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Abstract Age-related cataracts is a highly prevalent eye disorder that results in the clouding of the crystalline lens and is one of the leading causes of visual impairment and blindness. The disease is influenced by multiple factors including genetics, prolonged exposure to ultraviolet radiation, and a history of diabetes. However, the extent to which each of these factors contributes to the development of cataracts remains unclear. Our study identified 101 independent genome-wide significant loci, 57 of which are novel. We identified multiple genes and biological pathways associated with the cataracts, including four drug-gene interactions. Our results suggest a causal association between type 1 diabetes and cataracts. Also, we highlighted a surrogate measure of UV light exposure as a marker of cataract risk in adults.

Oral reading fluency is crucial to successful reading comprehension. Difficulties to effectively read aloud with fluency often pose challenges to develop more complex reading skills. Although there exists research on teaching oral reading fluency using repeated readings, there is limited research on the effectiveness of listening while reading with error correction procedures for children struggling with reading. Using a single-case, alternating treatments design, this research evaluated the effectiveness of repeated readings with word rehearsal when compared to listening while reading with error correction on the number of words read correctly per minute for three 2nd graders who struggled with reading. In addition, silent reading was assessed as a control condition in this study. The results of this research indicated an acceleration in the correct number of words read as a result of practice, as well as a deceleration of incorrect words read, overall, for both reading interventions. Listening while reading with error correction and repeated reading with word rehearsal did not seem produce a larger effect than the other. However, the implementation of silent reading resulted in both correct and incorrect words accelerating. This may suggest that silent reading may not be as effective as repeated reading and listening while reading. Furthermore, best-quality reading instruction appears to need some form of corrective feedback (e.g., error correction or word rehearsal) to obtain best outcomes for students.

Abstract Background Optical coherence tomography (OCT) is a non-invasive technique to measure retinal layer thickness, providing insights into retinal ganglion cell integrity. Studies have shown reduced retinal nerve fibre layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thickness in Parkinson’s disease (PD) patients. However, it is unclear if there is a common genetic overlap between the macula and peripapillary estimates with PD and if the genetic risk of PD is associated with changes in ganglion cell integrity estimates in young adults. Method Western Australian young adults underwent OCT imaging. Their pRNFL, GCIPL, and overall retinal thicknesses were recorded, as well as their longitudinal changes between ages 20 and 28. Polygenic risk scores (PRS) were estimated for each participant based on genome-wide summary data from the largest PD genome-wide association study conducted to date. We further evaluated whether PD PRS was associated with changes in thickness at a younger age. To evaluate the overlap between retinal integrity estimates and PD, we annotated and prioritised genes using mBAT-combo and performed colocalisation through the GWAS pairwise method and HyPrColoc. We used a multi-omic approach and single-cell expression data of the retina and brain through a Mendelian randomisation framework to evaluate the most likely causal genes. Genes prioritised were analysed for missense variants that could have a pathogenic effect using AlphaMissense. Results We found a significant association between the Parkinson’s disease polygenic risk score (PD PRS) and changes in retinal thickness in the macula of young adults assessed at 20 and 28 years of age. Gene-based analysis identified 27 genes common to PD and retinal integrity, with a notable region on chromosome 17. Expression analyses highlighted NSF, CRHR1, and KANSL1 as potential causal genes shared between PD and ganglion cell integrity measures. CRHR1 showed consistent results across multiple omics levels. Interpretation Our findings suggest that retinal measurements, particularly in young adults, could be a potential marker for PD risk, indicating a genetic overlap between retinal structural integrity and PD. The study highlights specific genes and loci, mainly on chromosome 17, as potential shared etiological factors for PD and retinal changes. Our results highlight the importance of further longitudinal studies to validate retinal structural metrics as early indicators of PD predisposition.

Frontotemporal dementia (FTD) has a complex genetic etiology, where the precise mechanisms underlying the selective vulnerability of brain regions remain unknown. We leveraged summary-based data from genome-wide association studies (GWAS) and performed LD score regression to estimate pairwise genetic correlations between FTD risk and cortical brain imaging. Then, we isolated specific genomic loci with a shared etiology between FTD and brain structure. We also performed functional annotation, summary-data-based Mendelian randomization for eQTL using human peripheral blood and brain tissue data, and evaluated the gene expression in mice targeted brain regions to better understand the dynamics of the FTD candidate genes. Pairwise genetic correlation estimates between FTD and brain morphology measures were high but not statistically significant. We identified 5 brain regions with a strong genetic correlation (rg > 0.45) with FTD risk. Functional annotation identified 8 protein-coding genes. Building upon these findings, we show in a mouse model of FTD that cortical N-ethylmaleimide sensitive factor (NSF) expression decreases with age. Our results highlight the molecular and genetic overlap between brain morphology and higher risk for FTD, specifically for the right inferior parietal surface area and right medial orbitofrontal cortical thickness. In addition, our findings implicate NSF gene expression in the etiology of FTD.

Abstract Most patients with late-onset neurodegenerative diseases such as Alzheimer’s and Parkinson’s have a complex aetiology resulting from numerous genetic risk variants of small effects located across the genome, environmental factors, and the interaction between genes and environment. Over the last decade, genome-wide association studies (GWAS) and post-GWAS analyses have shed light on the polygenic architecture of these diseases, enabling polygenic risk scores (PRS) to estimate an individual’s relative genetic liability for presenting with the disease. PRS can screen and stratify individuals based on their genetic risk, potentially years or even decades before the onset of clinical symptoms. An emerging body of evidence from various research studies suggests that genetic susceptibility to late-onset neurodegenerative diseases might impact early life outcomes, including cognitive function, brain structure and function, and behaviour. This article summarises recent findings exploring the potential impact of genetic susceptibility to neurodegenerative diseases on early life outcomes. A better understanding of the impact of genetic susceptibility to neurodegenerative diseases early in life could be valuable in disease screening, detection, and prevention and in informing treatment strategies before significant neural damage has occurred. However, ongoing studies have limitations. Overall, our review found several studies focused on APOE haplotypes and Alzheimer’s risk, but a limited number of studies leveraging polygenic risk scores or focused on genetic susceptibility to other late-onset conditions.

The limits of the pulp screening operation can be defined as the maximum throughput before the apertures start to plug permanently. This two-part article sought insights into the limits of screening operation. In part two, the operational window of the screen was characterized by performing a series of screening trials with different pulp furnishes, where the plugging point was conventionally measured with the pressure signal. The limits of operation, given by a slot velocity and rotor speed contour, showed a robust linear relationship at the point of plugging, which depended on the ratio of the fibre length to aperture size. For size ratios less than 1.5, the screen did not plug under the conditions tested. In addition, the plugging detection tool was conceptualized in part one based on the kurtosis of the distribution of fluctuation peaks, and it was employed here. Effectively, deviations from the Gaussian distribution of the pressure fluctuation peaks signal the onset of screen plugging. Thus, the utility of this tool was confirmed for detecting plugs using readily available pressure fluctuation data in pilot-scale screening operations.

Naphthol Green B (NGB) is a synthetic azo dye widely used in various industries, including textiles and leathers. NGB poses significant environmental and ecological concerns when released into natural water systems. This paper investigates the decolorization of NGB using UV/sulfite system. The % decolorization of NGB was optimized using 32 Full Factorial Design (FFD), and the ANOVA results show that the model has a good fit for the data (R2 = 99.54 %, R2(adj) = 98.76 %) and the significant factors contributing to the % decolorization are A, B, A2, and B2 where A = mM sulfite and B = pH. The model predicted ≥100 % decolorization with the optimum conditions 12 mM sulfite and pH 10. An actual experiment was conducted to verify the response, resulting in 96.2 % decolorization which is in good agreement with the model.

BackgroundGlioblastoma is one of the most devastating cancer worldwide based on its locally aggressive behavior and because it cannot be cured by current therapies. Defects in alternative splicing process are frequent in cancer. Recently, we demonstrated that dysregulation of the spliceosome is directly associated with glioma development, progression, and aggressiveness.MethodsDifferent human cohorts and a dataset from different glioma mouse models were analyzed to determine the mutation frequency as well as the gene and protein expression levels between tumor and control samples of the splicing-factor-3B-subunit-1 (SF3B1), an essential and druggable spliceosome component. SF3B1 expression was also explored at the single-cell level across all cell subpopulations and transcriptomic programs. The association of SF3B1 expression with relevant clinical data (e.g., overall survival) in different human cohorts was also analyzed. Different functional (proliferation/migration/tumorspheres and colonies formation/VEGF secretion/apoptosis) and mechanistic (gene expression/signaling pathways) assays were performed in three different glioblastomas cell models (human primary cultures and cell lines) in response to SF3B1 blockade (using pladienolide B treatment). Moreover, tumor progression and formation were monitored in response to SF3B1 blockade in two preclinical xenograft glioblastoma mouse models.ResultsOur data provide novel evidence demonstrating that the splicing-factor-3B-subunit-1 (SF3B1, an essential and druggable spliceosome component) is low-frequency mutated in human gliomas (~ 1 %) but widely overexpressed in glioblastoma compared with control samples from the different human cohorts and mouse models included in the present study, wherein SF3B1 levels are associated with key molecular and clinical features (e.g., overall survival, poor prognosis and/or drug resistance). Remarkably, in vitro and in vivo blockade of SF3B1 activity with pladienolide B drastically altered multiple glioblastoma pathophysiological processes (i.e., reduction in proliferation, migration, tumorspheres formation, VEGF secretion, tumor initiation and increased apoptosis) likely by suppressing AKT/mTOR/ß-catenin pathways, and an imbalance of BCL2L1 splicing.ConclusionsTogether, we highlight SF3B1 as a potential diagnostic and prognostic biomarker and an efficient pharmacological target in glioblastoma, offering a clinically relevant opportunity worth to be explored in humans.

ABSTRACT Streptococcus agalactiae [group B Streptococcus (GBS)] poses a major threat as the primary cause of early-onset neonatal invasive disease, particularly when mothers are colonized rectovaginally. Although culture remains the gold standard for antepartum GBS screening, quantitative polymerase chain reaction (qPCR) offers advantages in terms of sensitivity and turnaround time. The aim of this study was to validate the clinical utility of an automated qPCR laboratory-developed test (LDT) for antepartum GBS screening using the Panther Fusion Open Access system (Hologic, California, USA). The LDT targeted a conserved region of the GBS surface immunogenic protein gene, demonstrating no cross-reactivity and high coverage (99.82%–99.99%). The limit of detection (LoD) was 118 CFU/mL. Comparison with commercial qPCR assays (Panther Fusion GBS and VIASURE Streptococcus B Real-Time) revealed an overall agreement of 99.7%, with a robust Cohen’s kappa coefficient of 0.992. Testing of 285 rectovaginal swabs from pregnant women and 15 external quality assessment samples demonstrated exceptional diagnostic performance of the LDT, achieving a diagnostic sensitivity and specificity of 100%, underscoring its accuracy. Prevalence and predictive values were also determined to reinforce test reliability. Our research highlights the limitations of culture-based screening and supports the suitability of our qPCR-based LDT for GBS detection in a clinical setting.IMPORTANCERectovaginal colonization by GBS is a major risk factor for early-onset invasive neonatal disease. The most effective approach to reducing the incidence of early-onset disease (EOD) has been described as universal screening, involving assessment of GBS colonization status in late pregnancy and intrapartum antibiotic prophylaxis. Despite its turnaround time and sensitivity limitations, culture remains the gold standard method for GBS screening. However, nucleic acid amplification-based tests, such as qPCR, have been utilized due to their speed and high sensitivity and specificity. This study validated the clinical usefulness of an automated qPCR-LDT for antepartum GBS screening through the Panther Fusion Open Access system (Hologic). Our study addresses the critical need for more robust, sensitive, and rapid strategies for GBS screening in pregnant women that could favorably impact the incidence of EOD.

ObjectiveTo introduce MexOMICS, a Mexican Consortium focused on establishing electronic databases to collect, cross-reference, and share health-related and omics data on the Mexican population.MethodsSince 2019, the MexOMICS Consortium has established three electronic-based registries: the Mexican Twin Registry (TwinsMX), Mexican Lupus Registry (LupusRGMX), and the Mexican Parkinson's Research Network (MEX-PD), designed and implemented using the Research Electronic Data Capture web-based application. Participants were enrolled through voluntary participation and on-site engagement with medical specialists. We also acquired DNA samples and Magnetic Resonance Imaging scans in subsets of participants.ResultsThe registries have successfully enrolled a large number of participants from a variety of regions within Mexico: TwinsMX (n = 2,915), LupusRGMX (n = 1,761) and MEX-PD (n = 750). In addition to sociodemographic, psychosocial, and clinical data, MexOMICS has collected DNA samples to study the genetic biomarkers across the three registries. Cognitive function has been assessed with the Montreal Cognitive Assessment in a subset of 376 MEX-PD participants. Furthermore, a subset of 267 twins have participated in cognitive evaluations with the Creyos platform and in MRI sessions acquiring structural, functional, and spectroscopy brain imaging; comparable evaluations are planned for LupusRGMX and MEX-PD.ConclusionsThe MexOMICS registries offer a valuable repository of information concerning the potential interplay of genetic and environmental factors in health conditions among the Mexican population.

Pressure screening is a critical step in the production of high-quality paper. In efforts to meet sustainable market demands, mill operators are forced to push the limits of screening operation to the point where plugging becomes a recurrent issue. This two-part study provides insights into the limits of screening operations. In the first part, some published imaging data was analyzed to delve into the plugging mechanisms. The observed hysteresis and intermittency were measured by image processing techniques, which revealed that an intermittent behavior of plug-and-release events is intensified as permanent, stable plugs start to form. The intermittency was characterized as changes in the distribution of open area fluctuation peaks. Thus, the kurtosis of the fluctuation peak distribution is proposed as a metric for a plugging soft-sensor. In part 2 of this investigation, the limits of screening operation were characterized by performing a series of screening trials. The utility of the soft-sensor metric for plugging was assessed with the pressure fluctuation data.

Abstract This work constitutes the first approach for automatically classifying the surface that the voiding flow impacts in non-invasive sound uroflowmetry tests using machine learning. Often, the voiding flow impacts the toilet walls (traditionally made of ceramic) instead of the water in the toilet. This may cause a reduction in the strength of the recorded audio signal, leading to a decrease in the amplitude of the extracted envelope. As a result, just from analysing the envelope, it is impossible to tell if that reduction in the envelope amplitude is due to a reduction in the voiding flow or an impact on the toilet wall. In this work, we study the classification of sound uroflowmetry data in male subjects depending on the surface that the urine impacts within the toilet: the three classes are water, ceramic and silence (where silence refers to an interruption of the voiding flow). We explore three frequency bands to study the feasibility of removing the human-speech band (below 8 kHz) to preserve user privacy. Regarding the classification task, three machine learning algorithms were evaluated: the support vector machine, random forest and k-nearest neighbours. These algorithms obtained accuracies of 96%, 99.46% and 99.05%, respectively. The algorithms were trained on a novel dataset consisting of audio signals recorded in four standard Spanish toilets. The dataset consists of 6481 1-s audio signals labelled as silence, voiding on ceramics and voiding on water. The obtained results represent a step forward in evaluating sound uroflowmetry tests without requiring patients to always aim the voiding flow at the water. We open the door for future studies that attempt to estimate the flow parameters and reconstruct the signal envelope based on the surface that the urine hits in the toilet.

Conservation strategies for huemul (Hippocamelus bisulcus), listed as an endangered cervid by IUCN, have not helped to reverse its declining population trends. Recent evaluations of historical data revealed that they also inhabited lower valleys and grasslands as residents or only during winter. However, the dogma persists that huemuls do not need such habitats. To determine if more solid evidence exists to back up or refute our hypothesis that huemuls once inhabited lower valleys and grasslands, we researched the literature and discovered additional relevant historical sources on this species. These new findings substantiate that huemuls also occupied unforested areas, reaching the Atlantic coast, and resided on various islands including Tierra del Fuego, and that their co-occurrence with guanaco was frequent. Their extreme naivety towards humans resulted in their extirpation on winter ranges settled by humans, resulting in refugee huemuls year-round on remote mountain summer ranges. The ease by which indigenous people could kill them for subsistence and commercial export of hides to Europe, followed by the lowlands becoming modified by settlers and their exotic species facilitated the huemuls’ extirpation. The hypothesis of a dramatic modification of the original biogeographical distribution of huemuls is supported by anatomical and ecological features along with historical accounts. Sedentariness on only rugged summer ranges makes long-term survival of this species crucially challenging and requires sound conservation strategies that incorporate geographical areas of their former distribution.

PHYLODB is a modular and extensible framework for large-scale phylogenetic analyses of sequence based typing data, which are essential for understanding epidemics evolution. It relies on the Neo4j graph database for data storage and processing, providing a schema and an API for representing and querying phylogenetic data. Custom algorithms are also supported, allowing users to perform heavy computations directly over the data, and to store results in the database. Multiple computation results are stored as multilayer networks, promoting and facilitating comparative analyses, as well as avoiding unnecessary ab initio computations. The experimental evaluation results showcase that PHYLODB is efficient and scalable with respect to both API operations and algorithms execution.

Objetivo: Demostrar la experiencia adquirida en un hospital de tercer nivel de atención en México desde la implementacio?n del programa de donacio?n renal pareada (KPD). Material y métodos: Estudio observacional, anali?tico, longitudinal y prospectivo de septiembre de 2018 a septiembre de 2022. Se incluyeron todos los enfermos renales cro?nicos G5 KDIGO que en el protocolo pretrasplante resultaron HLA o ABO incompatibles con sus donantes originales y que fueron trasplantados bajo programa KPD. Resultados: Se realizaron 34 trasplantes renales bajo este programa. A un año postrasplante, la sobrevida del injerto fue del 97%, la tasa de filtracio?n glomerular fue 76.18 (± 21.91) ml/min/1.73 m² SC y la incidencia de rechazos fue del 17.6%. Estos resultados fueron estadísticamente mejores que los presentados en un grupo histórico de trasplantados renales previa desensibilización por haber tenido una prueba cruzada originalmente incompatible: sobrevida del injerto 51.1% (p = 0.019), tasa de filtración glomerular 51.79 (± 26.29) ml/min/1.73 m² SC e incidencia de rechazos del 51.1%. Conclusiones: En México, el trasplante bajo programa de KPD constituye una modalidad exitosa cuando existe incompatibilidad HLA/ABO o sensibilización. La mayor utilizacio?n y la socializacio?n de este programa puede aumentar la tasa de trasplante renal nacional, disminuyendo la lista de espera.