Dark Energy and Gravity

I review the problem of dark energy focusing on the cosmological constant as the candidate and discuss its implications for the nature of gravity. Part 1 briefly overviews the currently popular `concordance cosmology' and summarises the evidence for dark energy. It also provides the observational and theoretical arguments in favour of the cosmological constant as the candidate and emphasises why no other approach really solves the conceptual problems usually attributed to the cosmological constant. Part 2 describes some of the approaches to understand the nature of the cosmological constant and attempts to extract the key ingredients which must be present in any viable solution. I argue that (i)the cosmological constant problem cannot be satisfactorily solved until gravitational action is made invariant under the shift of the matter lagrangian by a constant and (ii) this cannot happen if the metric is the dynamical variable. Hence the cosmological constant problem essentially has to do with our (mis)understanding of the nature of gravity. Part 3 discusses an alternative perspective on gravity in which the action is explicitly invariant under the above transformation. Extremizing this action leads to an equation determining the background geometry which gives Einstein's theory at the lowest order with Lanczos-Lovelock type corrections. (Condensed abstract).Comment: Invited Review for a special Gen.Rel.Grav. issue on Dark Energy, edited by G.F.R.Ellis, R.Maartens and H.Nicolai; revtex; 22 pages; 2 figure

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits

Joint analysis of Dark Energy Survey Year 3 data and CMB lensing from SPT and Planck . I. Construction of CMB lensing maps and modeling choices

Joint analyses of cross-correlations between measurements of galaxy positions, galaxy lensing, and lensing of the cosmic microwave background (CMB) offer powerful constraints on the large-scale structure of the Universe. In a forthcoming analysis, we will present cosmological constraints from the analysis of such cross-correlations measured using Year 3 data from the Dark Energy Survey (DES), and CMB data from the South Pole Telescope (SPT) and Planck. Here we present two key ingredients of this analysis: (1) an improved CMB lensing map in the SPT-SZ survey footprint and (2) the analysis methodology that will be used to extract cosmological information from the cross-correlation measurements. Relative to previous lensing maps made from the same CMB observations, we have implemented techniques to remove contamination from the thermal Sunyaev Zel’dovich effect, enabling the extraction of cosmological information from smaller angular scales of the cross-correlation measurements than in previous analyses with DES Year 1 data. We describe our model for the cross-correlations between these maps and DES data, and validate our modeling choices to demonstrate the robustness of our analysis. We then forecast the expected cosmological constraints from the galaxy survey-CMB lensing auto and cross-correlations. We find that the galaxy-CMB lensing and galaxy shear-CMB lensing correlations will on their own provide a constraint on S 8 = σ 8 √ Ω m / 0.3 at the few percent level, providing a powerful consistency check for the DES-only constraints. We explore scenarios where external priors on shear calibration are removed, finding that the joint analysis of CMB lensing cross-correlations can provide constraints on the shear calibration amplitude at the 5% to 10% level

Joint analysis of Dark Energy Survey Year 3 data and CMB lensing from SPT and Planck . II. Cross-correlation measurements and cosmological constraints

Cross-correlations of galaxy positions and galaxy shears with maps of gravitational lensing of the cosmic microwave background (CMB) are sensitive to the distribution of large-scale structure in the Universe. Such cross-correlations are also expected to be immune to some of the systematic effects that complicate correlation measurements internal to galaxy surveys. We present measurements and modeling of the cross-correlations between galaxy positions and galaxy lensing measured in the first three years of data from the Dark Energy Survey with CMB lensing maps derived from a combination of data from the 2500     deg 2 SPT-SZ survey conducted with the South Pole Telescope and full-sky data from the Planck satellite. The CMB lensing maps used in this analysis have been constructed in a way that minimizes biases from the thermal Sunyaev Zel’dovich effect, making them well suited for cross-correlation studies. The total signal-to-noise of the cross-correlation measurements is 23.9 (25.7) when using a choice of angular scales optimized for a linear (nonlinear) galaxy bias model. We use the cross-correlation measurements to obtain constraints on cosmological parameters. For our fiducial galaxy sample, which consist of four bins of magnitude-selected galaxies, we find constraints of Ω m = 0.272 + 0.032 − 0.052 and S 8 ≡ σ 8 √ Ω m / 0.3 = 0.736 + 0.032 − 0.028 ( Ω m = 0.245 + 0.026 − 0.044 and S 8 = 0.734 + 0.035 − 0.028 ) when assuming linear (nonlinear) galaxy bias in our modeling. Considering only the cross-correlation of galaxy shear with CMB lensing, we find Ω m = 0.270 + 0.043 − 0.061 and S 8 = 0.740 + 0.034 − 0.029 . Our constraints on S 8 are consistent with recent cosmic shear measurements, but lower than the values preferred by primary CMB measurements from Planck

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals where it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologs. Using RNA-sequencing, we show how 5’ splice site usage is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 bp region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide

Variation in neurosurgical management of traumatic brain injury

Background: Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods: A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results: The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion: Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care

Real-world Associations of US Cystic Fibrosis Newborn Screening Programs with Nutritional and Pulmonary Outcomes

Importance: Newborn screening (NBS) for cystic fibrosis (CF) has been universal in the US since 2010, but its association with clinical outcomes is unclear. Objective: To describe the real-world effectiveness of NBS programs for CF in the US on outcomes up to age 10 years. Design, Setting, and Participants: This was a retrospective cohort study using CF Foundation Patient Registry data from January 1, 2000, to December 31, 2018. The staggered implementation of NBS programs by state was used to compare longitudinal outcomes among children in the same birth cohort born before vs after the implementation of NBS for CF in their state of birth. Participants included children with an established diagnosis of CF born between January 1, 2000, to December 31, 2018, in any of the 44 states that implemented NBS for CF between 2003 and 2010. Data were analyzed from October 5, 2020, to April 22, 2022. Exposures: Birth before vs after the implementation of NBS for CF in the state of birth. Main Outcomes and Measures: Longitudinal trajectory of height and weight percentiles from diagnosis, lung function (forced expiratory volume in 1 second, [FEV1] percent predicted) from age 6 years, and age at initial and chronic infection with Pseudomonas aeruginosa using linear mixed-effects and time-to-event models adjusting for birth cohort and potential confounders. Results: A total of 9571 participants (4713 female participants [49.2%]) were eligible for inclusion, with 4510 (47.1%) in the pre-NBS cohort. NBS was associated with higher weight and height percentiles in the first year of life (weight, 6.0; 95% CI, 3.1-8.4; height, 6.6; 95% CI, 3.8-9.3), but these differences decreased with age. There was no association between NBS and FEV1at age 6 years, but the percent-predicted FEV1did increase more rapidly with age in the post-NBS cohort. NBS was associated with older age at chronic P aeruginosa infection (hazard ratio, 0.69; 95% CI, 0.54-0.89) but not initial P aeruginosa infection (hazard ratio, 0.88; 95% CI, 0.77-1.01). Conclusions and Relevance: NBS for CF in the US was associated with improved nutritional status up to age 10 years, a more rapid increase in lung function, and delayed chronic P aeruginosa infection. In the future, as highly effective modulator therapies become available for infants with CF, NBS will allow for presymptomatic initiation of these disease-modifying therapies before irreversible organ damage.. © 2022 American Medical Association. All rights reserved.12 month embargo; published online: 01 August 2022This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]