Duchenne muscular dystrophy is a monogenic disease potentially treatable by gene replacement. Use of recombinant adeno-associated virus (AAV) will ultimately require a vascular approach to broadly ...transduce muscle cells. We tested the impact of preexisting AAV antibodies on microdystrophin expression following vascular delivery to nonhuman primates. Rhesus macaques were treated by isolated limb perfusion using a fluoroscopically guided catheter. In addition to serostatus stratification, the animals were placed into one of the three immune suppression groups: no immune suppression, prednisone, and triple immune suppression (prednisone, tacrolimus, and mycophenolate mofetil). The animals were analyzed for transgene expression at 3 or 6 months. Microdystrophin expression was visualized in AAV, rhesus serotype 74 sero-negative animals (mean: 48.0 ± 20.8%) that was attenuated in sero-positive animals (19.6 ± 18.7%). Immunosuppression did not affect transgene expression. Importantly, removal of AAV binding antibodies by plasmapheresis in AAV sero-positive animals resulted in high-level transduction (60.8 ± 18.0%), which is comparable with that of AAV sero-negative animals (53.7 ± 7.6%), whereas non-pheresed sero-positive animals demonstrated significantly lower transduction levels (10.1 ± 6.0%). These data support the hypothesis that removal of AAV binding antibodies by plasmapheresis permits successful and sustained gene transfer in the presence of preexisting immunity (natural infection) to AAV.
Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls ...and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.
Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results ...from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17,989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.
Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought ...replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10(-11) and 2.7 × 10(-11)), which were also in strong linkage disequilibrium (r(2)=0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10(-05)) and Parkinson's disease pathways (P-value=3.6 × 10(-05)).
von Willebrand disease (VWD) is a bleeding disorder caused by inherited defects in the concentration, structure, or function of von Willebrand factor (VWF). VWD is classified into three primary ...categories. Type 1 includes partial quantitative deficiency, type 2 includes qualitative defects, and type 3 includes virtually complete deficiency of VWF. VWD type 2 is divided into four secondary categories. Type 2A includes variants with decreased platelet adhesion caused by selective deficiency of high‐molecular‐weight VWF multimers. Type 2B includes variants with increased affinity for platelet glycoprotein Ib. Type 2M includes variants with markedly defective platelet adhesion despite a relatively normal size distribution of VWF multimers. Type 2N includes variants with markedly decreased affinity for factor VIII. These six categories of VWD correlate with important clinical features and therapeutic requirements. Some VWF gene mutations, alone or in combination, have complex effects and give rise to mixed VWD phenotypes. Certain VWD types, especially type 1 and type 2A, encompass several pathophysiologic mechanisms that sometimes can be distinguished by appropriate laboratory studies. The clinical significance of this heterogeneity is under investigation, which may support further subdivision of VWD type 1 or type 2A in the future.
Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging ...from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19,713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64-0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother-offspring (r=0.42; P-value=3.60 × 10(-61)) than father-offspring correlation (r=0.33; P-value=7.01 × 10(-5)), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10(-5)). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10(-30)) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10(-23)) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10(-10)). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.
We present photometry and spectroscopy for 27 pulsating hydrogen-atmosphere white dwarfs (DAVs; a.k.a. ZZ Ceti stars) observed by the Kepler space telescope up to K2 Campaign 8, an extensive ...compilation of observations with unprecedented duration (>75 days) and duty cycle (>90%). The space-based photometry reveals pulsation properties previously inaccessible to ground-based observations. We observe a sharp dichotomy in oscillation mode line widths at roughly 800 s, such that white dwarf pulsations with periods exceeding 800 s have substantially broader mode line widths, more reminiscent of a damped harmonic oscillator than a heat-driven pulsator. Extended Kepler coverage also permits extensive mode identification: we identify the spherical degree of 87 out of 201 unique radial orders, providing direct constraints of the rotation period for 20 of these 27 DAVs, more than doubling the number of white dwarfs with rotation periods determined via asteroseismology. We also obtain spectroscopy from 4 m-class telescopes for all DAVs with Kepler photometry. Using these homogeneously analyzed spectra, we estimate the overall mass of all 27 DAVs, which allows us to measure white dwarf rotation as a function of mass, constraining the endpoints of angular momentum in low- and intermediate-mass stars. We find that 0.51-0.73 M white dwarfs, which evolved from 1.7-3.0 M ZAMS progenitors, have a mean rotation period of 35 hr with a standard deviation of 28 hr, with notable exceptions for higher-mass white dwarfs. Finally, we announce an online repository for our Kepler data and follow-up spectroscopy, which we collect at http://k2wd.org.
Here, we present a sample-variance-limited measurement of the temperature power spectrum (TT) of the cosmic microwave background using observations of a ~1500 deg2 field made by the SPT-3G in 2018. ...We report multifrequency power spectrum measurements at 95, 150, and 220 GHz covering the angular multipole range 750 ≤ ℓ < 3000. We combine this TT measurement with the published polarization power spectrum measurements from the 2018 observing season and update their associated covariance matrix to complete the SPT-3G 2018 TT/TE/EE dataset. This is the first analysis to present cosmological constraints from SPT TT, TE, and EE power spectrum measurements jointly. We blind the cosmological results and subject the dataset to a series of consistency tests at the power spectrum and parameter level. We find excellent agreement between frequencies and spectrum types and our results are robust to the modeling of astrophysical foregrounds. We report results for Λ CDM and a series of extensions, drawing on the following parameters: the amplitude of the gravitational lensing effect on primary power spectra AL, the effective number of neutrino species Neff, the primordial helium abundance YP, and the baryon clumping factor due to primordial magnetic fields b. We find that the SPT-3G 2018 TT/TE/EE data are well fit by Λ CDM with a probability to exceed of 15%. For Λ CDM, we constrain the expansion rate today to H0 = 68.3 ± 1.5 km s–1 Mpc–1 and the combined structure growth parameter to S8 = 0.797 ± 0.042. The SPT-based results are effectively independent of Planck, and the cosmological parameter constraints from either dataset are within <1σ of each other. The addition of temperature data to the SPT-3G TE/EE power spectra improves constraints by 8–27% for each of the Λ CDM cosmological parameters. When additionally fitting AL, Neff, or Neff + YP, the posteriors of these parameters tighten by 5–24%. In the case of primordial magnetic fields, complete TT/TE/EE power spectrum measurements are necessary to break the degeneracy between b and ns, the spectral index of primordial density perturbations. We report a 95% confidence upper limit from SPT-3G data of b<1.0. The cosmological constraints in this work are the tightest from SPT primary power spectrum measurements to date and the analysis forms a new framework for future SPT analyses.
Background
Nomenclature for mesh insertion during ventral hernia repair is inconsistent and confusing. Several terms, including ‘inlay’, ‘sublay’ and ‘underlay’, can refer to the same anatomical ...planes in the indexed literature. This frustrates comparisons of surgical practice and may invalidate meta‐analyses comparing surgical outcomes. The aim of this study was to establish an international classification of abdominal wall planes.
Methods
A Delphi study was conducted involving 20 internationally recognized abdominal wall surgeons. Different terms describing anterior abdominal wall planes were identified via literature review and expert consensus. The initial list comprised 59 possible terms. Panellists completed a questionnaire that suggested a list of options for individual abdominal wall planes. Consensus on a term was predefined as occurring if selected by at least 80 per cent of panellists. Terms scoring less than 20 per cent were removed.
Results
Voting started August 2018 and was completed by January 2019. In round 1, 43 terms (73 per cent) were selected by less than 20 per cent of panellists and 37 new terms were suggested, leaving 53 terms for round 2. Four planes reached consensus in round 2, with the terms ‘onlay’, ‘inlay’, ‘preperitoneal’ and ‘intraperitoneal’. Thirty‐five terms (66 per cent) were selected by less than 20 per cent of panellists and were removed. After round 3, consensus was achieved for ‘anterectus’, ‘interoblique’, ‘retro‐oblique’ and ‘retromuscular’. Default consensus was achieved for the ‘retrorectus’ and ‘transversalis fascial’ planes.
Conclusion
Consensus concerning abdominal wall planes was agreed by 20 internationally recognized surgeons. Adoption should improve communication and comparison among surgeons and research studies.
Antecedentes
La nomenclatura de la inserción de una malla para la reparación de una hernia incisional ventral (ventral hernia, VH) es inconsistente y confusa. En la literatura indexada se usan varios términos, tales como ‘inlay’, ‘sublay’, y ‘underlay’ que pueden referirse a los mismos planos anatómicos. Este hecho frustra las comparaciones de técnicas quirúrgicas e invalida los metaanálisis que comparan resultados quirúrgicos en función del plano de inserción de la malla. En consecuencia, el objetivo de este estudio fue establecer una clasificación internacional de los planos de la pared abdominal (International Classification of Abdominal Wall Planes, ICAP).
Métodos
Se realizó un estudio Delphi, en el que participaron 20 cirujanos de pared abdominal reconocidos internacionalmente. Se identificaron diferentes términos que describían los planos de la pared abdominal anterior mediante la revisión de la literatura y el consenso de expertos. La lista inicial incluía 59 términos posibles. Los panelistas completaron un cuestionario que sugería una lista de opciones para los planos individuales de la pared abdominal. El consenso sobre un término fue predefinido cuando dicho término había sido seleccionado por ≥ 80% de panelistas. Se eliminaron los términos con una puntuación < 20%.
Resultados
La votación comenzó en agosto de 2018 y se completó en enero de 2019. Durante la Ronda 1, 43 (73%) términos fueron seleccionados por < 20% de los panelistas y se sugirieron 37 términos nuevos, dejando 53 términos para la Ronda 2. Cuatro planos alcanzaron un consenso en la Ronda 2 con los términos ‘onlay’, ‘inlay’, ‘pre‐peritoneal’ e ‘intra‐peritoneal’. Treinta y cinco (66%) términos fueron seleccionados por < 20% de los panelistas y fueron eliminados. Después de la Ronda 3, se logró un consenso para ‘anterectus’ (ante‐recto), ‘interoblique’ (inter‐oblicuo), ‘retrooblique’ (retro‐oblicuo) y ‘retromuscular’. Se alcanzó un consenso por defecto para los planos ‘retrorectus’ (retro‐recto) y ‘transversalis fascial’ (fascial transverso).
Conclusión
La ICAP ha sido desarrollada por el consenso de 20 cirujanos reconocidos internacionalmente. Su implementación debería mejorar la comunicación y la comparación entre cirujanos y estudios de investigación.
Current nomenclature for abdominal wall planes is inconsistent; this confuses clinical practice and frustrates comparative studies. A Delphi study was performed, involving 20 international hernia experts, to define abdominal wall planes precisely. Via consensus, an international classification of abdominal wall planes was established.
Order created by consensus
Understanding how atoms interact with hot dense matter is essential for astrophysical and laboratory plasmas. Interactions in high-density plasmas broaden spectral lines, providing a rare window into ...interactions that govern, for example, radiation transport in stars. However, up to now, spectral line-shape theories employed at least one of three common approximations: second-order Taylor treatment of broadening operator, dipole-only interactions between atom and plasma, and classical treatment of perturbing electrons. In this Letter, we remove all three approximations simultaneously for the first time and test the importance for two applications: neutral hydrogen and highly ionized magnesium and oxygen. We found 15%-50% change in the spectral line widths, which are sufficient to impact applications including white-dwarf mass determination, stellar-opacity research, and laboratory plasma diagnostics.
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