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Asthma is a highly heterogenous disease which researchers over time have attempted to classify into different phenotypes and endotypes to improve diagnosis, prognosis and treatment. Earlier classifications based on reaction to environmental allergens, age, sex and lung function have evolved, and today, the use of precision medicine guided by biomarkers offers new perspectives on asthma management. Identifying biomarkers that may reveal the underlying pathophysiology of the disease will help to select the patients who will benefit most from specific treatments. This review explores the classification of asthma phenotypes and focuses on the most recent advances in using biomarkers to guide treatment. [ABSTRACT FROM AUTHOR]

The article explores the concept of phenotypic connectance and correlation pleiades in wheat and chickpea datasets, focusing on trait linkage and independence. The study reveals a power law distribution of connectance in both crops, with varying levels of connectance across different traits and genotypes. The findings suggest a relationship between connectance, heritability, and phenotypic plasticity, highlighting the importance of understanding phenotypic integration in crop sciences. The research emphasizes the need to consider genotype- and trait-dependent variation in phenotypic integration to enhance plant development and yield. [Extracted from the article]

Background: Incontinentia pigmenti (IP) is an X-linked dominant multisystemic disorder caused by pathogenic variants in the IKBKG gene. Population-based research into the epidemiology of IP is lacking. Methods: This nationwide cross-sectional study from Jan 1st, 1995 to August 25th, 2021, searched the Danish National Patient Registry (DNPR), the Danish National Database of Rare Genetic Diseases (RareDis) and the Danish Genodermatosis Database to identify patients recorded with a diagnosis of IP. This search was followed by diagnosis validation and collection of clinical data from patient medical records. We investigated the clinical characteristics and genetics of the final cohort of validated IP cases. We estimated the point prevalence in the Danish population, based on non-deceased IP patients currently living in Denmark. Furthermore, we estimated the birth prevalence from 1995 to 2020, assuming a diagnostic delay of up to six months. Results: We identified a validated cohort of 75 IP patients, including 71 (94.7%) females and 4 (5.3%) males. We estimated a birth prevalence of 2.37 (95% CI: 1.74–3.25) per 100,000 or 1 in 42,194. A total of 54 (72%) patients had a genetic diagnosis, including 39 (72.2%) with the recurrent exon 4–10 deletion and 10 (18.5%) with point mutations in IKBKG. A positive family history was reported in 53.3%. Besides the recognizable blaschkolinear skin lesions reported in 70 (93.3%) of the patients, commonly reported manifestations included the involvement of the teeth (58.7%), the central nervous system (30.7%), hair (26.7%), and eyes (22.6%), as well as nail dystrophy (16.0%). Conclusions: We identified and characterized a nationwide population-based cohort of IP patients and report a birth prevalence of 2.37 per 100,000 live births, which is twice as high as previous estimates. [ABSTRACT FROM AUTHOR]

Despite the prevalence of sequencing data in biomedical research, the methylome remains underrepresented. Given the importance of DNA methylation in gene regulation and disease, it is crucial to address the need for reliable differential methylation methods. This work presents a novel, transferable approach for extracting information from DNA methylation data. Our agnostic, graph-based pipeline overcomes the limitations of commonly used differential methylation techniques and addresses the “small n, big k” problem. Pheochromocytoma and Paraganglioma (PPGL) tumours with known genetic aetiologies experience extreme hypermethylation genome wide. To highlight the effectiveness of our method in candidate discovery, we present the first phenotypic classifier of PPGLs based on DNA methylation achieving 0.7 ROC-AUC. Each sample is represented by an optimised parenclitic network, a graph representing the deviation of the sample’s DNA methylation from the expected non-aggressive patterns. By extracting meaningful topological features, the dimensionality and, hence, the risk of overfitting is reduced, and the samples can be classified effectively. By using an explainable classification method, in this case logistic regression, the key CG loci influencing the decision can be identified. Our work provides insights into the molecular signature of aggressive PPGLs and we propose candidates for further research. Our optimised parenclitic network implementation improves the potential utility of DNA methylation data and offers an effective and complete pipeline for studying such datasets. [ABSTRACT FROM AUTHOR]

The article from Movement Disorders Clinical Practice discusses the importance of accurately describing clinical features of movement disorders for effective research reporting. It emphasizes the need for precise characterization of clinical features to support advanced technologies like neuroimaging and genetics. The article provides strategies for learning movement disorders, approaches to patient evaluation, and methods for describing movement disorders. It also highlights the significance of clinical descriptions in scientific publications and offers dos and don'ts for reporting clinical features. The authors stress the value of astute observation, collaboration, and creativity in clinical reporting. [Extracted from the article]

Objective: Obsessive-compulsive and related disorders (OCRDs) and disorders due to addictive behavior (DABs) are prevalent conditions that share common neurobiological and behavioral characteristics. This scoping review aims to identify and map the range of subjective assessment tools (e.g., interviews and self-report instruments) for assessing Research Domain Criteria (RDoC) and related constructs underlying DABs and OCRDs, such as impaired response inhibition, habit formation, and compulsivity. Method: A scoping review was performed following the PRISMA Extension for Scoping Reviews (PRISMA ScR). The search was conducted in Medline, Web of Science, PsycINFO, and EMBASE databases. No constraints of data or document type were adopted. Results: The search yielded 615 instruments, of which 79 were deemed transdiagnostic and capable of assessing at least one of the target constructs. Noteworthy tools included are the Cambridge-Chicago Compulsivity Trait Scale, the Self-report Habit Index, the Reward Probability Index, the Threat-Related Reassurance-Seeking Scale, and the recent Positive Valence Systems Scale. Conclusions: Despite the growing body of literature on OCRDs and DABs as new diagnostic chapters and the number of tools with the potential to assess their transdiagnostic constructs clinically, most instruments were designed to capture dimensions or psychopathology not directly (or primarily) related to OCRDs, DABs and the concepts of impaired response inhibition, habit formation, and compulsivity in the context of these conditions. Further studies exploring the correlation between subjective assessments, corresponding behavior paradigms, and neuroimaging data would be of great value in the translation of RDoC constructs and domains into clinical settings. [ABSTRACT FROM AUTHOR]

Background: Migraine is the fourth most common cause of disability in women and the eighth most common cause in men. Central sensitization phenomena predispose to chronic migraine and are generally more pronounced in women. Objective: The aim of this retrospective observational study was to look for sex differences in a population of migraine subjects attending a tertiary headache center, focusing on symptoms of central sensitization such as allodynia and pericranial tenderness. Methods: This study is based on data collected at a tertiary headache center between January 1, 2018, and December 31, 2022. The clinical interview included the main features of migraine, allodynia, a disability questionnaire, the pericranial tenderness score, and anxiety and depression scales. Results: We selected a total of 1,087 migraine subjects (233 men). Osmophobia predominated in women, as did nausea. Disability scores, headache intensity, allodynia, anxiety, and depression predominated in women, without menopausal age playing a role. The frequency of symptomatic medication use was similar in both sexes. Allodynia score was the largest discriminating factor between women and men. Conclusions: Women with migraine are more likely than men to report acute allodynia, nausea, and osmophobia and are also more likely to be anxious, depressed, and disabled. These features appear to be independent of fertile age and are probably related to sex-specific genetic characteristics. These symptoms represent a tendency toward sensory hypersensitivity and central sensitization that should be carefully assessed in both women and men with migraine with a view to possibly predicting chronic development. [ABSTRACT FROM AUTHOR]

Atopic Dermatitis (AD) is associated with a number of published disparities, including those related to self-identified racial/ethnic populations. Black/African American populations in the United States experience greater AD prevalence, severity, and persistence compared to other demographic groups, such as those who self-identify as White. There is consistent evidence that healthcare, environmental, and socioeconomic factors affect the prevalence, severity, and/or persistence of AD. Additionally, because of institutional and systemic racism, these same risk factors are more prevalent in racial and ethnic minority populations. Herein, we review the underlying causes of racial/ethnic disparities in AD and potential strategies to improve AD diagnosis and disease control. [ABSTRACT FROM AUTHOR]

Background: Both a probable usual interstitial pneumonia (UIP) pattern (p-UIP) and a definite UIP pattern (d-UIP) on high-resolution computed tomography (HRCT) are sufficient to establish a diagnosis of idiopathic pulmonary fibrosis (IPF) without the need for a surgical lung biopsy, according to the 2022 IPF guidelines. However, it remains unknown whether patients with p-UIP and d-UIP have similar disease behaviors and clinical courses. Material and Methods: We retrospectively collected clinical data of patients with IPF and divided the patients into two groups according to their HRCT patterns: a p-UIP group and a d-UIP group. The baseline characteristics, survival rates, and pulmonary function tests were compared between the two groups. The risk factors for mortality were determined by Cox regression in p-UIP and d-UIP separately. Results: There were 304 patients in the p-UIP group and 480 patients in the d-UIP group. Patients in the d-UIP group were more likely to have smoking histories (p < 0.001) and had lower baseline FVC% (74% vs. 77%, p = 0.021) and DLCO% (50% vs. 58%, p < 0.001). Survival rates were higher in p-UIP compared with d-UIP (p = 0.004). There were no differences in changes in FVC% or DLCO% between the two groups. Baseline DLCO% was the only independent risk factor for mortality in p-UIP. Baseline FVC% was independently associated with mortality in d-UIP. Symptom of cough was a risk factor for disease progression (OR = 1.2, p = 0.002) in p-UIP, while symptom of dyspnea might be associated with disease progression in d-UIP (OR = 2.7, p = 0.065). Male patients (OR = 1.88, p = 0.002) with a smoking history (OR = 1.16, p = 0.002) were at higher risk of developing d-UIP. Conclusions: We observed the different disease trajectories between p-UIP and d-UIP. P-UIP on HRCT might identify a subgroup of IPF patients who are in the early stage with a better prognosis. [ABSTRACT FROM AUTHOR]

Objectives: To determine the effects of hyperandrogenemia and other phenotypic parameters on endometrial vitamin D receptor (VDR-X2 and VDR-X4) expression in women with polycystic ovary syndrome (PCOS) undergoing ovarian stimulation and total embryo freezing. Methods: Forty-four PCOS patients were divided into four phenotypes according to the criteria for hyperandrogenemia (HA), ovulatory dysfunction (OD), and polycystic ovary morphology (PCOM): phenotype A (HA+OD+PCOM), phenotype B (HA+OD), phenotype C (HA+PCOM), and phenotype D (OD+PCOM). Endometrial VDR expression was determined by real-time PCR and immunohistochemistry. Twenty age- and body mass index (BMI)-matched couples with male infertility were included as controls. Results: VDR-X2 and VDR-X4 expression levels were significantly lower in the PCOS group than in the control group. A significant downregulation was detected in the relative VDR-X2 and X4 expression in phenotypes A, B, and C compared to the control group. VDR-X2 and X4 expression in phenotype D was significantly higher than in phenotypes A and B. A significant negative correlation was detected among VDR-X2, VDR-X4, serum testosterone (T), androstenedione (A), DHEAS, and insulin resistance (IR). Multivariate analysis revealed that serum T, A, DHEAS, and IR levels were independently associated with both VDR-X2 and VDR X4 relative gene expression after adjusting for age and BMI. The VDR mRNA and immunoreactivity of each phenotype overlapped. The clinical pregnancy rates for each phenotype were similar. Conclusion: VDR expression in the endometria of patients with PCOS was defective. Hyperandrogenemia and insulin resistance are the key drivers of defective VDR expression in the endometrium of patients with PCOS. [ABSTRACT FROM AUTHOR]

Mitochondrial diseases (MtDs) present diverse clinical phenotypes, yet large‐scale studies are hindered by their rarity. This retrospective, multicenter study, conducted across five Chinese hospitals' neurology departments from 2009 to 2019, aimed to address this gap. Nationwide, 1351 patients were enrolled, with a median onset age of 14.0 (18.5) years. The predominant phenotype was mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes (MELAS) (45.0%). Mitochondrial DNA (mtDNA) mutations were prevalent (87.4%), with m.3243A>G being the most common locus (48.7%). Meanwhile, POLG mutations in nuclear DNA (nDNA) accounted for 16.5%. Comparative analysis based on age groups (with a cut‐off at 14 years) revealed the highest prevalence of MELAS, with Leigh syndrome (LS) and chronic progressive external ophthalmoplegia (CPEO) being the second most common phenotypes in junior and senior groups, respectively. Notably, the most commonly mutated nuclear genes varied across age groups. In conclusion, MELAS predominated in this Chinese MtD cohort, underscored by m.3243A>G and POLG as principal mtDNA mutations and pathogenic nuclear genes. The phenotypic and genotypic disparities observed among different age cohorts highlight the complex nature of MtDs. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to compare postoperative patellar tilt at 4 months follow‐up in a consecutive series of randomised patients that received individualised or off‐the‐shelf (OTS) primary total knee arthroplasty (TKA). The hypothesis was that patellar tilt would be lower and less variable in patients who received individualised TKA compared to patients who received OTS TKA. Methods: A consecutive series of 385 patients randomised (1:1) to receive either OTS TKA or individualised TKA were analysed. Pre‐ and postoperative radiographs at 4 months were obtained of weight‐bearing long leg, anterior–posterior and lateral knee views and a skyline view at 30° of flexion. Postoperative patellar tilt was measured between the anterior femoral line and patellar resection surface (β) and the anterior femoral line and mediolateral patellar axis (σ). Postoperative patellar tilt (absolute value) was compared between the individualised and OTS TKA groups based on preoperative phenotypes of their femoral mechanical angle, tibial mechanical angle and hip–knee–ankle angle. Variability in postoperative patellar tilt was compared using the 95% confidence intervals (CIs). Results: Comparisons of baseline patient characteristics revealed no difference between the individualised and OTS TKA groups. Comparison of absolute postoperative patellar tilt revealed significant differences between individualised and OTS TKA (|β|, 1.0° ± 1.0° and 2.5° ± 2.2°, respectively, p < 0.001; |σ|, 1.7° ± 1.6° and 2.8° ± 2.3°, respectively, p < 0.001). The 95% CI of postoperative patellar tilt (|β|) was narrower in patients that received individualised compared to OTS TKA (0.0° to 3.8° and 0.1° to 8.3°, respectively), irrespective of their preoperative phenotype. Conclusion: Patients who underwent individualised TKA had lower and less variable postoperative patellar tilt than those with OTS TKA, irrespective of preoperative phenotype. Individualised TKA allows the decoupling of the tibiofemoral and patellofemoral joints, replicating anatomical trochlear orientation and improving patellar tilt, which could facilitate better clinical outcomes. Clinical Trial Registration: This study constitutes a part of a larger registered randomised controlled trial comparing patient satisfaction following OTS versus individualised TKA (NCT04460989). Level of Evidence: Level II. [ABSTRACT FROM AUTHOR]

Neotropical species of the genus Fannia remain poorly known despite their potential collection as biological evidence in criminal investigations. This is partly due to taxonomic difficulties and a lack of specialists. Identifying neotropical species of Fannia relies mainly on the classical morphological characters of adult males, as females show high similarity between species. Here, landmark-based geometric morphometrics of the wing could constitute an additional tool for associating adult females with conspecifics in this genus. In this study, we used a reference dataset of males belonging to ten putative species of Fannia from Colombia and molecular data to test this hypothesis. We found a strong wing shape sexual dimorphism, resulting in an almost perfect sex assignment based solely on this trait. However, the differences in wing shape between sexes were greater than those between species, making conspecific identification difficult. Our data show that wing shape could only feasibly be used for identifying adult males and females of F. lamosca, and males of F. dorsomaculata and F. pseudoconstricta. Low discrimination scores among remaining species may be partly explained by high intraspecific variation, slight wing shape differences among closely related species, or sampling bias. Although this study provides the first wing size and shape comparison among neotropical Fannia species, more samples and species are needed to validate these findings and identify the potential factors influencing this trait. Furthermore, the wing shape sexual dimorphism across Fannia species suggests different life-history strategies between sexes and possible genetic canalization mechanisms. [ABSTRACT FROM AUTHOR]

To address the problems of low accuracy and poor robustness of traditional point cloud segmentation algorithms, a point clouds network++ based on K-nearest neighbor algorithm and feature fusion (KF-PointNet++) three-dimensional point cloud segmentation algorithm was proposed. Firstly, the K-nearest neighbors (KNN) algorithm was used to group the point cloud. Secondly, the local features in point clouds network (PointNet) were spliced with the global features of the center point to enhance the ability of the algorithm to capture geometric details and global context, so as to improve the segmentation accuracy and robustness of the algorithm and realize the accurate segmentation of rape point cloud organs. The self-made rape point cloud data set was used for experiments. The results showed that the overall accuracy (OA) of the KF-PointNet ++ algorithm in rape point cloud segmentation could reach 97.1%, and the mean intersection over union (mloU) was 86.4%. The KF-PointNet++ algorithm was superior to the classical PointNet, PointNet++ and kernal point convolution (KPConv) in segmentation performance. It shows high accuracy and strong robustness in point cloud segmentation tasks, which can provide a reliable basis for subsequent rapeseed phenotype research. [ABSTRACT FROM AUTHOR]

1. This study determined the effective indicators and proteins involved in long-duration fertility (DF) in chickens. 2. Three lines of Chinese Xinhua chickens (900) were compared using seven phenotypic trait indicators, and the best was determined based on repeatability value. Subsequently, differential expression analysis, functional annotation and protein-protein interaction (PPI) network analyses were performed to investigate the pathways and hub proteins. Finally, qPCR analysis was conducted to validate the expression of identified hub proteins, and functional annotation with previously published genes was performed to explain how hub proteins work to maintain the trait. 3. The study found that the number of fertilised eggs (FN) and maximum fertilised eggs (MCF) were the most repeatable among the seven indicators. It identified 231 differentially expressed proteins, with 144 being down-regulated and 87 being up-regulated. The differentially expressed proteins exhibited high clustering within various cellular compartments, including the cytosol and cytoplasm and GTP binding. Multiple pathways were identified, including tight and adherens junctions, TGF-beta signalling, autophagy-animal, regulation of actin cytoskeleton and the ribosome that may regulate the trait. Three hub proteins, KRAS, RPL5 (p < 0.001), and HSPA4 (p < 0.01), were significantly differentially expressed between high and low DF groups. 4. This study identified FN and MCF as effective indicators for addressing DF. As it is a quantitative trait, KRAS, HSPA4, and RPL5 are potential hub proteins that work with other genes to maintain the trait. [ABSTRACT FROM AUTHOR]

Salinity significantly reduces global rice yield, especially in Eastern and Southern Africa, necessitating the development of salinity-tolerant varieties. We collected and analyzed 201 rice varieties, including Tanzanian landraces. Using 1k-RiCA SNP markers, we found that 36 out of 201 genotypes possessed the Saltol allele, a marker for salinity tolerance. Only two genotypes, K5 and Intsindagira bigega, were both phenotypically tolerant and had the Saltol allele. Interestingly, 16 genotypes without Saltol showed salinity tolerance, suggesting other salinity tolerance QTLs. The distribution of Saltol and phenotypically tolerant genotypes varied across Tanzanian agro-ecological zones, with the Coastal Zone showing a higher proportion of tolerant genotypes, possibly due to farmer selection pressure. However, ancestral population proportion correlated with decreased salinity tolerance. This study highlights the complex relationship between environmental factors and population structure in shaping the genetic and phenotypic composition of landraces. The identified tolerant genotypes could be utilized in breeding for new salinity-tolerant-rice varieties. [ABSTRACT FROM AUTHOR]

Uncovering the genetic characteristics of important traits in wheat cultivars is essential for targeted wheat breeding. Here, a liquid 100K single-nucleotide polymorphism (SNP) chip panel, integrating markers of known function, was selected and used to analyze genetic characteristics for 115 spring wheat cultivars from a high-altitude region of China. A total of 102 reported functional markers closely related to important traits were identified, including 54 related to yield and grain quality and 33 associated with disease resistance and stress tolerance. Of the cultivars, 58.2% of cultivars contained excellent marker genes in the range of 20 to 29. Genetic structure analysis revealed that the cultivars were grouped into five subgroups. Genome-wide association studies identified 218 significant loci on 20 chromosomes, with the exception of chromosome 3D, associated with nine traits and which explained 14.15–29% of phenotypic variance, with 199 potential candidate genes being annotated for the nine traits studied. Notably, 21 previously unidentified candidate genes, with associated SNPs, were closely associated with seven traits, explaining 14.26–19.86% of the phenotypic variance. The current study revealed the genetic characteristics of spring wheat cultivars from a high-altitude region of China. This will provide a reference for spring wheat breeding for high-altitude regions and promote the fine-mapping of new genetic loci controlling important traits. [ABSTRACT FROM AUTHOR]

Background: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors in multiple endocrine organs, caused by variants in the MEN1 gene. This study analyzed the clinical and genetic features of MEN1 in a Korean cohort, identifying prevalent manifestations and genetic variants, including novel variants. Methods: This multicenter retrospective study reviewed the medical records of 117 MEN1 patients treated at three tertiary centers in Korea between January 2012 and September 2022. Patient demographics, tumor manifestations, outcomes, and MEN1 genetic testing results were collected. Variants were classified using American College of Medical Genetics and Genomics (ACMG) and French Oncogenetics Network of Neuroendocrine Tumors propositions (TENGEN) guidelines. Results: A total of 117 patients were enrolled, including 55 familial cases, with a mean age at diagnosis of 37.4±15.3 years. Primary hyperparathyroidism was identified as the most common presentation (84.6%). The prevalence of gastroenteropancreatic neuroendocrine tumor and pituitary neuroendocrine tumor (PitNET) was 77.8% (n=91) and 56.4% (n=66), respectively. Genetic testing revealed 61 distinct MEN1 variants in 101 patients, with 18 being novel. Four variants were reclassified according to the TENGEN guidelines. Patients with truncating variants (n=72) exhibited a higher prevalence of PitNETs compared to those with non-truncating variants (n=25) (59.7% vs. 36.0%, P=0.040). Conclusion: The association between truncating variants and an increased prevalence of PitNETs in MEN1 underscores the importance of genetic characterization in guiding the clinical management of this disease. Our study sheds light on the clinical and genetic characteristics of MEN1 among the Korean population. [ABSTRACT FROM AUTHOR]

DNA-based therapeutics have emerged as a revolutionary approach for addressing the treatment gap in rare inherited conditions by targeting the fundamental genetic causes of disease. Charcot–Marie–Tooth (CMT) disease, a group of inherited neuropathies, represents one of the most prevalent Mendelian disease groups in neurology and is characterized by diverse genetic aetiology. Axonal forms of CMT, known as CMT2, are caused by dominant mutations in >30 different genes that lead to degeneration of lower motor neuron axons. Recent advances in antisense oligonucleotide therapeutics have shown promise in targeting neurodegenerative disorders. Here, we elucidate pathomechanistic changes contributing to variant specific molecular phenotypes in CMT2E, caused by a single nucleotide substitution (p.N98S) in the neurofilament light chain gene (NEFL). We used a patient-derived induced pluripotent stem cell-induced motor neuron model that recapitulates several cellular and biomarker phenotypes associated with CMT2E. Using an antisense oligonucleotide treatment strategy targeting a heterozygous gain-of-function variant, we aimed to resolve molecular phenotypic changes observed in the CMT2E p.N98S subtype. To determine the therapeutic potential of antisense oligonucleotide, we applied our treatment strategy in induced pluripotent stem cell-derived motor neurons and used both established and new biomarkers of peripheral nervous system axonal degeneration. Our findings demonstrated a significant decrease in clinically relevant biomarkers of axonal degeneration, presenting the first clinically viable genetic therapeutic for CMT2E. Similar strategies could be used to develop precision medicine approaches for otherwise untreatable gain-of-function inherited disorders. [ABSTRACT FROM AUTHOR]

Altered development and function of the prefrontal cortex (PFC) during adolescence is implicated in the origin of mental disorders. Deficits in the GABAergic system prominently contribute to these alterations. Nav1.1 is a voltage-gated Na+ channel critical for normal GABAergic activity. Here, we studied the role of Nav1.1 in PFC function and its potential relationship with the aetiology of mental disorders. Dysfunction of Nav1.1 activity in the medial PFC (mPFC) of adolescent mice enhanced the local excitation/inhibition ratio, resulting in epileptic activity, cognitive deficits and depressive-like behaviour in adulthood, along with a gene expression profile linked to major depressive disorder (MDD). Additionally, it reduced extracellular serotonin concentration in the dorsal raphe nucleus and brain-derived neurotrophic factor expression in the hippocampus, two MDD-related brain areas beyond the PFC. We also observed alterations in oscillatory activity and impaired hippocampal-mPFC coherence during sleep. Finally, we found reduced expression levels of SCN1A , the gene encoding Nav1.1, in post-mortem PFC samples from human MDD subjects. Collectively, our results provide a novel mechanistic framework linking adolescence-specific alterations in Nav1.1 function in the PFC to the pathogenesis of epilepsy and comorbidities such as cognitive impairment and depressive disorders. [ABSTRACT FROM AUTHOR]

Background: A centrally limited radiological pattern, marked by mucosal thickening in the central sinonasal cavity with relatively unaffected surrounding sinuses, has been linked to allergy in chronic rhinosinusitis (CRS). However, a comparison between allergic and non-atopic CRS patients is lacking. The role of anatomical variations in the ostiomeatal complex also remains unclear. Methods: Adult CRS patients with allergic rhinitis, asthma, eczema, and positive allergy tests were recruited. CRS patients without atopic disease and negative allergy tests were controls. CT scans were evaluated for the centrally limited radiologic pattern. Anatomical variations in the ostiomeatal complex were also examined. Results: The study included 15 allergic CRS and 17 non-atopic CRS participants. Allergic CRS patients showed a higher prevalence of centrally limited sinus disease compared to non-atopic CRS patients (50% vs. 14.7%, p < 0.01). No anatomical variations were conclusively linked to allergy status or the centrally limited sinus disease. Conclusion: Centrally limited sinus disease on radiology is associated with underlying allergy in CRS but should not be the primary diagnostic tool. Anatomical variants did not clearly relate to allergy status or the radiologic pattern but this requires further studies. [ABSTRACT FROM AUTHOR]

Extreme longevity in humans is known to be a heritable trait. In a well‐established twin erythrocyte metabolomics and proteomics database, we identified the longevity factor spermidine and a cluster of correlated molecules with high heritability estimates. Erythrocyte spermidine is 82% heritable and significantly correlated with 59 metabolites and 22 proteins. Thirty‐eight metabolites and 19 proteins were >20% heritable, with a mean heritability of 61% for metabolites and 49% for proteins. Correlated metabolites are concentrated in energy metabolism, redox homeostasis, and autophagy pathways. Erythrocyte mean cell volume (MCV), an established heritable trait, was consistently negatively correlated with the top 25 biomolecules most strongly correlated with spermidine, indicating that smaller MCVs are associated with higher concentrations of spermidine and correlated molecules. Previous studies have linked larger MCVs with poorer memory, cognition, and all‐cause mortality. Analysis of 432,682 unique patient records showed a linear increase in MCV with age but a significant deviation toward smaller than expected MCVs above age 86, suggesting that smaller MCVs are associated with extreme longevity. Consistent with previous reports, a subset of 78,158 unique patient records showed a significant skewing toward larger MCV values in a deceased cohort compared to an age‐matched living cohort. Our study supports the existence of a complex, heritable phenotype in erythrocytes associated with health and longevity. [ABSTRACT FROM AUTHOR]

Xylanase is a heteropolysaccharide found in the plant cell wall, which aids in the absorption and utilisation of nutrients. When embedded in animal feed, it enhances nutrient availability, leading to improved animal performance. The aim of this study was to explore the effect of xylanase supplementation in wheat-based feeds on the hepatic development, antioxidant capacity, and immune response in Tibetan sheep. Sixty healthy, weaned, non-neutered male lambs (19.35 ± 2.18 kg) were randomly assigned to two equal groups (n = 30 per group). Dietary treatments were: basal diet (H group), and basal diet with 0.2% xylanase supplementation (E group). After a 10–day adaptation period, the feeding trial was carried out for 90 days. The live weight, morphology, antioxidant capacity and immune response were measured. The differential genes in liver were identified by RNA-sequencing. Our results showed that the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) were significantly higher in E group than in H group (p < 0.05). Enzyme-linked immunosorbent assay (ELISA) revealed that immunoglobulin A (IgA), IgM, and IgG were significantly higher in E group than in H group (p < 0.05). The hepatocytes of sheep fed xylanase diet showed arranged radially into hepatic plates cantered around the central vein, and the plates linked with each other to form a lost-like structure. A total of 4,509 differential genes (DEGs) were identified, among which 4,427 were up-regulated and 82 down-regulated. Additionally, the expression of antioxidant-related genes in cluding catalase (CAT), superoxide dismutase 1 (SOD1), oxidation resistance 1 (OXR1) and glutathione peroxidase 2 (GPX2), and immunity-related gene including mitogen-activated protein kinase 1 (MAPK1), signal transducer and activator of transcription 5B (STAT5B), janus kinase 3 (JAK3) and jun proto-oncogene (JUN) were verified using the quantitative reverse transcription polymerase chain reaction (qRT-PCR). Conclusion: In conclusion, dietary 0.2% xylanase supplementation promoted hepatic antioxidant capacity and immune response via modulating the expression of functional genes in Tibetan sheep. [ABSTRACT FROM AUTHOR]

Background: Crown lengthening (CL) in esthetic areas has become a versatile procedure with applications in many clinical situations. Knowledge concerning different periodontal phenotypes, and the supracrestal tissue attachment (STA)—former biological width—has allowed for a better understanding of surgical management, allowing for the individualization of surgical therapy. This review presented an individualized surgical approach to CL in esthetic areas based on evaluating the phenotype and current considerations about the STA, correlating them to suggestive surgical techniques. Methods: For an individualized surgical approach, it is primarily necessary to understand STA, including the relationship and distance between the cementoenamel junction (CEJ) and the bone crest (BC) and the position of the free gingival margin (FGM); secondarily, it is necessary to verify the periodontal phenotype to prepare surgical planning (gingivectomy or osseous resection/contouring). Three periodontal phenotypes are recognized, presenting different biological behaviors due to specific characteristics implicitly correlated to soft tissue management. Results: Then, after assessing the distance from the CEJ to the BC, the position of the FGM, and the periodontal phenotype, it is possible to individualize the treatment according to the phenotype. In cases of a thin and scalloped periodontium with delicate gingiva, there might be the presence of bone dehiscence, fenestration, and instability in the healing of the gingival margin, bringing extra attention to tissue manipulation and suggesting a minimally invasive technique (no flap). A partial-thickness flap is recommended for a thick and scalloped periodontium, keeping the periosteum adhered to the bone. For periodontium B (fibrous and dense gingiva and tissue resistant to injuries), the surgical approach recommended is an open full-thickness flap with osteotomy for horizontal and vertical bone volume removal. Then, observing first the specific parameters, such as the STA, CEJ, BC, FGM, and KTW, and then the characteristics of periodontal phenotypes, it is possible to determine the individualized surgical strategy and a reasonable surgical approach to tissue manipulation in clinical CL surgeries. Conclusions: The surgical approach must be defined according to individualized planning since several variables can influence the dynamics of the periodontal tissues. [ABSTRACT FROM AUTHOR]

Objectives We sought to investigate the morphologic and immunophenotypic characteristics of TCL1 family–negative T-cell prolymphocytic leukemia (T-PLL) Methods Twenty cases of TCL1 family–negative T-PLL were studied. Results The doubling time of leukemic cells ranged from less than 2 days to more than 5 years, with a median of 5.5 months. Leukemic cells were small to medium-sized, with round to irregular nuclei, variably condensed chromatin, and small amounts of agranular cytoplasm. A visible nucleolus was identified in 11 (55%) cases. Cytoplasmic blebs/protrusions were identified in all cases, but their occurrence was highly variable from case to case. Bone marrow biopsy showed an interstitial pattern in 90% of cases and a diffuse pattern in the remaining 10% of cases. Flow cytometric immunophenotypic analysis showed that the leukemic cells in all cases were CD4 positive; 3 (15%) also showed concurrent CD8 expression. All cases were positive for CD2 and CD5. Surface CD3 and CD7 were positive in 19 of 20 (95%) cases, and all CD3-positive cases expressed the T-cell receptor αβ. Compared with prototypic T-PLL cases, these 2 groups shared many immunophenotypic findings, except CD8 and CD26, both of which were more commonly expressed in prototypic T-PLL cases. Conclusions TCL1 family–negative T-PLL cases have morphologic and immunophenotypic features that are similar to prototypic T-PLL. They are characterized by neoplastic proliferation of small to medium-sized mature T cells with CD4-positive T-cell receptor αβ phenotype. Tumor cells frequently maintain pan-T antigen expression. Recognizing these morphologic and immunophenotypic features will aid in accurately diagnosing this rare subset of T-PLL. [ABSTRACT FROM AUTHOR]

Ecosourcing seed of 'local genetic stock' for ecological restoration has been practiced in New Zealand for about 50 years. However, we believe that it has become unnecessarily restrictive. Ecosourcing ensures plants used for restoration are adapted to local conditions and maintains current distributional patterns. It also restricts genetic diversity, confines species to their historic range, and reduces the conservation options for threatened species. For example, New Zealand tree species, the life form most frequently used in restoration plantings, have low population genetic differentiation and high net migration of alleles throughout their range. Therefore, very little is gained through restrictive ecosourcing of tree seed. Furthermore, avoidance of the danger of inbreeding depression and widening the scope for closer environmental matching, argues for larger rather smaller source areas. Climate change, extinctions across multiple trophic levels, habitat loss and fragmentation, spread of invasive species, and novel habitats have completely altered the contemporary biotic landscape. Conservation needs to engage with these changes if it is to protect and restore ecosystems. Restrictive ecosourcing is counter-productive as it limits utilising genotypic, phenotypic and ecotypic diversity, and thus the evolutionary potential of indigenous species and ecosystems. It also reduces opportunities to protect biodiversity when populations are small, and limits response to climate change. A new approach is needed. We recommend that phylogeographic patterns and biogeographic boundaries be used to set nine broad ecosourcing regions and, within these regions, phenotypic adaptation to particular environments be used as a guide to seed selection. This more relaxed approach to ecosourcing will improve restoration outcomes through increasing species and genetic diversity, reducing the detrimental effects of inbreeding and promoting the genetic rescue of populations of threatened species. Examples of adopting an eco-evolutionary approach to ecosourcing are provided for the early-successional coloniser Kunzea ericoides and late-successional conifer species. [ABSTRACT FROM AUTHOR]

First introduced in 2021, MetOrigin has quickly established itself as a powerful web server to distinguish microbial metabolites and identify the bacteria responsible for specific metabolic processes. Building on the growing understanding of the interplay between the microbiome and metabolome, and in response to user feedback, MetOrigin has undergone a significant upgrade to version 2.0. This enhanced version incorporates three new modules: (1) Quick search module that facilitates the rapid identification of bacteria associated with a particular metabolite; (2) Orthology analysis module that links metabolic enzyme genes with their corresponding bacteria; (3) Mediation analysis module that investigates potential causal relationships among bacteria, metabolites, and phenotypes, highlighting the mediating role of metabolites. Additionally, the backend MetOrigin database has been updated with the latest data from seven public databases (KEGG, HMDB, BIGG, ChEBI, FoodDB, Drugbank, and T3DB), with expanded coverage of 210,732 metabolites, each linked to its source organism. MetOrigin 2.0 is freely accessible at http://metorigin.met-bioinformatics.cn. Highlights: MetOrigin 2.0 has integrated three analytical modes and eight distinct modules for advanced microbial metabolite discrimination.The updated database and three new features including quick search, orthology analysis, and mediation analysis expand the platform's versatility and functionality.MetOrigin 2.0 serves as a comprehensive web server for microbiome‐metabolome data integration, streamlining the identification of microbial metabolites and their origins. [ABSTRACT FROM AUTHOR]

The severity and course of sepsis-associated acute kidney injury (SA-AKI) are correlated with the mortality rate. Early detection of SA-AKI subphenotypes might facilitate the rapid provision of individualized care. In this post-hoc analysis of a multicenter prospective study, we combined conventional kidney function variables with serial measurements of urine (tissue inhibitor of metalloproteinase-2 [TIMP-2])* (insulin-like growth factor-binding protein [IGFBP7]) at 0, 6, 12, and 24 h) and then using an unsupervised hierarchical clustering of principal components (HCPC) approach to identify different phenotypes of SA-AKI. We then compared the subphenotypes with regard to a composite outcome of in-hospital death or the initiation of renal replacement therapy (RRT). We included 184 patients presenting SA-AKI within 6 h of the initiation of catecholamines. Three distinct subphenotypes were identified: subphenotype A (99 patients) was characterized by a normal urine output (UO), a low SCr and a low [TIMP-2]*[IGFBP7] level; subphenotype B (74 patients) was characterized by existing chronic kidney disease (CKD), a higher SCr, a low UO, and an intermediate [TIMP-2]*[IGFBP7] level; and subphenotype C was characterized by very low UO, a very high [TIMP-2]*[IGFBP7] level, and an intermediate SCr level. With subphenotype A as the reference, the adjusted hazard ratio (aHR) [95%CI] for the composite outcome was 3.77 [1.92–7.42] (p < 0.001) for subphenotype B and 4.80 [1.67–13.82] (p = 0.004) for subphenotype C. Combining conventional kidney function variables with urine measurements of [TIMP-2]*[IGFBP7] might help to identify distinct SA-AKI subphenotypes with different short-term courses and survival rates. [ABSTRACT FROM AUTHOR]

Introduction: Physical inactivity due to shortness of breath is common among patients with uncontrolled asthma. We evaluated the body mass composition and exercise capacity of patients with poorly controlled asthma, despite maximal inhalation therapy. Methods:  We recruited 56 patients from the Asthma Clinic of the University Hospital of Liège between September 2020 and December 2023, and 14 healthy subjects. Patients with asthma underwent detailed investigations, including induced sputum, exercise testing, and Dual-Energy X-ray Absorptiometry (DXA), to determine overall body fat mass and fat-free mass, while healthy subjects only underwent DXA. This study was approved by the Ethics Committee (2019/362). Results:  The mean age of patients with asthma was 45 years ± 12; 58% were female, 10% were active smokers, and mean post-BD Forced Expiratory Volume in one second was 85.7% predicted. Compared to healthy subjects, asthmatics had a higher BMI (28.5± 5.1 kg/m2 vs 22.5 ± 2.8 kg/m2, p< 0.0001) and fat mass index (FMI; 10.3 ± 3.7 vs 5.9 ± 2.8 kg/m2, p=0.0005), lower lean and bone mass (62% vs 71%, p=0.0012), and greater android fat distribution (1.00 ± 0.22 vs 0.80 ± 0.13, p< 0.0001). Eosinophilic asthma (sputum eosinophil count of ≥ 3%) was characterized by a better VO2 max compared to non-eosinophilic asthma (20.7 [17.8– 24.3] vs 17.3 [14.0– 18.9], p=0.04). Higher lean mass was correlated with better asthma control and lower depression scores. Lean mass and bone mineral content correlated with maximal expiratory, inspiratory, and maximal aerobic power. Conclusion:  Our study confirmed that patients with uncontrolled asthma were overweight and had decreased exercise capacity. Plain Language Summary: Schleich et al conducted a study on a population of 56 patients with asthma and compared their body composition (fat and lean mass proportion, distribution, and bone mineral content) to that of 14 healthy subjects. Patients with uncontrolled asthma have symptoms of dyspnea that may induce a vicious circle in which shortness of breath limits physical activity. Physical inactivity and treatment with corticosteroids may induce changes in body composition. Therefore, the team evaluated the body mass composition and exercise capacity of patients with poorly controlled asthma, despite maximal inhalation therapy. Patients with asthma also underwent detailed investigations, including lung function testing, exhaled nitric oxide, and induced sputum, to establish the inflammatory phenotype. Compared to healthy subjects, asthmatics had higher body mass index and fat mass index levels, lower lean and bone mass, and more android fat distribution. Eosinophilic asthma was characterized by better exercise tolerance than that of non-eosinophilic asthma. Moreover, higher lean mass was associated with better asthma control and lower depression scores. In conclusion, this study confirmed that patients with uncontrolled asthma are overweight and have decreased exercise capacity. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has intensified concerns over bacterial infections and antimicrobial resistance, particularly in Romania. This systematic review explores bacterial infection patterns and resistance during the pandemic to address critical gaps in knowledge. Methods: A systematic review, following PRISMA guidelines, was conducted using databases such as PubMed and Scopus, focusing on studies of bacterial infections from 2020 to 2022. Articles on bacterial infections in Romanian patients during the pandemic were analyzed for demographic data, bacterial trends, and resistance profiles. Results: A total of 87 studies were included, detailing over 20,000 cases of bacterial infections. The review found that Gram-negative bacteria, particularly Escherichia coli and Klebsiella pneumoniae, were the most frequently identified pathogens, alongside Gram-positive Staphylococcus aureus and Enterococcus spp. Multidrug resistance (MDR) was noted in 24% of the reported strains, with common resistance to carbapenems and cephalosporins. Conclusions: The pandemic has amplified the complexity of managing bacterial infections, particularly in critically ill patients. The rise in MDR bacteria underscores the need for stringent antimicrobial stewardship and infection control measures. Continuous monitoring of bacterial trends and resistance profiles will be essential to improve treatment strategies in post-pandemic healthcare settings. [ABSTRACT FROM AUTHOR]

The mutualistic relationship between Streptococcus thermophilus (S. thermophilus) and L. delbrueckii subsp. bulgaricus (L. bulgaricus) is responsible for milk coagulation, gel formation, and the flavour of yogurt. Under set-style yogurt processing conditions, the performance of a mixed culture composed of these species depends on key technological parameters such as the capacity for acidification and proteolytic activity. This study aimed to determine the extent of phenotypic diversity by comparing the key traits of acidification and proteolytic activity among isolates found in yogurt starter cultures. Seventy-two isolates from three industrial starter cultures were ranked by either their fast or slow acidification activity (time to reach pH 4.6, 16 h), proteolytic activity, cell envelope proteinase (CEP) activity, redox potential and titratable acidity. The integration of multiple phenotype measures by hierarchical clustering and non-metric dimensional scaling (NMDS) clustered groups of isolates by multifactor similarity. A significant difference (p-value < 0.05) was observed between the clusters regarding redox potential and the proteolytic activity of both S. thermophilus and L. bulgaricus. The integration of multiple phenotypes points to the diversification that may have occurred over repeated culturing of yogurt starter bacteria. The phenotypic diversity may explain the divergence in starter performance and be used to refine the formulation of new starter cultures. Future work will investigate the correlation between the activity of specific enzymes based on the phenotype to explain the separation between the fast and slow acidification of isolates. [ABSTRACT FROM AUTHOR]

Turner syndrome (TS) is defined by partial or complete absence of a sex chromosome. Little is known about the phenotype of individuals with TS mosaic with trisomy X (45,X/47,XXX or 45,X/46,XX/47,XXX) (~3% of TS). We compared the diagnostic, perinatal, medical, and neurodevelopmental comorbidities of mosaic 45,X/47,XXX (n = 35, 9.4%) with nonmosaic 45,X (n = 142) and mosaic 45,X/46,XX (n = 66). Females with 45,X/47,XXX had fewer neonatal concerns and lower prevalence of several TS‐related diagnoses compared with 45,X; however the prevalence of neurodevelopmental and psychiatric diagnoses were not different. Compared to females with 45,X/46,XX, the 45,X/47,XXX group was significantly more likely to have structural renal anomalies (18% vs. 3%; p = 0.03). They were twice as likely to have congenital heart disease (32% vs. 15%, p = 0.08) and less likely to experience spontaneous menarche (46% vs. 75% of those over age 10, p = 0.06), although not statistically significant. Congenital anomalies, hypertension, and hearing loss were primarily attributable to a higher proportion of 45,X cells, while preserved ovarian function was most associated with a higher proportion of 46,XX cells. In this large TS cohort, 45,X/47,XXX was more common than previously reported, individuals were phenotypically less affected than those with 45,X, but did have trends for several more TS‐related diagnoses than individuals with 45,X/46,XX. [ABSTRACT FROM AUTHOR]

Understanding the role of gut microbiota in fish health is crucial for optimizing aquaculture practices and ensuring sustainable fish populations. In this study, the diversity and compositional differences of intestinal microbiota were comparatively analyzed between wild and cultured striped knifejaw (Oplegnathus fasciatus Kroyer, 1845). Using high-throughput 16S rDNA sequencing and bioinformatics, an in-depth investigation of the gut microbiota in both populations was conducted. The results revealed that the number of intestinal bacterial sequences was significantly higher in the cultured population than in the wild population. The study included 16 individuals from the wild population and 38 individuals from the cultured population, with an average weight of 67.7 ± 12.4 g and 44.9 ± 16.8 g, respectively. Alpha diversity analysis indicated that intestinal microbiota species richness and diversity were both greater in the cultured O. fasciatus. Furthermore, significant differences were observed in the intestinal bacterial communities between the two populations, with Pseudomonadota, Verrucomicrobia, and Bacillota dominating in the cultured population, whereas Pseudomonadota overwhelmingly dominated in the wild population. Functional prediction analysis revealed differences between the intestinal microbiota in pathways related to genetic and environmental information processing, as well as metabolism. This study provides critical data for understanding the structure and function of intestinal microbial communities in O. fasciatus and offers a theoretical foundation for optimizing farming strategies to improve fish health and growth performance. [ABSTRACT FROM AUTHOR]

Most approaches to advance simplified physiology-based precision medicine strategies for obstructive sleep apnea (OSA) focus on sleep parameters (i.e., OSA endotypes). However, wakefulness physiology measures can also provide prediction insight for certain OSA therapies, yet their relationship with sleep parameters has not been extensively investigated. This study aimed to investigate potential relationships between awake ventilatory control parameters and sleep OSA endotypes and their potential to predict changes in OSA severity with morphine. Data were acquired from a randomized, crossover trial that investigated the effects of morphine versus placebo on OSA severity and underlying mechanisms. Here, awake ventilatory chemoreflex testing before overnight polysomnography was compared with direct measures of sleep respiratory control (e.g., hypercapnic ventilatory responses and loop gain) and OSA endotypes during a separate overnight physiology study [pharyngeal critical closure pressure (Pcrit), muscle responsiveness via genioglossus intramuscular electromyography, and arousal threshold via epiglottic pressure catheter to transient continuous positive airway pressure reductions]. Twenty-one men with OSA completed both study arms. During placebo, 1) awake chemosensitivity correlated with Pcrit (r = 0.726, P = 0.001), 2) arousal threshold correlated with awake CO2 ventilatory response threshold (r = −0.467, P = 0.047) and basal ventilation (r = −0.500, P = 0.029). Awake chemosensitivity and Pcrit also correlated with the apnea-hypopnea index (P < 0.001) during placebo. Awake chemosensitivity was predictive of changes in OSA severity with morphine (r = −0.535, P = 0.013). In conclusion, awake measures of respiratory control are related to physiological endotypes, such as airway collapsibility and arousal threshold during sleep and OSA severity. Awake ventilatory chemosensitivity has the best potential to predict changes in OSA severity with morphine. NEW & NOTEWORTHY: Both awake ventilatory control measures and OSA endotypes measured during sleep have reported potentials in endotyping/phenotyping OSA, although no randomized, controlled trial has compared/linked between the two techniques. From a double-blind, randomized placebo-controlled crossover trial, we found that awake measures of respiratory control are related to physiological endotypes such as airway collapsibility and arousal threshold during sleep and OSA severity. Awake ventilatory chemosensitivity has the best potential to predict changes in OSA severity with morphine. [ABSTRACT FROM AUTHOR]

Digital biomarkers derived from mobile sensors could enable more frequent and objective monitoring of motor disorder symptoms. In this study, we examined the sensitivity of five tablet-based tests in predicting changes in the MDS-UPDRS-III scores following controlled Levodopa administration, utilizing regression models trained on data from 28 patients. Our experiments revealed that the best-performing single-test models exhibited an inverse prediction in 5 patients. A combined model incorporating two tests reduced misclassification to three patients. Further stratification of patients into symptom-specific groups, based on the presence of medication-induced tremor changes, and training two subgroup-specific models led to only one subject being misclassified. These results underscore the potential of mobile device biomarkers for prediction of symptom changes in Parkinson's disease patients and the need for individualization. [ABSTRACT FROM AUTHOR]

It is unclear how rare RNF213 variants, other than the p.R4810K founder variant, affect the clinical phenotype or the function of RNF213 in moyamoya disease (MMD). This study included 151 Japanese patients with MMD. After performing targeted resequencing for all coding exons in RNF213, we investigated the clinical phenotype and statistically analyzed the genotype–phenotype correlation. We mapped RNF213 variants on a three-dimensional (3D) model of human RNF213 and analyzed the structural changes due to variants. The RNF213 p.R4810K homozygous variant, p.R4810K heterozygous variant, and wild type were detected in 10 (6.6%), 111 (73.5%), and 30 (19.9%) MMD patients, respectively. In addition, 15 rare variants were detected in 16 (10.6%) patients. In addition to the influence of the p.R4810K homozygous variant, the frequency of cerebral infarction at disease onset was higher in pediatric patients with other rare variants (3/6, 50.0%, P = 0.006) than in those with only the p.R4810K heterozygous variant or with no variants (2/51, 3.9%). Furthermore, on 3D modelling of RNF213, the majority of rare variants found in pediatric patients were located in the E3 module and associated with salt bridge loss, contrary to the results for adult patients. The clinical phenotype of rare RNF213 variants, mapped mutation position, and their predicted structural change differed between pediatric and adult patients with MMD. Rare RNF213 variants, in addition to the founder p.R4810K homozygous variant, can influence MMD clinical phenotypes or structural change which may contribute to the destabilization of RNF213. [ABSTRACT FROM AUTHOR]

Cleofe del Pilar Yovera-Ancajima,1,2 Luis Yuri Calderon Cumpa,1,3 Irene Doraliza Lezama-Cotrina,1,4 Eder Walttuoni-Picón,1 Wilmer William Cárdenas-Mendoza,1,5 Jennie Evelyn Culqui-García,1 Wilmer Raul Retuerto-Salazar,1 Roberto Carlos Céspedes Poma1,6 1Comunidad de conocimiento: Enfermedades infecciosas y no infecciosas tropicales, Universidad Nacional Federico Villarreal, Lima, Perú; 2Centro de Hemoterapia y Banco de Sangre tipo II Hospital Nacional Cayetano Heredia, Lima, Perú; 3Centro de Hemoterapia y Banco de Sangre tipo II Hospital Nacional Guillermo Almenara Irigoyen, Lima, Perú; 4Centro de Hemoterapia y Banco de Sangre tipo II Hospital María Auxiliadora, Lima, Perú; 5Servicio de Emergencia. Hospital Nacional Guillermo Almenara Irigoyen, Lima, Perú; 6Instituto de Estandarización En Laboratorio Clínico Del Perú, Lima, PerúCorrespondence: Eder Walttuoni-Picón, Email 2020008671@unfv.edu.peBackground: Red blood cell alloimmunization currently continues to be a significant problem during the blood transfusion process, where phenotypic identification plays a clinically relevant role in its prevention. The objective of the study was to carry out the phenotypic identification of blood groups in blood donors from three hospitals in Lima.Methods: A cross-sectional study was conducted, including 20,141 blood donors in three hospitals in Lima, Perú during the period from January to June 2023. Red blood cell phenotyping was performed by the gel agglutination method using gel cards with the IH-500 automated system.Results: A predominance of donors within the age group of 29 to 38 years (30.9%) was observed, with the majority being men (69.5%). Most donors were Peruvian (97.9%), and among foreign donors (2.1%), Venezuelans predominated (1.5%). In the distribution of the ABO and RhD blood groups, the O Rh+ phenotype predominated in 79% of the donors. In the phenotypic distribution of the Rh system, the presence of the D antigen was observed in 98.1% of the donors, with the c phenotype being the most frequent (76.4%). For the Kidd system, 70.7% of the donors presented the Jka antigen and 81.9% the Jkb antigen. In the Duffy system, 77.7% of the donors presented the Fya antigen and 50% the Fyb antigen. For the MNS system, 93.7% of donors had the S antigen and 76.1% had the s antigen. It was also found that 1.5% of donors are carriers of the Kell antigen, all of which are clinically important.Conclusion: The phenotypic identification of blood groups in blood donors from three hospitals in Lima highlighted the clinical relevance of identifying less common antigens in the Kell, Kidd, Duffy, and MNS systems to prevent alloimmunization during blood transfusions.Keywords: alloimmunization, phenotype, blood group antigens, blood donors

[Objective] To explore the effectiveness of applying the PDCA (Plan-Do-Check-Act) cycle to enhance the compatibility rate of five Rh blood group antigen phenotypes between donors and recipients across multiple hospital campuses. [Methods] Clinical blood transfusion data from May to July 2022 were selected. Specific improvement measures were formulated based on the survey results, and the PDCA cycle management model was implemented from August 2022. The post-intervention phase spanned from August 2022 to October 2023. The Rh phenotype compatibility rate, the detection rate of Rh system antibodies, and the proportion of Rh system antibodies among unexpected antibodies were compared between the pre-intervention phase (May to July 2022) and the post-intervention phase. [Results] After the continuous improvement with the PDCA cycle, the compatibility rate for the five Rh blood group antigen phenotypes between donors and recipients from August to October 2023 reached 81.90%, significantly higher than the 70.54% recorded during the pre-intervention phase (May to July 2022, P

The aim of this study is to describe genotype and phenotype of patients with bestrophinopathy. The case records were reviewed retrospectively, findings of multimodal imaging such as color fundus photograph, optical coherence tomography (OCT), fundus autofluorescence, electrophysiological, and genetic tests were noted. Twelve eyes of six patients from distinct Indian families with molecular diagnosis were enrolled. Exon 4 of BEST1 was mutated in 3 cases, while exons 2, 3, and 7 in others. Deletion is seen in Exon 7 and missense mutation in other exons. Sporadic autosomal dominant and recessive inheritance was observed in these families. Two patients had primary angle closure glaucoma with a history of consanguineous marriage and glaucoma in the family. Based on our findings, multifocal vitelliform subretinal deposits were the most common fundus finding in patients with autosomal recessive mutation while macular vitelliform lesion was seen with sporadic or autosomal dominant mutation; however, cosegregation analysis was not done. Baseline OCT showed macular and extramacular subretinal exudates, subretinal fluid, intraretinal cystic and schitic spaces, and thickened photoreceptors outer segment tips. Two patients developed abnormal vasculature and focal choroidal excavation in OCT. A severe reduction in the electro-oculogram Ardens ratio was noted while electroretinography was normal. Bestrophinopathy has a varied presentation with complex genotype-phenotype relationships. OCT is a noninvasive tool for monitoring and prognostication. Genetic testing of other family members should be facilitated.

Background. Osteoarthritis is a heterogeneous disease characterized by lesions of one or more joints, diversity of clinical features, and a large palette of biochemical and molecular characteristics, which together suggests the existence of multiple phenotypes and endotypes of osteoarthritis. In modern medicine, osteoarthritis is considered as part of a multisystem active pathologic process in the human body, triggered by a group of systemic (genetic, transcriptomic, metabolomic, proteomic, neuroimmunoendocrine) and local (biomechanical) factors. Today, osteoarthritis should be treated as a systemic disease, taking into account individual patient factors such as genetics, inflammatory response, and lifestyle.Objective. The purpose of the review of medical literature was to search for modern effective and safe therapeutic interventions for generalized osteoarthritis (GOA).Results. An analysis of the results of studies of the epidemiology of GOA, genetic characteristics and data on pheno- and endotyping of GOA was carried out. Current mechanisms of development of GOA are presented, including the role of neoangiogenesis and neoinnervation. The multimodal approach and modern directions and classification of disease-modifying therapy for GOA are considered. An analysis of the mechanisms of action, effectiveness and prospects for the use of chondroitin sulfate (CS), glucosamine sulfate (GS) and undenatured collagen (UC) type II was performed, taking into account the endotype for a specific phenotype of GOA with the development of personalized regimens therapy of OA for the parenteral form of CS.Conclusion. Therefore, GOA should be treated as a systemic disease, taking into account its genetics, inflammatory response and lifestyle, and medical care should be more holistic and personalized.

Background/aim Familial Mediterranean fever (FMF) is an autoinflammatory disease, with a high prevalence in the Mediterranean region. It is brought out by variants in the MEFV gene. The present goal is to describe the demographic, clinical features, and MEFV gene variants among Egyptian FMF patients and to explore the relation of MEFV variants with clinical features and selected laboratory markers. Patients and methods The present study enrolled 302 patients with FMF from both sexes with a mean age 18.01±8.73 years. Patients were recruited from the Clinical Genetic Clinic, Medical Research Centre of Excellence, National Research Centre, Cairo, Egypt, during the period from 2021 to 2023. All patients were subjected to complete history taking, clinical evaluation, and laboratory investigations. C-reactive protein, serum amyloid A (SAA) protein and vitamin D were measured using enzyme-linked immuno-sorbent assay technique, while erythrocyte sedimentation rate was measured by Westergren method. In addition, MEFV genetic variants were investigated using a real-time PCR genotyping assay and direct sequencing of exon 2 and exon 10 of the MEFV gene. Results The average age of FMF cases was 18.01±8.73 years (with a range between 2 and 34 years), and the female/male ratio was 1.07. The most prevalent symptoms were abdominal pain, fever, and arthritis. Genotyping of the MEFV gene demonstrated that 215 (71.2%) patients were heterozygotes, 26 (8.6%) patients were compound heterozygotes and 12 (4.0%) patients were homozygotes, while 49 (16.2%) patients had no detected mutation. p. Met 694Ile was the most common MEFV variant (36.7%), followed by p. Met680Ile (21.5%), p.Val726Ala (9.6%), p.Glu148Gln (8.94%), and p.Met694Val (7.94%). There was no significant variation in clinical manifestations between different MEFV gene variants. The level of SAA protein was higher in FMF patients carrying the Met694Val variant, while carriers of the p. Glu148Gln variant showed lower erythrocyte sedimentation rate, SAA, and higher serum vitamin D. Conclusion The most commonly encountered MEFV gene variants among our Egyptian FMF cases were p. Met694Ile followed by p. Met680Ile. No phenotype-genotype association was observed. The p. Met694Val variant could be a possible risk factor for developing amyloidosis. Investigating the whole MEFV gene is recommended to fully understand the molecular background of FMF cases and properly establish a good correlation with the variable phenotypes.

BACKGROUND: Although ABO and RhD are the clinically significant blood group antigens that are routinely tested for, other blood group antigens may become important in multiply transfused patients due to risk of alloimmunization. Knowledge of antigen prevalence in a population is important in the context of alloimmunization and antigen matching. This study aims to do the same in a population of voluntary blood donors of a center in South India. AIMS AND OBJECTIVES: To study the ABO, Rh (D, C, c, E, and e), and Kell (K) antigen and Rh phenotype prevalence in whole blood donors donating at the blood bank of a tertiary care hospital in South India. MATERIALS AND METHODS: One thousand and two hundred eligible whole blood donors were chosen by random sampling between November 2017 and April 2019. After administration of informed consent and routine testing for ABO grouping, RhD typing, and indirect antiglobulin test, Rh and Kell typing was done on appropriate gelcards and the data were analyzed to arrive at phenotypes. RESULTS: 97.6% of the donors were male and 2.4% were female. They were divided into 7 different categories based on the regions of origin: Kerala, Andhra Pradesh, Tamil Nadu, Karnataka, West Bengal, North India, and others with the largest number of donors hailing from Karnataka (38.5%). The ABO distribution, in descending order, was as follows: O (38%), B (34.5%), A (20.6%), and AB (6.8%). The prevalence of the Rh antigens was as follows: D: 93.4%, C: 87.9%, c: 55.6%, E: 19.3%, and e: 98.8%. K was present in 1.4% of the population. Since genotyping has not been done, the most common “presumed” Rh phenotype among RhD-positive donors was R1R1 (46.4% of total donors and 49.5% of RhD-positive donors). The most common phenotype among RhD-negative donors was rr (5.9% of total donors and 92.2% of RhD-negative donors). The order of prevalence of the ABO, Rh, and K antigens and the Rh phenotypes remained the same irrespective of gender, ABO group, and region of origin. CONCLUSION: This population-based study analyzes a donor population as a whole and separately as per regions of origin and shows that antigen prevalence and thereby risk of alloimmunization does not vary markedly among the different population subsections. Hence, even where extended phenotyping and antigen matching cannot be done, risk of alloimmunization may be low. Limiting antigen matching to specific patient subsets like in multiply transfused patients with uncommon phenotypes may, therefore, be an efficient and cost-effective approach.

Abstract Introduction Diamond Blackfan anaemia (DBA) is a rare disorder characterized by failure of red blood cell production, congenital abnormalities and cancer predisposition, primarily caused by pathogenic germline variants in genes encoding ribosomal proteins. Methods We conducted a genotype‐phenotype and outcome study of 121 patients with DBA spanning the 20‐year history of the National Cancer Institute's Inherited Bone Marrow Failure Syndromes study. Patient phenotypes were compared by large versus small ribosomal protein genes, across genes with >5 cases (RPS19, RPS29, RPS26 and RPL35A) and by type of pathogenic variants (hypomorphic versus null, large deletions versus others). Results A pathogenic germline variant was identified in 71% of patients (n = 86/121) from 54 families. After adjusting for multiple testing, we found that patients with RPS29 variants were least likely to need treatment for anaemia while those with large ribosomal protein subunit variants had a higher proportion of intellectual disability and gastrointestinal abnormalities compared with small ribosomal protein subunit variants (p

Aims: Patients with PTEN hamartoma tumour syndrome (PHTS) have an increased risk of developing cancer due to a pathogenic germline variant in the PTEN tumour suppressor gene. Early recognition of PHTS facilitates initiation of cancer surveillance which is highly effective in preventing the development of advanced malignancies. PHTS is rare and due to its varied phenotype, even within families, oral abnormalities may be a valuable tool in the identification of these patients at an early stage before cancer development. Materials and methods: Between 1997 and 2020, phenotypic characteristics were evaluated in 81 paediatric (median age: 9 years) and 86 adult (median age: 40 years) PHTS patients by one of 2 medical experts during yearly surveillance visits at a Dutch PHTS expertise centre. Oral features evaluated included gingival hypertrophy, oral papillomas, and high palate (in adults). Results: Within adults, gingival hypertrophy was present in 94%, oral papillomas in 88%, and a high palate in 89%. All adult patients had at least one of these oral features, and 99% showed at least 2 oral features. Oral features were less common in paediatric patients, especially under 11 years of age. Gingival hypertrophy was observed in 44% and oral papillomas in 54% of paediatric patients. Conclusions: The presence of 2 or 3 oral features may indicate PHTS in adults or adolescents, especially if macrocephaly is present. Dental professionals are well-positioned to recognise these oral manifestations could be related to PHTS. They can initiate an overall clinical assessment of the patient by alerting the patient's medical practitioner of the findings and the possible need for genetic testing. This could significantly improve outcomes, including life expectancy, for patients and possibly for their relatives. Clinical relevance: Dental professionals are ideally placed to recognise oral features and initiate early assessment of PHTS which could significantly improve patient outcomes.

Sexual antagonism occurs when males and females differ in their phenotypic fitness optima but are constrained in their evolution to these optima because of their shared genome. The sex chromosomes, which have distinct evolutionary "interests" relative to the autosomes, are theorized to play an important role in sexually antagonistic conflict. However, the evolutionary responses of sex chromosomes and autosomes have usually been considered independently, that is, via contrasting the response of a gene located on either an X chromosome or an autosome. Here, we study the coevolutionary response of the X chromosome and autosomes to sexually antagonistic selection acting on a polygenic phenotype. We model a phenotype initially under stabilizing selection around a single optimum, followed by a sudden divergence of the male and female optima. We find that, in the absence of dosage compensation, the X chromosome promotes evolution toward the female optimum, inducing coevolutionary male-biased responses on the autosomes. Dosage compensation obscures the female-biased interests of the X, causing it to contribute equally to male and female phenotypic change. We further demonstrate that fluctuations in an adaptive landscape can generate prolonged intragenomic conflict and accentuate the differential responses of the X and autosomes to this conflict.

Individual cancers are composed of heterogeneous tumor cells with distinct phenotypes and genotypes, with triple negative breast cancers (TNBC) demonstrating the most heterogeneity among breast cancer types. Variability in transcriptional phenotypes could meaningfully limit the efficacy of monotherapies and fuel drug resistance, although to an unknown extent. To determine if transcriptional differences between tumor cells lead to differential drug responses we performed single cell RNA-seq on cell line and PDX models of breast cancer revealing cell subpopulations in states associated with resistance to standard-of-care therapies. We found that TNBC models contained a subpopulation in an inflamed cellular state, often also present in human breast cancer samples. Inflamed cells display evidence of heightened cGAS/STING signaling which we demonstrate is sufficient to cause tumor cell resistance to chemotherapy. Accordingly, inflamed cells were enriched in human tumors taken after neoadjuvant chemotherapy and associated with early recurrence, highlighting the potential for diverse tumor cell states to promote drug resistance.

Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4+ T cells3 and agonism of the pregnane X receptor4. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.

ObjectiveThis study was undertaken to assess reproducibility of the epilepsy outcome and phenotype in a lateral fluid percussion model of posttraumatic epilepsy (PTE) across three study sites.MethodsA total of 525 adult male Sprague Dawley rats were randomized to lateral fluid percussion-induced brain injury (FPI) or sham operation. Of these, 264 were assigned to magnetic resonance imaging (MRI cohort, 43 sham, 221 traumatic brain injury [TBI]) and 261 to electrophysiological follow-up (EEG cohort, 41 sham, 220 TBI). A major effort was made to harmonize the rats, materials, equipment, procedures, and monitoring systems. On the 7th post-TBI month, rats were video-EEG monitored for epilepsy diagnosis.ResultsA total of 245 rats were video-EEG phenotyped for epilepsy on the 7th postinjury month (121 in MRI cohort, 124 in EEG cohort). In the whole cohort (n = 245), the prevalence of PTE in rats with TBI was 22%, being 27% in the MRI and 18% in the EEG cohort (p > .05). Prevalence of PTE did not differ between the three study sites (p > .05). The average seizure frequency was .317 ± .725 seizures/day at University of Eastern Finland (UEF; Finland), .085 ± .067 at Monash University (Monash; Australia), and .299 ± .266 at University of California, Los Angeles (UCLA; USA; p  .05). Of the 219 seizures, 53% occurred as part of a seizure cluster (≥3 seizures/24 h; p >.05 between the study sites). Of the 209 seizures, 56% occurred during lights-on period and 44% during lights-off period (p > .05 between the study sites).SignificanceThe PTE phenotype induced by lateral FPI is reproducible in a multicenter design. Our study supports the feasibility of performing preclinical multicenter trials in PTE to increase statistical power and experimental rigor to produce clinically translatable data to combat epileptogenesis after TBI.

Genome-wide association studies (GWASs) have uncovered susceptibility loci associated with psychiatric disorders such as bipolar disorder (BP) and schizophrenia (SCZ). However, most of these loci are in non-coding regions of the genome, and the causal mechanisms of the link between genetic variation and disease risk is unknown. Expression quantitative trait locus (eQTL) analysis of bulk tissue is a common approach used for deciphering underlying mechanisms, although this can obscure cell-type-specific signals and thus mask trait-relevant mechanisms. Although single-cell sequencing can be prohibitively expensive in large cohorts, computationally inferred cell-type proportions and cell-type gene expression estimates have the potential to overcome these problems and advance mechanistic studies. Using bulk RNA-seq from 1,730 samples derived from whole blood in a cohort ascertained from individuals with BP and SCZ, this study estimated cell-type proportions and their relation with disease status and medication. For each cell type, we found between 2,875 and 4,629 eGenes (genes with an associated eQTL), including 1,211 that are not found on the basis of bulk expression alone. We performed a colocalization test between cell-type eQTLs and various traits and identified hundreds of associations that occur between cell-type eQTLs and GWASs but that are not detected in bulk eQTLs. Finally, we investigated the effects of lithium use on the regulation of cell-type expression loci and found examples of genes that are differentially regulated according to lithium use. Our study suggests that applying computational methods to large bulk RNA-seq datasets of non-brain tissue can identify disease-relevant, cell-type-specific biology of psychiatric disorders and psychiatric medication.

OBJECTIVE: To determine i) pain phenotypes (PP) in people with early-stage knee osteoarthritis (EKOA); ii) the longitudinal association between the phenotypes and pain worsening at two years. DESIGN: We studied participants with EKOA from the Multicenter Osteoarthritis Study defined as pain intensity ≤3/10, Kellgren and Lawrence grade ≤2, intermittent pain none to sometimes, and no constant pain. Two models of PP were explored. Model A included pressure pain thresholds, temporal summation, conditioned pain modulation, pain catastrophizing, sleep quality, depression, and widespread pain (WSP). In Model B, gait characteristics, quadriceps strength, comorbidities, and magnetic resonance imaging features were added to Model A. Latent Class Analysis was used to create phenotypes, and logistic regression was used to determine their association with pain worsening. RESULTS: 750 individuals (60% females), mean age [standard deviation (SD)]: 60.3 (9.4) were included in Model A and 333 individuals (60% females), mean age (SD): 59.4 (8.1) in Model B. 3-class and 4-class solutions were chosen for Model A and Model B. In Model A, the most severe phenotype was dominated by psychosocial factors, WSP, and measures of nervous system sensitization. Similarly in Model B, the Model A phenotype plus gait variables, quadriceps strength, and comorbidities were dominant. Surprisingly, none of the phenotypes in either model had a significant relationship with pain worsening. CONCLUSION: Phenotypes based upon various factors thought to be important for the pain experience were identified in those with EKOA but were not significantly related to pain worsening. These phenotypes require validation with clinically relevant endpoints.