 to 0.92), but the landmark method was more successful for subclavian vein procedures (1.48, 1.03 to 2.14). No significant difference was found between these techniques for cannulation of the internal jugular vein in infants. An indirect comparison of relative risks suggested that two dimensional ultrasonography would be more successful than Doppler guidance for subclavian vein procedures in adults (0.09, 0.02 to 0.38). CONCLUSIONS: Evidence supports the use of two dimensional ultrasonography for central venous cannulation

TReATS: a novel method for TAT-Cre recombinase mediated floxed Allele modification in ex vivo tissue slices

Precision-Cut Lung Slices (PCLS) are used for a variety of applications. However, methods to manipulate genes in PCLS are currently limited. We developed a novel method, TAT-Cre Recombinase-mediated floxed Allele modification in Tissue Slices (TReATS), to induce highly effective and temporally controlled gene deletion or activation in ex vivo PCLS. Treatment of PCLS from Rosa26-flox-stop-flox-EYFP mice with cell-permeant TAT-Cre recombinase induced ubiquitous EYFP protein expression, indicating successful Cre-mediated excision of the upstream loxP-flanked stop sequence. Quantitative real-time PCR confirmed induction of EYFP. We successfully replicated the TReATS method in PCLS from Vangl2flox/flox mice, leading to the deletion of loxP-flanked exon 4 of the Vangl2 gene. Cre-treated Vangl2flox/flox PCLS exhibited cytoskeletal abnormalities, a known phenotype caused by VANGL2 dysfunction. We report a novel method that by-passes conventional Cre-Lox breeding, allowing rapid and highly effective gene manipulation in ex vivo tissue models

A rapid review indicated higher recruitment rates in treatment trials than in prevention trials

Objectives To test the hypothesis that the percentage of patients screened that randomize differs between prevention and therapy trials. Study Design and Setting Rapid review of randomized controlled trials (RCTs) identified through published systematic reviews in August 2013. Individually randomized, parallel group controlled RCTs were eligible if they evaluated metformin monotherapy or exercise for the prevention or treatment of type 2 diabetes. Numbers of patients screened and randomized were extracted by a single reviewer. Percentages were calculated for each study for those randomized: as a function of those approached, screened, and eligible. Percentages (95% confidence intervals) from each individual study were weighted according to the denominator and pooled rates calculated. Statistical heterogeneity was assessed using I2. Results The percentage of those screened who subsequently randomized was 6.2% (6.0%, 6.4%; 3 studies, I2 = 100.0%) for metformin prevention trials; 50.7% (49.9%, 51.4%; 21 studies, I2 = 99.6%) for metformin treatment trials; 4.8% (4.7%, 4.8%; 14 studies, I2 = 99.9%) for exercise prevention trials; and 43.3% (42.6%, 43.9%; 28 studies, I2 = 99.8%) for exercise treatment trials. Conclusion This study provides qualified support for the hypothesis that prevention trials recruit a smaller proportion of those screened than treatment trials. Statistical heterogeneity associated with pooled estimates and other study limitations is discussed. Keywords Prevention; Treatment; RCTs; Recruitment rates; Exercise; Screening failures; Consent rates; Eligibilit

Investigating organic aerosol loading in the remote marine environment

Aerosol loading in the marine environment is investigated using aerosol composition measurements from several research ship campaigns (ICEALOT, MAP, RHaMBLe, VOCALS and OOMPH), observations of total AOD column from satellite (MODIS) and ship-based instruments (Maritime Aerosol Network, MAN), and a global chemical transport model (GEOS-Chem). This work represents the most comprehensive evaluation of oceanic OM emission inventories to date, by employing aerosol composition measurements obtained from campaigns with wide spatial and temporal coverage. The model underestimates AOD over the remote ocean on average by 0.02 (21 %), compared to satellite observations, but provides an unbiased simulation of ground-based Maritime Aerosol Network (MAN) observations. Comparison with cruise data demonstrates that the GEOS-Chem simulation of marine sulfate, with the mean observed values ranging between 0.22 μg m−3 and 1.34 μg m−3, is generally unbiased, however surface organic matter (OM) concentrations, with the mean observed concentrations between 0.07 μg m−3 and 0.77 μg m−3, are underestimated by a factor of 2–5 for the standard model run. Addition of a sub-micron marine OM source of approximately 9 TgC yr−1 brings the model into agreement with the ship-based measurements, however this additional OM source does not explain the model underestimate of marine AOD. The model underestimate of marine AOD is therefore likely the result of a combination of satellite retrieval bias and a missing marine aerosol source (which exhibits a different spatial pattern than existing aerosol in the model)

New obstructions to symplectic embeddings

In this paper we establish new restrictions on symplectic embeddings of certain convex domains into symplectic vector spaces. These restrictions are stronger than those implied by the Ekeland-Hofer capacities. By refining an embedding technique due to Guth, we also show that they are sharp.Comment: 80 pages, 3 figures, v2: improved exposition and minor corrections, v3: Final version, expanded and improved exposition and minor corrections. The final publication is available at link.springer.co

Live imaging of alveologenesis in precision-cut lung slices reveals dynamic epithelial cell behaviour

Damage to alveoli, the gas-exchanging region of the lungs, is a component of many chronic and acute lung diseases. In addition, insufficient generation of alveoli results in bronchopulmonary dysplasia, a disease of prematurity. Therefore visualising the process of alveolar development (alveologenesis) is critical for our understanding of lung homeostasis and for the development of treatments to repair and regenerate lung tissue. Using long-term, time-lapse imaging of precision-cut lung slices, we show alveologenesis for the first time. We reveal that during this process, epithelial cells are highly mobile and we identify specific cell behaviours that contribute to alveologenesis: cell clustering, hollowing and cell extension. Using the cytoskeleton inhibitors blebbistatin and cytochalasin D, we showed that cell migration is a key driver of alveologenesis. This study reveals important novel information about lung biology and provides a new system in which to manipulate alveologenesis genetically and pharmacologically

Understanding the needs and preferences for cancer care among First Nations people: an integrative review.

This systematic review aimed to identify the needs and preferences for cancer care services among Australian First Nations people. An integrative review was conducted. A wide range of search terms were used to increase the sensitivity and specificity of the searches in electronic databases. Methodological quality assessment, data extraction, was conducted independently by two reviewers, and a narrative synthesis was conducted. Forty‐two studies were included. A total of 2965 Australian First Nations adults, both men and women of various ages across the lifespan, were represented; no First Nations children affected by cancer were represented in the studies. Three themes emerged which included: (1) discrimination, racism and trauma, resulting from colonization, directly impacted First National people's cancer care experience; (2) cultural ways of knowing, being and doing are fundamental to how First Nations people engage with cancer care services; and (3) First Nations people need culturally safe person‐centred cancer care services that address practical needs. Most participants represented in this review experienced discrimination, racism and trauma, resulting from colonization, which directly negatively impacted Aboriginal peoples' cancer care experience. While the Optimal Cancer Pathway (OCP) was launched in Australia several years ago, people with cancer may continue to experience distressing unmet care needs. Our team includes both First Nations people, non‐First Nations researchers and healthcare professionals with expertise in cancer care. The researchers employed decolonizing restorative approaches to ensure voice, respect, accountability and reciprocity in this review work. Members of the multidisciplinary team including nurses and policymakers should reflect on these findings, ensure that they have up‐to‐date cultural safety training and stand together with Indigenous and non‐Indigenous cancer leaders to take proactive steps to stamp out and dismantle oppression in health, and safely implement the OCP