Autosomal-dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation

We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole-exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A > G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations.We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole-exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A > G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations

Examining the Decline in the C~IV Content of the Universe over 4.3 ≲ z ≲ 6.3 using the E-XQR-30 Sample

Intervening C iv absorbers are key tracers of metal-enriched gas in galaxy haloes over cosmic time. Previous studies suggest that the C iv cosmic mass density (⁠[Math Processing Error]⁠) decreases slowly over 1.5 [Math Processing Error] 5 before declining rapidly at z ≳ 5, but the cause of this downturn is poorly understood. We characterize the [Math Processing Error] evolution over 4.3 ≲ z ≲ 6.3 using 260 absorbers found in 42 XSHOOTER spectra of z ∼ 6 quasars, of which 30 come from the ESO Large Program XQR-30. The large sample enables us to robustly constrain the rate and timing of the downturn. We find that [Math Processing Error] decreases by a factor of 4.8 ± 2.0 over the ∼300 Myr interval between z ∼ 4.7 and ∼5.8. The slope of the column density (log N) distribution function does not change, suggesting that C iv absorption is suppressed approximately uniformly across 13.2 ≤ log N/cm−2 < 15.0. Assuming that the carbon content of galaxy haloes evolves as the integral of the cosmic star formation rate density (with some delay due to stellar lifetimes and outflow travel times), we show that chemical evolution alone could plausibly explain the fast decline in [Math Processing Error] over 4.3 ≲ z ≲ 6.3. However, the C iv/C ii ratio decreases at the highest redshifts, so the accelerated decline in [Math Processing Error] at z ≳ 5 may be more naturally explained by rapid changes in the gas ionization state driven by evolution of the UV background towards the end of hydrogen reionization

Bovine Lactoferrin Prevents Invasive Fungal Infections in Very Low Birth Weight Infants: A Randomized Controlled Trial.

BACKGROUND: Lactoferrin is a mammalian milk glycoprotein involved in innate immunity. Recent data show that bovine lactoferrin (bLF) prevents late-onset sepsis in preterm very low birth weight (VLBW) neonates. METHODS: This is a secondary analysis of data from a multicenter randomized controlled trial where preterm VLBW neonates randomly received bLF (100 mg/day; group A1), bLF + Lactobacillus rhamnosus GG (10(6) colony-forming units per day; group A2), or placebo (group B) for 6 weeks. Here we analyze the incidence rates of fungal colonization, invasive fungal infection (IFI), and rate of progression from colonization to infection in all groups. RESULTS: This study included 472 neonates whose clinical, nutritional, and demographical characteristics were similar. Overall, the incidence of fungal colonization was comparable (17.6%, 16.6%, and 18.5% in A1, A2, and B, respectively; P = .89 [A1] and .77 [A2]). In contrast, IFIs were significantly decreased in A1 and A2 (0.7% and 2.0%, respectively) compared with B (7.7%; P = .002 [A1] and .02 [A2]), and this was significantly true both in <1000 g (0.9% [A1] and 5.6% [A2], vs 15.0%) and in 1001 to 1500 g infants (0% and 0% vs 3.7%). The progression rate colonization-infection was significantly lower in the bLF groups: 3.7% (A1) and 12% (A2), vs 41.9%; P < .001 (A1) and P = .02 (A2). No IFI-attributable deaths occurred in the treatment groups, versus 2 in placebo. No adverse effects or intolerances occurred. CONCLUSIONS: Prophylactic oral administration of bLF reduces the incidence of IFI in preterm VLBW neonates. No effect is seen on colonization. The protective effect on IFI is likely due to limitation of ability of fungal colonies to progress toward invasion and systemic disease in colonized infants

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Pathological Complete Response in Patients With Resected Pancreatic Adenocarcinoma After Preoperative Chemotherapy

Importance: Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking. Objective: To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy. Design, Setting, and Participants: This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months. Exposures: Preoperative chemotherapy (with or without radiotherapy) followed by resection. Main Outcomes and Measures: The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively. Results: Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P &lt; .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89). Conclusions and Relevance: This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma

Ecoacoustics and multispecies semiosis: naming, semantics, semiotic characteristics, and competencies

Biosemiotics to date has focused on the exchange of signals between organisms, in line with bioacoustics; consideration of the wider acoustic environment as a semiotic medium is under-developed. The nascent discipline of ecoacoustics, that investigates the role of environmental sound in ecological processes and dynamics, fills this gap. In this paper we introduce key ecoacoustic terminology and concepts in order to highlight the value of ecoacoustics as a discipline in which to conceptualise and study intra- and interspecies semiosis. We stress the inherently subjective nature of all sensory scapes (vivo-, land-, vibro- and soundscapes) and propose that they should always bear an organismic attribution. Key terms to describe the sources (geophony, biophony, anthropophony, technophony) and scales (sonotopes, soundtopes, sonotones) of soundscapes are described. We introduce epithets for soundscapes to point to the degree to which the global environment is implicated in semiosis (latent, sensed and interpreted soundscapes); terms for describing key ecological structures and processes (acoustic community, acoustic habitat, ecoacoustic events) and examples of ecoacoustic events (choruses and noise) are described. The acoustic eco-field is recognized as the semiotic model that enables soniferous species to intercept core resources like food, safety and roosting places. We note that whilst ecoacoustics to date has focused on the critical task of the development of metrics for application in conservation and biodiversity assessment, these can be enriched by advancing conceptual and theoretical foundations. Finally, the mutual value of integrating ecoacoustic and biosemiotics perspectives is considered

XQR-30: The ultimate XSHOOTER quasar sample at the reionization epoch

The final phase of the reionization process can be probed by rest-frame UV absorption spectra of quasars at z ≳ 6, shedding light on the properties of the diffuse intergalactic medium within the first Gyr of the Universe. The ESO Large Programme 'XQR-30: the ultimate XSHOOTER legacy survey of quasars at z ≃ 5.8-6.6' dedicated ∼250 h of observations at the VLT to create a homogeneous and high-quality sample of spectra of 30 luminous quasars at z ∼6, covering the rest wavelength range from the Lyman limit to beyond the Mg ii emission. Twelve quasar spectra of similar quality from the XSHOOTER archive were added to form the enlarged XQR-30 sample, corresponding to a total of ∼350 h of on-source exposure time. The median effective resolving power of the 42 spectra is R ≃ 11 400 and 9800 in the VIS and NIR arm, respectively. The signal-to-noise ratio per 10 km s-1 pixel ranges from ∼11 to 114 at λ ≃ 1285 Å rest frame, with a median value of ∼29. We describe the observations, data reduction, and analysis of the spectra, together with some first results based on the E-XQR-30 sample. New photometry in the H and K bands are provided for the XQR-30 quasars, together with composite spectra whose characteristics reflect the large absolute magnitudes of the sample. The composite and the reduced spectra are released to the community through a public repository, and will enable a range of studies addressing outstanding questions regarding the first Gyr of the Universe