Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double-blind, pilot study.

The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain

Psychological factors associated with uptake of the childhood influenza vaccine and perception of post-vaccination side-effects : a cross-sectional survey in England

Objectives To identify predictors of: uptake of the childhood influenza vaccine in the 2015–2016 influenza season, parental perceptions of side-effects from the influenza vaccine and intention to vaccinate one's child for influenza in the 2016–2017 influenza season. Design Cross-sectional online survey. Setting Data were collected in England shortly after the end of the 2015–2016 immunization campaign. Participants 1001 parents or guardians of children aged between two and seven. Main outcome measures Self-reported uptake of the childhood influenza vaccine in the 2015–2016 influenza season, perception of side-effects from the influenza vaccine and intention to vaccinate one's child in the 2016–2017 influenza season. Results Self-reported uptake of the childhood influenza vaccine was 52.8%. Factors strongly positively associated with uptake included the child having previously been vaccinated against influenza, perceiving the vaccine to be effective and perceiving the child to be susceptible to flu. Factors strongly negatively associated with uptake included perceiving the vaccine to be unsafe, to cause short-term side-effects or long-term health problems and believing that yearly vaccination may overload the immune system. Predictors of intended vaccine uptake in 2016–2017 were similar. Participants who perceived side-effects after the 2015–2016 vaccination reported being less likely to vaccinate their child next year. Side-effects were more likely to be reported in first-born children, by participants who knew another child who had side-effects, those who thought that the vaccine would interact with medication that the child was currently taking, and those who believed the vaccine causes short-term side-effects. Conclusions Perceptions about the childhood influenza vaccine show strong associations with uptake, intended uptake and perception of side-effects. Attempts to improve uptake rates from their current low levels must address these perceptions

Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study

Objectives To validate the clinical efficacy and practical feasibility of massively parallel maternal plasma DNA sequencing to screen for fetal trisomy 21 among high risk pregnancies clinically indicated for amniocentesis or chorionic villus sampling

Precision measurement of cardiac structure and function in cardiovascular magnetic resonance using machine learning

BACKGROUND: Measurement of cardiac structure and function from images (e.g. volumes, mass and derived parameters such as left ventricular (LV) ejection fraction [LVEF]) guides care for millions. This is best assessed using cardiovascular magnetic resonance (CMR), but image analysis is currently performed by individual clinicians, which introduces error. We sought to develop a machine learning algorithm for volumetric analysis of CMR images with demonstrably better precision than human analysis. METHODS: A fully automated machine learning algorithm was trained on 1923 scans (10 scanner models, 13 institutions, 9 clinical conditions, 60,000 contours) and used to segment the LV blood volume and myocardium. Performance was quantified by measuring precision on an independent multi-site validation dataset with multiple pathologies with n = 109 patients, scanned twice. This dataset was augmented with a further 1277 patients scanned as part of routine clinical care to allow qualitative assessment of generalization ability by identifying mis-segmentations. Machine learning algorithm ('machine') performance was compared to three clinicians ('human') and a commercial tool (cvi42, Circle Cardiovascular Imaging). FINDINGS: Machine analysis was quicker (20 s per patient) than human (13 min). Overall machine mis-segmentation rate was 1 in 479 images for the combined dataset, occurring mostly in rare pathologies not encountered in training. Without correcting these mis-segmentations, machine analysis had superior precision to three clinicians (e.g. scan-rescan coefficients of variation of human vs machine: LVEF 6.0% vs 4.2%, LV mass 4.8% vs. 3.6%; both P < 0.05), translating to a 46% reduction in required trial sample size using an LVEF endpoint. CONCLUSION: We present a fully automated algorithm for measuring LV structure and global systolic function that betters human performance for speed and precision

Structure-guided identification of a family of dual receptor-binding PfEMP1 that is associated with cerebral malaria

Cerebral malaria is a deadly outcome of infection by Plasmodium falciparum, occurring when parasite-infected erythrocytes accumulate in the brain. These erythrocytes display parasite proteins of the PfEMP1 family that bind various endothelial receptors. Despite the importance of cerebral malaria, a binding phenotype linked to its symptoms has not been identified. Here, we used structural biology to determine how a group of PfEMP1 proteins interacts with intercellular adhesion molecule 1 (ICAM-1), allowing us to predict binders from a specific sequence motif alone. Analysis of multiple Plasmodium falciparum genomes showed that ICAM-1-binding PfEMP1s also interact with endothelial protein C receptor (EPCR), allowing infected erythrocytes to synergistically bind both receptors. Expression of these PfEMP1s, predicted to bind both ICAM-1 and EPCR, is associated with increased risk of developing cerebral malaria. This study therefore reveals an important PfEMP1-binding phenotype that could be targeted as part of a strategy to prevent cerebral malaria

Facemasks, Hand Hygiene, and Influenza among Young Adults: A Randomized Intervention Trial

Limited vaccine availability and the potential for resistance to antiviral medications have led to calls for establishing the efficacy of non-pharmaceutical measures for mitigating pandemic influenza. Our objective was to examine if the use of face masks and hand hygiene reduced rates of influenza-like illness (ILI) and laboratory-confirmed influenza in the natural setting. A cluster-randomized intervention trial was designed involving 1,178 young adults living in 37 residence houses in 5 university residence halls during the 2007–2008 influenza season. Participants were assigned to face mask and hand hygiene, face mask only, or control group during the study. Discrete-time survival models using generalized estimating equations to estimate intervention effects on ILI and confirmed influenza A/B infection over a 6-week study period were examined. A significant reduction in the rate of ILI was observed in weeks 3 through 6 of the study, with a maximum reduction of 75% during the final study week (rate ratio [RR] = 0.25, [95% CI, 0.07 to 0.87]). Both intervention groups compared to the control showed cumulative reductions in rates of influenza over the study period, although results did not reach statistical significance. Generalizability limited to similar settings and age groups. Face masks and hand hygiene combined may reduce the rate of ILI and confirmed influenza in community settings. These non-pharmaceutical measures should be recommended in crowded settings at the start of an influenza pandemic

Impact of electronic medical record on physician practice in office settings: a systematic review

<p>Abstract</p> <p>Background</p> <p>Increased investments are being made for electronic medical records (EMRs) in Canada. There is a need to learn from earlier EMR studies on their impact on physician practice in office settings. To address this need, we conducted a systematic review to examine the impact of EMRs in the physician office, factors that influenced their success, and the lessons learned.</p> <p>Results</p> <p>For this review we included publications cited in Medline and CINAHL between 2000 and 2009 on physician office EMRs. Studies were included if they evaluated the impact of EMR on physician practice in office settings. The Clinical Adoption Framework provided a conceptual scheme to make sense of the findings and allow for future comparison/alignment to other Canadian eHealth initiatives.</p> <p>In the final selection, we included 27 controlled and 16 descriptive studies. We examined six areas: prescribing support, disease management, clinical documentation, work practice, preventive care, and patient-physician interaction. Overall, 22/43 studies (51.2%) and 50/109 individual measures (45.9%) showed positive impacts, 18.6% studies and 18.3% measures had negative impacts, while the remaining had no effect. Forty-eight distinct factors were identified that influenced EMR success. Several lessons learned were repeated across studies: (a) having robust EMR features that support clinical use; (b) redesigning EMR-supported work practices for optimal fit; (c) demonstrating value for money; (d) having realistic expectations on implementation; and (e) engaging patients in the process.</p> <p>Conclusions</p> <p>Currently there is limited positive EMR impact in the physician office. To improve EMR success one needs to draw on the lessons from previous studies such as those in this review.</p

Chapter 4 Design Options, Implementation Issues and Evaluating Success of Ecologically Engineered Shorelines

Human population growth and accelerating coastal development have been the drivers for unprecedented construction of artificial structures along shorelines globally. Construction has been recently amplified by societal responses to reduce flood and erosion risks from rising sea levels and more extreme storms resulting from climate change. Such structures, leading to highly modified shorelines, deliver societal benefits, but they also create significant socioeconomic and environmental challenges. The planning, design and deployment of these coastal structures should aim to provide multiple goals through the application of ecoengineering to shoreline development. Such developments should be designed and built with the overarching objective of reducing negative impacts on nature, using hard, soft and hybrid ecological engineering approaches. The design of ecologically sensitive shorelines should be context-dependent and combine engineering, environmental and socioeconomic considerations. The costs and benefits of ecoengineered shoreline design options should be considered across all three of these disciplinary domains when setting objectives, informing plans for their subsequent maintenance and management and ultimately monitoring and evaluating their success. To date, successful ecoengineered shoreline projects have engaged with multiple stakeholders (e.g. architects, engineers, ecologists, coastal/port managers and the general public) during their conception and construction, but few have evaluated engineering, ecological and socioeconomic outcomes in a comprehensive manner. Increasing global awareness of climate change impacts (increased frequency or magnitude of extreme weather events and sea level rise), coupled with future predictions for coastal development (due to population growth leading to urban development and renewal, land reclamation and establishment of renewable energy infrastructure in the sea) will increase the demand for adaptive techniques to protect coastlines. In this review, we present an overview of current ecoengineered shoreline design options, the drivers and constraints that influence implementation and factors to consider when evaluating the success of such ecologically engineered shorelines

Noninvasive Prenatal Diagnosis of Fetal Trisomy 18 and Trisomy 13 by Maternal Plasma DNA Sequencing

Massively parallel sequencing of DNA molecules in the plasma of pregnant women has been shown to allow accurate and noninvasive prenatal detection of fetal trisomy 21. However, whether the sequencing approach is as accurate for the noninvasive prenatal diagnosis of trisomy 13 and 18 is unclear due to the lack of data from a large sample set. We studied 392 pregnancies, among which 25 involved a trisomy 13 fetus and 37 involved a trisomy 18 fetus, by massively parallel sequencing. By using our previously reported standard z-score approach, we demonstrated that this approach could identify 36.0% and 73.0% of trisomy 13 and 18 at specificities of 92.4% and 97.2%, respectively. We aimed to improve the detection of trisomy 13 and 18 by using a non-repeat-masked reference human genome instead of a repeat-masked one to increase the number of aligned sequence reads for each sample. We then applied a bioinformatics approach to correct GC content bias in the sequencing data. With these measures, we detected all (25 out of 25) trisomy 13 fetuses at a specificity of 98.9% (261 out of 264 non-trisomy 13 cases), and 91.9% (34 out of 37) of the trisomy 18 fetuses at 98.0% specificity (247 out of 252 non-trisomy 18 cases). These data indicate that with appropriate bioinformatics analysis, noninvasive prenatal diagnosis of trisomy 13 and trisomy 18 by maternal plasma DNA sequencing is achievable

Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity

BACKGROUND: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. METHODS: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity. RESULTS: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy. CONCLUSIONS: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as "OGDHL-related disorders"