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Background: SMA is a neurodegenerative disease caused by biallelic deletion/mutation of the survival motor neuron (SMN1) gene. In the phase 1 trial (NCT02122952), SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of 15 symptomatic SMA1 patients (3 at a lower dose [cohort 1] and 12 at the proposed therapeutic dose [cohort 2]). This report describes long-term follow-up study design and data from the phase 1 study. Methods: Patients in the phase 1 study could rollover into a long-term follow-up study (NCT03421977). The primary objective is to collect long-term safety data (serious adverse events, hospitalizations, and adverse events of special interest). Annual follow-up will occur for 15 years. Additionally, patient record transfers from local clinician(s) will be requested. Safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. Efficacy assessments include physical examination to assess developmental milestones. Results: As of September 27, 2018, the oldest patients are 59.2 (cohort 1) and 52.1 (cohort 2) months old and free of permanent ventilation. Preliminary data, including survival and developmental milestones, will be presented. Conclusions: Patients treated with a one-time dose of AVXS-101 continue to gain strength, develop, and achieve new milestones, demonstrating a long-term, durable response.
Introduction: Very low concentrations of high-sensitivity cardiac troponin can rule-out myocardial infarction (MI) at ED arrival in patients with chest pain. However, this single troponin rule-out strategy works poorly in patients with renal impairment and elevated baseline troponin levels. The objective of this study was to develop and validate a troponin adjustment strategy to accurately rule-out MI with a single hs-cTnTmeasurement in patients with kidney dysfunction. Methods: We used data from three cohorts of ED chest pain patients to develop an adjustment score for a high-sensitivity troponin T (hs-cTnT) assay in patients with kidney dysfunction. The derivation cohort (n = 8846) used administrative and registry data. Two validation cohorts (n = 1187 and 1092) were prospectively-collected. The score assigned points for increasing hs-cTnT levels and subtracted points for lower estimated glomerular filtration rate (eGFR). In the derivation cohort, hs-cTnT concentrations achieving 98.5% sensitivity in of patients with eGFR ≥60, 45-59, 30-44, 15-29 and <15 were assigned ascending positive integer values. Negative integer values were assigned to eGFR values 45-59, 30-44, 15-29 and <15. The scpres for troponin and eGFR were summed for each patient, with scores ranging from −4 to +5. The proportion of patients with 7-day MI ruled out by a score ≤0, sensitivity, NPV, negative likelihood ratio (LR-) and area under the curve (AUC) were quantified in each study cohort. Results: The derivation and validation cohorts had 7-day MI rates of 5.7, 8.6 and 9.1%. In the derivation cohort, a score ≤0 ruled out MI in 35% of patients, with a sensitivity for 7-day MI of 99.5% (95% CI 98-100), NPV of 99.9% (95% CI 98.4-99.9), LR- of 0.02 (95% CI 0.01-0.05) and AUC of 0.88. In the first validation cohort, a score ≤0 ruled out MI in 45% of patients, with a sensitivity for 7-day MI of 97% (95% CI 90-100%), NPV of 99% (95% CI 98-100%), LR- 0.06 (0.02-0.18) and AUC of 0.89. In the second validation cohort, a score ≤0 ruled out MI in 20% of patients, with a sensitivity for 7-day MI of 96% (95% CI 93-99%), NPV of 98% (95% CI 96-100%), LR- of 0.16 (95% CI 0.07-0.39) and AUC of 0.78. Conclusion: We developed and validated a simple scoring system to adjust hs-cTnT concentrations for a patient's kidney function that enables MI to be ruled out in a large proportion of chest pain patients using a single measurement on ED presentation.
Introduction: Intravenous insertion (IVI) is identified by children as extremely painful and the resultant distress can have lasting negative consequences. There is an urgent need to effectively manage such procedures. Our primary objective was to compare the pain and distress of IVI with the addition of humanoid robot-based distraction to standard care, versus standard care alone. Methods: This two-armed randomized controlled trial (RCT) was conducted from April 2017 to May 2018 at the Stollery Children's Hospital emergency department (ED). Children aged 6 to 11 years who required IVI were included. Exclusion criteria included hearing or visual impairments, neurocognitive delays, sensory impairment to pain, previous enrolment, and discretion of the ED clinical staff. Primary outcomes were measured using the Observational Scale of Behavioural Distress-Revised (OSBD-R) (distress) and the Faces Pain Scale-Revised (FPS-R) (pain). A total of 426 pediatric patients were screened and 340 were excluded. Results: We recruited 86 children, of which 55% (47/86) were male; 9% (7/82) were premature at birth; 82% (67/82) had a previous ED visit; 30% (25/82) required previous hospitalization; 78% (64/82) had previous IV placement and 96% (78/81) received topical anesthesia. The mean total OSBD-R score was 1.49 ± 2.36 (standard care) compared to 0.78 ± 1.32 (robot group) (p = 0.047). The median FPS-R during the IV procedure was 4 (IQR 2,6) in the standard care group alone, compared to 2 (IQR 0,4) with the addition of humanoid robot-based distraction (p = 0.10). Change in parental state anxiety pre-procedure versus post-procedure was not significantly different between groups (p = 0.49). Parental satisfaction with the IV start was 93% (39/42) in the robot arm compared to 74% (29/39) in the standard care arm (p = 0.03). Parents were also more satisfied with management of their child's pain in the robot group (95% very satisfied) compared with standard care (72% very satisfied) (p = 0.002). Conclusion: A statistically significant reduction in distress was observed with the addition of robot-based distraction to standard care. Humanoid robot-based distraction therapy reduces distress and to a lesser extent, pain, in children undergoing IVI in the ED. Further trials are required to confirm utility in other age groups and settings.
Despite many interventions aiming to reduce excessive gestational weight gain (GWG), it is currently unclear the impact on infant anthropometric outcomes. The aim of this review was to evaluate offspring anthropometric outcomes in studies designed to reduce GWG. A systematic search of seven international databases, one clinical trial registry and three Chinese databases was conducted without date limits. Studies were categorised by intervention type: diet, physical activity (PA), lifestyle (diet + PA), other, gestational diabetes mellitus (GDM) (diet, PA, lifestyle, metformin and other). Meta-analyses were reported as weighted mean difference (WMD) for birthweight and birth length, and risk ratio (RR) for small for gestational age (SGA), large for gestational age (LGA), macrosomia and low birth weight (LBW). Collectively, interventions reduced birthweight, risk of macrosomia and LGA by 71 g (WMD: −70.67, 95% CI −101.90 to −39.43, P<0.001), 16% (RR: 0.84, 95% CI 0.73–0.98, P=0.026) and 19% (RR: 0.81, 95% CI 0.69–0.96, P=0.015), respectively. Diet interventions decreased birthweight and LGA by 99 g (WMD −98.80, 95% CI −178.85 to −18.76, P=0.016) and 65% (RR: 0.35, 95% CI 0.17–0.72, P=0.004). PA interventions reduced the risk of macrosomia by 51% (RR: 0.49, 95% CI 0.26–0.92, P=0.036). In women with GDM, diet and lifestyle interventions reduced birthweight by 211 and 296 g, respectively (WMD: −210.93, 95% CI −374.77 to −46.71, P=0.012 and WMD:−295.93, 95% CI −501.76 to −90.10, P=0.005, respectively). Interventions designed to reduce excessive GWG lead to a small reduction in infant birthweight and risk of macrosomia and LGA, without influencing the risk of adverse outcomes including LBW and SGA.
Human fascioliasis is a worldwide, pathogenic food-borne trematodiasis. Impressive clinical pictures comprising puzzling polymorphisms, manifestation multifocality, disease evolution changes, sequelae and mortality, have been reported in patients presenting with neurological, meningeal, neuropsychic and ocular disorders caused at distance by flukes infecting the liver. Proteomic and mass spectrometry analyses of the Fasciola hepatica excretome/secretome identified numerous, several new, plasminogen-binding proteins enhancing plasmin generation. This may underlie blood-brain barrier leakage whether by many simultaneously migrating, small-sized juvenile flukes in the acute phase, or by breakage of encapsulating formations triggered by single worm tracks in the chronic phase. Blood-brain barrier leakages may subsequently occur due to a fibrinolytic system-dependent mechanism involving plasmin-dependent generation of the proinflammatory peptide bradykinin and activation of bradykinin B2 receptors, after different plasminogen-binding protein agglomeration waves. Interactions between diverse parasitic situations and non-imbalancing fibrinolysis system alterations are for the first time proposed that explain the complexity, heterogeneity and timely variations of neurological disorders. Additionally, inflammation and dilation of blood vessels may be due to contact system–dependent generation bradykinin. This baseline allows for search of indicators to detect neurological risk in fascioliasis patients and experimental work on antifibrinolytic treatments or B2 receptor antagonists for preventing blood-brain barrier leakage.
Human fascioliasis infection sources are analysed for the first time in front of the new worldwide scenario of this disease. These infection sources include foods, water and combinations of both. Ingestion of freshwater wild plants is the main source, with watercress and secondarily other vegetables involved. The problem of vegetables sold in uncontrolled urban markets is discussed. Distinction between infection sources by freshwater cultivated plants, terrestrial wild plants, and terrestrial cultivated plants is made. The risks by traditional local dishes made from sylvatic plants and raw liver ingestion are considered. Drinking of contaminated water, beverages and juices, ingestion of dishes and soups and washing of vegetables, fruits, tubercles and kitchen utensils with contaminated water are increasingly involved. Three methods to assess infection sources are noted: detection of metacercariae attached to plants or floating in freshwater, anamnesis in individual patients, and questionnaire surveys in endemic areas. The infectivity of metacercariae is reviewed both under field conditions and experimentally under the effects of physicochemical agents. Individual and general preventive measures appear to be more complicated than those considered in the past. The high diversity of infection sources and their heterogeneity in different countries underlie the large epidemiological heterogeneity of human fascioliasis throughout.
Globally, the prevalence of tuberculosis (TB) disease is higher in males. This study examined the effect of sex and age on Mycobacterium tuberculosis (Mtb) infection. Demographic and exposure data were collected on household contacts of sputum smear-positive pulmonary TB patients in Brazil. Contacts with tuberculin skin test induration ⩾10 mm at baseline or 12 weeks were considered Mtb infected. The study enrolled 917 household contacts from 160 households; 508 (55.4%) were female, median age was 21.0 years (range 0.30–87.0) and 609 (66.4%) had Mtb infection. The proportion infected increased with age from 63.3% in girls <5 years to 75.4% in women ⩾40 years and from 44.9% in boys <5 years to 73.6% in men ⩾40 years. Multivariable modelling showed the odds of infection increased between age 5 and 14 years among female contacts (OR 1.5 per 5-year age increase; 95% CI 1.1–2.2; P = 0.02) and between ages 0–4 and 15–39 years among male contacts (OR 2.7, 95% CI 0.83–8.9 and 1.1, 95% CI 0.99–1.3 per 5-year age increase; P = 0.10, 0.07, respectively). The study suggests that the age at which Mtb infection increases most is different in females compared with males. Studies are needed to explore whether these findings are due to differences in host susceptibility, exposure outside the household or other factors.
Litter size has a great impact on the profit of swine producers. Uterine development is an important determinant of reproduction efficiency and could hence affect litter size. Chinese Erhualian pig is one of the most prolific breeds in the world, even though large phenotypic variation in litter size was observed within Erhualian sows. To dissect the genetic basis of the phenotypic variation, we herein conducted genome-wide association studies for total number born and number born alive (NBA) of Erhualian sows. In total, one significant single nucleotide polymorphism (SNP) (P<1.78e−06) and 11 suggestive SNPs (P<3.57e−05) were identified on 10 chromosomes, confirming seven previously reported quantitative trait loci (QTL) and uncovering six QTL for litter size or uterus length. One locus on Sus scrofa chromosome (SSC) 13 (79.28 to 90.43 Mb) harbored a cluster of suggestive SNPs associated with multiparous NBA. The SNP (rs81447100) within this region was confirmed to be significantly (P<0.05) associated with litter size in Erhualian (n=313), Sutai (n=173) and Yorkshire (n=488) populations. Retinol binding protein 2 and retinol binding protein 1 functionally related to the development of uterus were located in a region of 2 Mb around rs81447100. Moreover, four genes related to embryo implantation and development were also detected around other significant SNPs. Taken together, our findings provide a potential marker (rs81447100) for the genetic improvement of litter size not only in Chinese Erhualian pigs but also in European commercial pig breeds like Yorkshire, and would facilitate the final identification of causative variant(s) underlying the effect of SSC13 QTL on litter size.
This article documents the development of a community-based drug intervention for low- to mild-risk drug users who surrendered as part of the Philippine government's anti-drug campaign. It highlights the importance of developing evidence-informed drug recovery interventions that are appropriate to the Asian culture and to developing economies. Interviews and consultations with users and community stakeholders reveal the need for an intervention that would improve the drug recovery skills and life skills of users. Evidence-based interventions were adapted using McKleroy and colleagues’ (2006) Map of Adaptation Process (MAP) framework. The resulting intervention reflected the country's collectivist culture, relational values, propensity for indirect and non-verbal communication, and interdependent self-construal. The use of small groups, interactive and creative methodologies, and the incorporation of music and prayer also recognised the importance of these in the Philippine culture.
The discovery of the first electromagnetic counterpart to a gravitational wave signal has generated follow-up observations by over 50 facilities world-wide, ushering in the new era of multi-messenger astronomy. In this paper, we present follow-up observations of the gravitational wave event GW170817 and its electromagnetic counterpart SSS17a/DLT17ck (IAU label AT2017gfo) by 14 Australian telescopes and partner observatories as part of Australian-based and Australian-led research programs. We report early- to late-time multi-wavelength observations, including optical imaging and spectroscopy, mid-infrared imaging, radio imaging, and searches for fast radio bursts. Our optical spectra reveal that the transient source emission cooled from approximately 6 400 K to 2 100 K over a 7-d period and produced no significant optical emission lines. The spectral profiles, cooling rate, and photometric light curves are consistent with the expected outburst and subsequent processes of a binary neutron star merger. Star formation in the host galaxy probably ceased at least a Gyr ago, although there is evidence for a galaxy merger. Binary pulsars with short (100 Myr) decay times are therefore unlikely progenitors, but pulsars like PSR B1534+12 with its 2.7 Gyr coalescence time could produce such a merger. The displacement (~2.2 kpc) of the binary star system from the centre of the main galaxy is not unusual for stars in the host galaxy or stars originating in the merging galaxy, and therefore any constraints on the kick velocity imparted to the progenitor are poor.
Based on unstructured hybrid grid and dynamic overlapping grid technique, numerical simulations of Unsteady Reynolds Averaged Navier-Stokes equations were performed and investigation on isolated propeller aerodynamic characteristics and effects of propeller slipstream on turboprops were undertaken. The computational grid consisted of rotational subzone of propeller and stationary major-zone of aircraft, and walls criterion was used in the automatic hole-cutting procedure. Distance weight interpolation and tri-linear interpolation were developed to transfer information between the rotational and stationary subzones. The boundaries of overlapping grids were optimized for fixed axis rotation. The governing equations were solved by dual-time method and Lower Upper-Symmetric Gauss-Seidel method. The method and grid technique were verified by isolated propeller configuration and the computational results were in well agreement with the experimental data. The grid independence was studied to establish the numerical results. Finally, the flow around a turboprop case was simulated and the influence of propeller slipstream was presented by analyzing the surface pressure contours, profile pressure distribution, vorticity contours and profile streamline. It's indicated that the slipstream accelerates and rotates the free stream flow, changing the local angle of attack, enhancing the downwash effects, affecting the pressure distribution on wing and horizontal tail, as well as increasing the drag coefficient, pitching moment coefficient and the slope of lift coefficient.
The use of limiters may impact both accuracy and resolution of a solution. And the accuracy and resolution are highly dependent on the amount of numerical dissipation in a scheme, so the ability of limiters to control numerical dissipation should be improved. In this view, based on the examination of several classical limiters to control dissipation, a class of general piecewise-linear flux limiters (termed GPL limiters) are presented in this paper for Multi-step time-space-separated unsteady schemes. The GPL limiters can satisfy the second-order TVD criterion and contain some existing limiters such as Superbee and Minmod. Using the decrement of discrete total entropy to represent the amount of numerical dissipation, an entropy dissipation function of GPL limiters is defined with three parameter variables. By proving the monotonicity of this function, a new GPL type limiter (named MDF individually), which can minimize the numerical dissipation and improve the calculation accuracy, is proposed. A high resolution entropy-consistent scheme is obtained by MDF limiter, which will be proved to satisfy entropy stability and entropy consistency. Computational results of this scheme for several 1-D and 2-D Euler test cases are presented, demonstrating the accuracy, monotonicity and robustness of MDF limiter.
Default mode network (DMN) is vulnerable to the effects of APOE genotype. Given the reduced brain volumes and APOE ε 4-related brain changes in elderly carriers, it is less known that whether these changes would influence the functional connectivity and to what extent. This study aimed to examine the functional connectivity within DMN, and its diagnostic value with age-related morphometric alterations considered.
Whole brain and seed-based resting-state functional connectivity (RSFC) analysis were conducted in cognitively normal APOE ε 4 carriers and matched non-carriers (N=38). The absolute values of mean correlation coefficients (z-values) were used as a measure of functional connectivity strength (FCS) between DMN subregions, which were also used to estimate their diagnostic value by receiver-operating characteristic (ROC) curves.
APOE ε 4 carriers demonstrated decreased interhemispheric FCS, particularly between right hippocampal formation (R.HF) and left inferior parietal lobular (L.IPL) (t=3.487, p<0.001). ROC analysis showed that the FCS of R.HF and L.IPL could differentiate APOE ε 4 carriers from healthy counterparts (AUC value=0.734, p=0.025). Moreover, after adjusting the impact of morphometry, the differentiated value of FCS of R.HF and L.IPL was markedly improved (AUC value=0.828, p=0.002).
Our findings suggest that APOE ε 4 allele affects the functional connectivity within posterior DMN, particularly the atrophy-corrected interhemispheric FCS before the clinical expression of neurodegenerative disease.
Much can be learned from terrestrial planets that appear to have had the potential to be habitable, but failed to realize that potential. Mars shows evidence of a once hospitable surface environment. The reasons for its current state, and in particular its thin atmosphere and dry surface, are of great interest for what they can tell us about habitable zone planet outcomes. A main goal of the MAVEN mission is to observe Mars’ atmosphere responses to solar and space weather influences, and in particular atmosphere escape related to space weather ‘storms’ caused by interplanetary coronal mass ejections (ICMEs). Numerical experiments with a data-validated MHD model suggest how the effects of an observed moderately strong ICME compare to what happens during a more extreme event. The results suggest the kinds of solar and space weather conditions that can have evolutionary importance at a planet like Mars.
Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a serious hospital and community-acquired infection and some strains are associated with greater severity. We investigated the clinical variability and molecular characteristics of MRSA infections in Shenzhen, China through a study at nine sentinel hospitals from January to December 2014. MRSA infections were classified as community-associated (CA-MRSA), healthcare-associated (HA-MRSA), and healthcare-associated community-onset (HACO-MRSA). In total, 812 MRSA isolates were collected and 183 of these were selected for further study. Patients with HA-MRSA infections were generally of greater age compared to other groups. Distinct body site and clinical presentations were evident in infected patients, e.g. CA-MRSA (skin and soft tissue, 53%), HA-MRSA (respiratory tract, 22%; surgical site, 20%; trauma wounds, 20%) and HACO-MRSA (mastitis, 47%). In contrast to HA-MRSA, other categories of strains were significantly more susceptible to gentamicin, sulfamethoxazole/trimethoprim, and tetracycline. No resistance to vancomycin or linezolid was recorded. The predominant clonal lineage within each strain category was CC59-t437-SCCmec IV/V-agr I (CA, 51·4%; HA, 28·9%; HACO, 52·9%) which exhibited characteristics of a traditional CA clone together with agr I which is more often associated with HA clones. In conclusion, for the three categories of MRSA infections, there were significant differences in clinical characteristics of patients, but the predominant clone in each category shared a similar genetic background which suggests that transmission of MRSA strains has occurred between the community and hospitals in Shenzhen.
This paper reviews strategies and methods to improve accuracies of genomic predictions from the perspective of a numerically small population. Improvements are realized by influencing one or both of the main factors: (1) improve or increase genomic connections to phenotypic records in training data. (2) Models and strategies to focus genomic predictions on markers closer to the causative variants. Combining populations into a joint reference population results in high improvements when combining populations of the same breed and diminishes as the genetic distance between populations increases. For distantly related breeds sophisticated Bayesian variable selection models in combination with denser markers sets or functional subsets of markers is needed. This is expected to be further improved by the efficient use of sequence information. In addition predictions can be improved by the use of phenotypes of genotyped and non-genotyped cows directly. For a small population the optimal approach will combine the above components.
Small reference populations limit the accuracy of genomic prediction in numerically small breeds, such like Danish Jersey. The objective of this study was to investigate two approaches to improve genomic prediction by increasing size of reference population in Danish Jersey. The first approach was to include North American Jersey bulls in Danish Jersey reference population. The second was to genotype cows and use them as reference animals. The validation of genomic prediction was carried out on bulls and cows, respectively. In validation on bulls, about 300 Danish bulls (depending on traits) born in 2005 and later were used as validation data, and the reference populations were: (1) about 1050 Danish bulls, (2) about 1050 Danish bulls and about 1150 US bulls. In validation on cows, about 3000 Danish cows from 87 young half-sib families were used as validation data, and the reference populations were: (1) about 1250 Danish bulls, (2) about 1250 Danish bulls and about 1150 US bulls, (3) about 1250 Danish bulls and about 4800 cows, (4) about 1250 Danish bulls, 1150 US bulls and 4800 Danish cows. Genomic best linear unbiased prediction model was used to predict breeding values. De-regressed proofs were used as response variables. In the validation on bulls for eight traits, the joint DK-US bull reference population led to higher reliability of genomic prediction than the DK bull reference population for six traits, but not for fertility and longevity. Averaged over the eight traits, the gain was 3 percentage points. In the validation on cows for six traits (fertility and longevity were not available), the gain from inclusion of US bull in reference population was 6.6 percentage points in average over the six traits, and the gain from inclusion of cows was 8.2 percentage points. However, the gains from cows and US bulls were not accumulative. The total gain of including both US bulls and Danish cows was 10.5 percentage points. The results indicate that sharing reference data and including cows in reference population are efficient approaches to increase reliability of genomic prediction. Therefore, genomic selection is promising for numerically small population.
Radio interferometric observations of extragalactic radio sources have been made with antennas at the Haystack Observatory in Massachusetts and the Owens Valley Radio Observatory in California during fourteen separate experiments distributed between September 1976 and May 1978. The components of the baseline vector and the coordinates of the sources were estimated from the data from each experiment separately. The root-weighted-mean-square scatter about the weighted mean (“repeatability”) of the estimates of the length of the 3900 km baseline was approximately 7 cm, and of the source coordinates, approximately or less, except for the declinations of low-declination sources. With the source coordinates all held fixed at the best available, a posteriori, values, and the analyses repeated for each experiment, the repeatability obtained for the estimate of baseline length was 4 cm. From analyses of the data from several experiments simultaneously, estimates were obtained of changes in the x component of pole position and in the Earth's rotation (UT1). Comparison with the corresponding results obtained by the Bureau International de l'Heure (BIH) discloses systematic differences. In particular, the trends in the radio interferometric determinations of the changes in pole position agree more closely with those from the International Polar Motion Service (IPMS) and from the Doppler observations of satellites than with those from the BIH.