The organization of frequency and binaural cues in the gerbil inferior colliculus: GRAÑA et al.

The inferior colliculus (IC) is the common target of separate pathways that transmit different types of auditory information. Beyond tonotopy, little is known about the organization of response properties within the 3-dimensional layout of the auditory midbrain in most species. Through study of interaural time difference (ITD) processing, the functional properties of neurons can be readily characterized and related to specific pathways. To characterize the representation of ITDs relative to the frequency and hodological organization of the IC, the properties of neurons were recorded and the sites recovered histologically. Subdivisions of the IC were identified based on cytochrome oxidase (CO) histochemistry. The results were plotted within a framework formed by an MRI atlas of the gerbil brain. The central nucleus was composed of two parts, and lateral and dorsal cortical areas were identified. The lateral part of the central nucleus had the highest CO activity in the IC and a high proportion of neurons sensitive to ITDs. The medial portion had lower CO activity and fewer ITD-sensitive neurons. A common tonotopy with a dorsolateral to ventromedial gradient of low to high frequencies spanned the two regions. The distribution of physiological responses was in close agreement with known patterns of ascending inputs. An understanding of the 3-dimensional organization of the IC is needed to specify how the single tonotopic representation in the IC central nucleus leads to the multiple tonotopic representations in core areas of the auditory cortex

Recall Bias in Client-Reported Outcomes in Canine Orthopaedic Patients Using Clinical Metrology Instruments.

Objective The aim of this study was to determine the accuracy of client recollection of their dogs' preconsultation status using clinical metrology instruments such as the Liverpool Osteoarthritis in Dogs (LOAD) and Canine Brief Pain Inventory (CBPI) questionnaires in dogs presenting to a referral orthopaedic clinic.Study design This is a longitudinal prospective cohort study of client-owned dogs presenting for investigations of lameness (n = 217). LOAD and CBPI questionnaires were completed by the owners at the first consultation (T0). Owners were contacted at 2 (T1), 6 (T2), and 12 (T3) months and asked to recall their dogs' T0 status by completing another LOAD and CBPI questionnaire. The agreement between the T0 and recalled LOAD and CBPI scores was determined using the two-way mixed effects intraclass correlation coefficient (ICC). The Wilcoxon signed-rank test was used to determine the difference between scores.Results For the LOAD scores, there was moderate agreement between T0 and T1 (ICC: 0.64) and T0 and T2 (ICC: 0.53) scores and poor agreement between T0 and T3 (ICC: 0.496). For the CBPI Pain Severity Scores, there was poor agreement between T0 and all three subsequent time points (ICC Conclusion The LOAD and CBPI questionnaires are subject to recall bias. Studies reporting retrospectively acquired CMI data should be interpreted with caution

Osteoinduction of Umbilical Cord and Palate Periosteum–Derived Mesenchymal Stem Cells on Poly(Lactic-Co-Glycolic) Acid Nanomicrofibers

The need for tissue engineered bone to treat complex craniofacial bone defects secondary to congenital anomalies, trauma, and cancer extirpation is sizeable. Traditional strategies for treatment have focused on autologous bone in younger patients and bone substitutes in older patients. However, the capacity for merging new technologies, including the creation of nano and microfiber scaffolds with advances in natal sources of stem cells, is crucial to improving our treatment options. The advantages of using smaller diameter fibers for scaffolding are two-fold: the similar fiber diameters mimic the in vivo extracellular matrix construct;, and smaller fibers also provide a dramatically increased surface area for cell-scaffold interactions. In this study, we compare the capacity for a polymer with Federal Drug Administration (FDA) approval for use in humans, poly-co-glycolytic acid (PLGA) from Delta polymer, to support osteoinduction of mesenchymal stem cells (MSCs) harvested from the umbilical cord (UC) and palate periosteum (PP). Proliferation of both UC- and PP-derived MSCs was improved on PLGA scaffolds. PLGA scaffolds promoted UC MSC differentiation (indicated by earlier gene expression and higher calcium deposition), but not in PP-derived MSCs. UC-derived MSCs on PLGA nano-micro-fiber scaffolds have potential clinical utility in providing solutions for craniofacial bone defects, with the added benefit of earlier availability

The Compound Action Potential in Subjects Receiving a Cochlear Implant

The compound action potential (CAP) is a purely neural component of the cochlea’s response to sound, and may provide information about the existing neural substrate in cochlear implant (CI) subjects that can help account for variance in speech perception outcomes

Biochemical Properties of Tissue-Engineered Cartilage

Microtia is treated with rib cartilage sculpting and staged procedures; though aesthetically pleasing, these constructs lack native ear flexibility. Tissue-engineered (TE) elastic cartilage may bridge this gap; however, TE cartilage implants lead to hypertrophic changes with calcification and loss of flexibility. Retaining flexibility in TE cartilage must focus on increased elastin, maintained collagen II, decreased collagen X, with prevention of calcification. This study compares biochemical properties of human cartilage to TE cartilage from umbilical cord mesenchymal stem cells (UCMSCs). Our goal is to establish a baseline for clinically useful TE cartilage

TOI-1338 : TESS' first transiting circumbinary planet

Funding: Funding for the DPAC has been provided by national institutions, in particular, the institutions participating in the Gaia Multilateral Agreement. W.F.W. and J.A.O.thank John Hood Jr. for his generous support of exoplanet research at SDSU. Support was also provided and acknowledged through NASA Habitable Worlds grant 80NSSC17K0741 and NASA XRP grant 80NSSC18K0519. This work is partly supported by NASA Habitable Worlds grant 80NSSC17K0741. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under grant No.(DGE-1746045). A.H.M.J.T. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 803193/BEBOP) and from a Leverhulme Trust Research Project grant No. RPG-2018-418. A.C. acknowledges support by CFisUC strategic project (UID/FIS/04564/2019).We report the detection of the first circumbinary planet (CBP) found by Transiting Exoplanet Survey Satellite (TESS). The target, a known eclipsing binary, was observed in sectors 1 through 12 at 30 minute cadence and in sectors 4 through 12 at 2 minute cadence. It consists of two stars with masses of 1.1 M⊙ and 0.3 M⊙ on a slightly eccentric (0.16), 14.6 day orbit, producing prominent primary eclipses and shallow secondary eclipses. The planet has a radius of ∼6.9 R⊕ and was observed to make three transits across the primary star of roughly equal depths (∼0.2%) but different durations—a common signature of transiting CBPs. Its orbit is nearly circular (e ≍ 0.09) with an orbital period of 95.2 days. The orbital planes of the binary and the planet are aligned to within ∼1°. To obtain a complete solution for the system, we combined the TESS photometry with existing ground-based radial-velocity observations in a numerical photometric-dynamical model. The system demonstrates the discovery potential of TESS for CBPs and provides further understanding of the formation and evolution of planets orbiting close binary stars.Publisher PDFPeer reviewe

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

A genome-wide association study of total child psychiatric problems scores

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.</p

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570