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The Farm Animal Genotype-Tissue Expression (FarmGTEx) project has been established to develop a public resource of genetic regulatory variants in livestock, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biological discovery and exploitation in animal breeding and human biomedicine. Here we show results from the pilot phase of PigGTEx by processing 5,457 RNA-sequencing and 1,602 whole-genome sequencing samples passing quality control from pigs. We build a pig genotype imputation panel and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We evaluate tissue specificity of regulatory effects and elucidate molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying 207 pig complex phenotypes and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, supporting the importance of pigs as a human biomedical model.

BACKGROUND: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. OBJECTIVE: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. METHODS: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. RESULTS: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. CONCLUSIONS: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.

Background Methods Results Conclusions Key points Plain Language Summary Orthodontic treatment in adults with thin periodontal phenotype presents challenges such as lengthy treatment time and increased risk for gingival recessions. In this case, surgically facilitated orthodontic treatment (SFOT) was proposed to accelerate orthodontic tooth movement while modifying the periodontal phenotype.An orthodontic patient was referred for periodontal evaluation of lower anterior teeth, which presented a thin gingival phenotype and bone dehiscence. SFOT was performed on the mandible using particulate allograft combined with platelet rich fibrin (PRF) and collagen membrane to augment soft and hard tissue, thereby preventing future recessions, while accelerating the treatment times.Six‐month and 3‐year follow‐ups confirmed radiographic bone fill, absence of gingival recession and thick band of keratinized gingiva. SFOT also resulted in a shorter treatment time where desired tooth movements were achieved within 6 months with periodontal stability.SFOT provided clinical benefits by accelerating orthodontic movement, improving periodontal phenotype, preventing the displacement of teeth beyond the alveolar housing and minimizing the risk for development of dehiscences and gingival recessions. Orthodontic movements can create recessions and dehiscence in thin periodontal phenotypes. SFOT can help prevent bone dehiscence and creates a thicker gingival phenotype while accelerating treatment time. Orthodontic movements can create recessions and dehiscence in thin periodontal phenotypes.SFOT can help prevent bone dehiscence and creates a thicker gingival phenotype while accelerating treatment time.Adults who face lengthy orthodontic treatments and have thin gums have risks of gum problems. Surgically facilitated orthodontic treatment (SFOT) can help by speeding up tooth movements and improving gum health and thickness.A patient with thin gums and lack of bone in the lower front teeth was evaluated. The SFOT procedure involved using a bone graft, healing factors, and a collagen membrane to strengthen the gums and bones. This approach aimed to prevent future gum problems and speed up orthodontic treatment.Follow‐ups at 6 months and 3 years after treatment showed good healing of the gums and bones, with no signs of gum recession and healthier, thicker gums. The desired tooth movements were achieved within 6 months, resulting in a shorter treatment time. The patient's gums remained stable throughout this period.SFOT offered significant clinical benefits, including faster tooth movement and improved gum health. It also helped prevent teeth from moving out of place and minimized the risk of gum recession and bone issues. This approach can be a valuable option for adults with thin gums undergoing orthodontic treatment. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionTo investigate whether genetic and clinical characteristics differ depending on generations using 326 patients (male/female, 259/67; mean age, 55.4 ± 12.5 years) with simple CSC.All patients were diagnosed with simple CSC, defined as a retinal pigment epithelium alteration area equal to or smaller than 2-disc areas based on multimodal imaging at the initial presentation. We cross-sectionally evaluated clinical characteristics at the initial visit and genotyped CFH rs800292 and rs1329428 for all patients using TaqMan technology.As generations decreased, the proportion of males, subfoveal choroidal thickness, and prevalence of fibrin significantly increased (p < 0.001, p < 0.001, and p = 0.012, respectively), and the best-corrected visual acuity improved (p < 0.001); in contrast, the prevalence of pachydrusen significantly decreased (p < 0.001). The younger presentation was significantly associated with male and risk variants (T allele) of CFH rs1329428 (p = 9.1 × 10−7 and p = 0.042, respectively), and patients were estimated to present 2 years younger per one T allele of CFH rs1329428 (p = 0.042, β = −1.95, stepwise regression analysis).Clinical and genetic characteristics differed significantly among patients with simple CSC, depending on their generation. [ABSTRACT FROM AUTHOR]

Background: Persistent airflow limitation (PAL) in childhood asthma is associated with a poor prognosis. The aim of this study was to categorize asthmatic children with PAL into distinct phenotypes and investigate the risk factors associated with each phenotype. Methods: We conducted a case-control study with a total of 119 PAL patients and 120 non-PAL (NPAL) individuals. To classify the patients into appropriate clusters, unsupervised cluster analysis using K-means clustering was employed. The clusters were then compared to explore different PAL phenotypes. Univariate and multivariate logistic regression analyses were performed to identify risk factors for PAL and calculate odds ratios (ORs) with 95% confidence intervals (95%CIs). Results: K-means clustering divided patients into three clusters: Cluster 0 included 120 NPAL patients, Cluster 1 characterized by elevated blood neutrophils included 66 PAL patients, and Cluster 2 exhibited elevated blood eosinophils and FeNO levels, containing 53 PAL patients. Independent risk factors for PAL included older age in both Cluster 1 (9 ∼ 11y: OR 12.67, 95%CI 3.30-55.74; ≥ 11y: OR 5.42, 95%CI 1.26-25.69) and Cluster 2 (9 ∼ 11y: OR 7.25, 95%CI 1.70-33.35; ≥ 11y: OR 11.28, 95%CI 2.79-51.89), as well as pneumonia history, with an OR of 6.41(95%CI 1.34-33.41) in Cluster 1 and an OR of 7.92(95%CI 1.83-37.44) in Cluster 2. Furthermore, specific factors associated with Cluster 1 included BMI above 22 kg/ m 2 (OR 12.28, 95%CI 2.68-70.45), asthma duration exceeding three years (OR 4.77, 95%CI 1.60-15.94), and a blood neutrophil percentage between 0.4 and 0.5 (OR 4.13, 95%CI 1.17-16.6). In Cluster 2, independent risk factors included a blood eosinophil percentage greater than 0.07 (OR 4.36, 95%CI 1.16-19.73) and a high FeNO level (OR 3.94, 95%CI 1.35-11.97). Conclusion: Our study identified two phenotypes of PAL in asthmatic children: non-eosinophilic and eosinophilic inflammation. Older age and a history of pneumonia were independent risk factors for both phenotypes. For non-eosinophilic inflammation PAL, specific contributing factors included higher BMI, long duration of asthma, and a blood neutrophil percentage between 0.4 and 0.5. Elevated FeNO levels and blood eosinophilic percentage were independently associated with eosinophilic inflammation PAL. [ABSTRACT FROM AUTHOR]

We present two rare cases of p67phox-deficient chronic granulomatous disease (CGD) caused by compound heterozygous mutations in the NCF2 gene. They developed cervical lymphadenitis as the initial manifestation of CGD but had distinct clinical progressions. Patient 1 presented with aspergillous meningitis, an extremely rare manifestation of neurological involvement in CGD, which has not been reported before. Patient 2 presented with non-infectious inflammatory lymphadenitis is also very rare and has not been reported previously. These cases emphasize the importance of considering p67phox-deficient CGD in children with late-onset invasive fungal infections and non-infectious inflammatory lesions. Additionally, we also reviewed previous reports of Chinese patients with P67phox-Deficient CGD. Our objective is to raise awareness about the clinical, diagnostic, and genetic characteristics of P67phox-deficient CGD in China, to reduce misdiagnosis and improve the management and prognosis of the disease. [ABSTRACT FROM AUTHOR]

AbstractThis study aimed to analyze the clinical phenotype of the HBA2: c.95G>A mutation in the Chinese population and to provide guidance for clinical diagnosis and genetic counseling. Peripheral blood samples were collected from 16 patients, including 6 newborns, 2 children, and 8 adults. Hematological parameters and hemoglobin electrophoresis were analyzed, and genotypes were identified using methods such as PCR combined with reverse dot blot (RDB), nested PCR, gap polymerase chain reaction (Gap-PCR), and DNA sequencing. The results showed that 10 patients had mild anemia, 2 had moderate anemia, and 12 exhibited microcytic hypochromic features with MCV values ranging from 53 to 74.7 fl and MCH values from 16.2 to 25.4 pg. Additionally, 3 cases displayed obvious HbH + HbBarts bands (>15%). Among the 16 cases, various combinations of the HBA2: c.95G>A mutation were observed: one case had –α3.7 combined with HBA2: c.95G>A, another had –α4.2 combined with HBA2: c.95G>A, and five had –SEA combined with HBA2: c.95G>A, while the remaining cases were HBA2: c.95G>A heterozygotes. The study concludes that the HBA2: c.95G>A mutation in the α2 globin gene causes α+ thalassemia. When this mutation is combined with the Southeast Asian deletion (–SEA), it results in HbH disease, characterized by moderate microcytic hypochromic anemia and the presence of HbH + HbBarts bands. [ABSTRACT FROM AUTHOR]

Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis and frontotemporal dementia, based on identification of likely pathogenic variants in patients from distinct amyotrophic lateral sclerosis and frontotemporal dementia cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in silico tools. In addition, gene burden analyses in the 100 000 Genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls [odds ratio: 57.0847 (10.2−576.7); P = 4.02 ×10−7]. Taken together, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation, including five confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from three patients harbouring distinct TUBA4A missense showed significant alterations in microtubule organization and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes. [ABSTRACT FROM AUTHOR]

Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype–phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8 -related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic–dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development. [ABSTRACT FROM AUTHOR]

Protein kinase A (PKA) neuronal function is controlled by the interaction of a regulatory (R) subunit dimer with two catalytic subunits. Recently, the L50R variant in the gene encoding the RIβ subunit was identified in individuals with a novel neurodegenerative disease. However, the mechanisms driving the disease phenotype remained unknown. In this study, we generated a mouse model carrying the RIβ-L50R mutation to replicate the human disease phenotype and study its progression with age. We examined post-mortem brains of affected individuals as well as live cell cultures. Employing biochemical assays, immunohistochemistry and behavioural assessments, we investigated the impact of the mutation on PKA complex assembly, protein aggregation and neuronal degeneration. We reveal that RIβ is an aggregation-prone protein that progressively accumulates in wildtype and Alzheimer's mouse models with age, while aggregation is accelerated in the RIβ-L50R mouse model. We define RIβ-L50R as a causal mutation driving an age-dependent behavioural and disease phenotype in human and mouse models. Mechanistically, this mutation disrupts RIβ dimerization, leading to aggregation of its monomers. Intriguingly, interaction with the catalytic subunit protects the RIβ-L50R from self-aggregating, in a dose-dependent manner. Furthermore, cAMP signaling induces RIβ-L50R aggregation. The pathophysiological mechanism elucidated here for a newly recognized neurodegenerative disease, in which protein aggregation is the result of disrupted homodimerization, sheds light on a remarkably under-appreciated but potentially common mechanism across several neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Mutations in the SLC1A4 transporter lead to neurodevelopmental impairments, spastic tetraplegia, thin corpus callosum and microcephaly in children. SLC1A4 catalyses obligatory amino acid exchange between neutral amino acids, but the physiopathology of SLC1A4 disease mutations and progressive microcephaly remain unclear. Here, we examined the phenotype and metabolic profile of three Slc1a4 mouse models: a constitutive Slc1a4-knockout mouse; a knock-in mouse with the major human Slc1a4 mutation (Slc1a4-K256E); and a selective knockout of Slc1a4 in brain endothelial cells (Slc1a4tie2-cre). We show that Slc1a4 is a bona fide L- serine transporter at the blood–brain barrier (BBB) and that acute inhibition or deletion of Slc1a4 leads to a decrease in serine influx into the brain. This results in microcephaly associated with decreased L- serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids, neurodegeneration, synaptic and mitochondrial abnormalities and behavioural impairments. Prenatal and early postnatal oral administration of L- serine at levels that replenish the serine pool in the brain rescued the observed biochemical and behavioural changes. Administration of L- serine until the second postnatal week also normalized brain weight in Slc1a4-E256K mice. Our observations suggest that the transport of 'non-essential' amino acids from the blood through the BBB is at least as important as that of essential amino acids for brain metabolism and development. We propose that SLC1A4 mutations cause a BBB aminoacidopathy with deficits in serine import across the BBB, required for optimal brain growth, leading to a metabolic microcephaly, which may be amenable to treatment with L- serine. [ABSTRACT FROM AUTHOR]

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous diseases caused by mutations affecting neuromuscular transmission. Even if the first symptoms mainly occur during childhood, adult neurologists must confront this challenging diagnosis and manage these patients throughout their adulthood. However, long-term follow-up data from large cohorts of CMS patients are lacking, and the long-term prognosis of these patients is largely unknown. We report the clinical features, diagnostic difficulties, and long-term prognosis of a French nationwide cohort of 235 adult patients with genetically confirmed CMS followed in 23 specialized neuromuscular centres. Data were retrospectively analysed. Of the 235 patients, 123 were female (52.3%). The diagnosis was made in adulthood in 139 patients, 110 of whom presented their first symptoms before the age of 18. Mean follow-up time between first symptoms and last visit was 34 years [standard deviation (SD) = 15.1]. Pathogenic variants were found in 19 disease-related genes. CHRNE -low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%). Genotypes were clustered into four groups according to the initial presentation: ocular group (CHRNE -LE, CHRND , FCCMS), distal group (SCCMS), limb-girdle group (RAPSN , COLQ , DOK7 , GMPPB , GFPT1), and a variable-phenotype group (MUSK , AGRN). The phenotypical features of CMS did not change throughout life. Only four genotypes had a proportion of patients requiring intensive care unit admission that exceeded 20%: RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%). In RAPSN and MUSK patients most ICU admissions occurred before age 18 years and in DOK7 and AGRN patients at or after 18 years of age. Different patterns of disease course (stability, improvement and progressive worsening) may succeed one another in the same patient throughout life, particularly in AGRN, DOK7 and COLQ. At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation; 36.3% of DOK7 patients, 25% of GMPPB patients and 20% of GFPT1 patients were wheelchair-bound; most of the patients who were both wheelchair-bound and ventilated were DOK7 patients. Six patients died in this cohort. The positive impact of therapy was striking, even in severely affected patients. In conclusion, even if motor and/or respiratory deterioration could occur in patients with initially moderate disease, particularly in DOK7 , SCCMS and GFPT1 patients, the long-term prognosis for most CMS patients was favourable, with neither ventilation nor wheelchair needed at last visit. CHRNE -LE patients did not worsen during adulthood and RAPSN patients, often severely affected in early childhood, subsequently improved. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to establish a comprehensive human erythrocyte antigen (HEA) frequency data set for Koreans. It also sought to develop a mobile app that facilitates the calculation of the frequencies of specific antigen-negative red blood cell units and the average number of units required for antigen typing. Methods Human erythrocyte antigen frequencies were compiled from large-scale blood donor data and 5 previous papers. Based on the collected data, we developed a mobile calculator app for HEA frequency and evaluated its usability. Results Human erythrocyte antigen frequency data for 20 blood group systems, including the ABO, Rh, MNS, Duffy, Kidd, and Diego systems, were established. The app was designed to enable users to select the desired phenotype from a drop-down menu and display the calculated frequency at the bottom. The number of units required for antigen typing to find 1 compatible red blood cell unit was also displayed. Five users participated in app evaluation and rated the functionality and information categories highly. In quizzes prompting users to calculate frequencies using the app, all participants provided correct answers, confirming the app's user-friendly functionality. Conclusions This app, which encompasses comprehensive HEA frequency data, is expected to find multiple uses in transfusion medicine, including optimizing blood bank workflow and defining rare blood groups in Korea. [ABSTRACT FROM AUTHOR]

Background Neurocognitive impairments are sequelae of childhood cancer treatment, however little guidance is given to clinicians on common phenotypes of impairment or modifiable risk factors that could lead to personalized interventions in survivorship. Methods Standardized clinical testing of neurocognitive function was conducted in 2958 (74.1%) eligible survivors, who were at least 5 years postdiagnosis and aged older than 18 years, and 477 community controls. Impairment was examined across 20 measures, and phenotypes were determined by latent class analysis. Multinomial logistic regression was used to estimate risk for phenotype, predicted by cancer diagnosis and treatment exposures, chronic health conditions, and lifestyle, adjusted for sex and age. Associations between phenotypes and social attainment were examined. Results Five neurocognitive phenotypes were identified in survivors (global impairment 3.7%, impaired attention 5.0%, memory impairment 7.2%, processing speed and executive function impairment 9.3%, no impairment 74.8%). Risk of global impairment was associated with severe chronic health condition burden (odds ratio [OR] = 20.17, 95% confidence interval [CI] = 11.41 to 35.63) including cerebrovascular disease (OR = 14.5, 95% CI = 5.47 to 38.44) and cerebrovascular accident (OR = 14.7, 95% CI = 7.50 to 26.40). Modifiable risk factors, such as quitting smoking, reduced risk for global impairment (OR = 0.21, 95% CI = 0.06 to 0.66). Low physical activity increased risk for global impairment (OR = 4.54, 95% CI = 2.86 to 7.21), attention impairment (OR = 2.01, 95% CI = 1.41 to 2.87), processing speed and executive function impairment (OR = 1.90, 95% CI = 1.46 to 2.48), and memory impairment (OR = 2.09, 95% CI = 1.54 to 2.82). Conclusions Results support the clinical utility of neurocognitive phenotyping to develop risk profiles and personalized clinical interventions, such as preventing cerebrovascular disease in anthracycline-treated survivors by preventing hypercholesterolemia, smoking, and sedentary lifestyle, to reduce the risk for global impairment. [ABSTRACT FROM AUTHOR]

Background: Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease primarily affecting paediatric patients, often leading to significant morbidity and mortality. Our principal objective is to describe the sociodemographic characteristics and evaluate the association between the number of SMN2 copies and SMA type in patients from the Colombian Foundation for Spinal Muscular Atrophy (FAMECOL) database. Methodology: An analytical cross-sectional study was conducted on 201 patients with a genetic diagnosis of SMA. Data were identified, extracted, and collected from patient records provided by FAMECOL as patients registered with the association, including 201 patients from April 2013 to April 2024, when the database was delivered. Qualitative variables were described using relative and absolute frequencies, while quantitative variables were described using central tendency and dispersion measures according to their distribution. The association between the SMA type and the SMN2 number of copies was assessed by Fisher's exact test (1 to 5 copies). Results: Of the 201 patients studied, 42% were female (n = 85), and 58% were male (n = 116). The median age was 9 years (IQR 4–16 years). The median age at diagnosis was 9 years (IQR 4–16), varying by subgroup: 2, 7, 14, and 41.5 years for each type, respectively. A total of 25% patients were from Antioquia (n = 51). Eighty-nine per cent had gastrostomy (n = 18). The association between the two variables was statistically significant (p < 0.05). Conclusion: This study highlights SMA clinical variability and its association with the number of SMN2 copies, underscoring the importance of a personalised approach to diagnosing and managing this disease. The findings may guide more effective therapeutic strategies to improve patients' quality of life. [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy (PSP) is a progressive atypical parkinsonian condition that results in severe disability. There are few studies of PSP in patients of non‐white European ancestry. Objectives: We aim to perform deep phenotyping in a South Asian PSP cohort to uncover possible ethnic differences in disease characteristics. Methods: Consecutive PSP patients had their clinical records reviewed for clinical features operationalized in the Movement Disorder Society (MDS)‐PSP diagnostic criteria and relevant investigations, including imaging and genetic tests. Clinical variables were summarized by descriptive statistics and Kaplan–Meier curves were generated for survival analysis. Results: Twenty‐seven patients, comprising Indians (78%), Pakistanis (11%) and Sri Lankans (11%) were included. Mean age of symptom onset was 63.8 ± 7.0 years and 22% of patients had an early age of onset (<60 years). The most common presenting symptom was parkinsonism (56%), followed by cognitive dysfunction (37%), falls (33%) and dysarthria (26%). The predominance types at final review were distributed across PSP‐RS (67%), PSP‐PGF (15%), PSP‐P (15%) and PSP‐F (4%). Atypical clinical features like cerebellar signs (33%), REM‐sleep behavior disorder (RBD) (55%), visual hallucinations (22%), and a family history of parkinsonism (20%) were evident in a proportion of patients. Conclusions: We present a South Asian cohort of PSP patients with a higher than previously reported percentages of early‐onset disease, family history and atypical clinical manifestations. These patients do not fit easily into the PSP phenotypes defined by the current MDS criteria. Dedicated clinicopathological and genetic tests are needed in this population to dissect the pathogenesis of clinically‐defined PSP. [ABSTRACT FROM AUTHOR]

The article discusses the importance of standardizing pain-related phenotypes and outcomes to enhance chronic pain management research. Topics discussed include harmonizing data collection across pragmatic trials, the use of common data elements to standardize outcome measures, and the role of interdisciplinary collaboration in developing a unified approach to pain management in military service members and veterans.

There is a group of beta (β)-thalassemia trait 'carriers' (with heterozygous mutations) who should be asymptomatic with minor abnormalities in their hematological parameters, but experience more severe disease manifestations than predicted based solely on their β-globin genotype. This review focuses on literature describing trans-acting genetic modifiers outside of the α- and β-globin gene clusters that could cause this phenomenon. These genetic modifiers are categorized into: mutations affecting the quantity of alpha-globin products, non-globin mutations affecting erythropoiesis, membranopathies, enzymopathies and erythrocyte-independent modifiers of complications relating to β-thalassemia. Although some genetic determinants seem to correlate more directly with β-thalassemia trait severity, such as mutations in SUPT5H, PIEZO1 and hereditary elliptocytosis, the difficulties of linking the contribution of other modulating factors are elucidated in this review. Targeted next generation sequencing of hemolytic anemias can be helpful but also raises another quandary in interpreting variants of uncertain significance. The accrual of knowledge, along with the increased availability of genetic testing for genetic modifiers has considerable potential for clinical applications such as genetic counselling, decision-making for clinical interventions and prognostication, and perhaps generating new therapeutic targets. [ABSTRACT FROM AUTHOR]

Background There are limited treatment options for prosthetic joint infections (PJI) due to multidrug-resistant Staphylococcus epidermidis (MDRSE). Fosfomycin (FOF) has gained attention as a potential therapy, but there is a paucity of information on the phenotypic and genotypic susceptibility amongst S. epidermidis , including MDRSE. Objectives To investigate phenotypical and genotypical susceptibility to FOF in S. epidermidis isolates prospectively collected from PJIs in Sweden. Methods MIC determination was performed using in-house agar dilution (AD) and a commercial AD panel. Genes and gene variants associated with FOF resistance were analysed. Results Multidrug resistance was common [74/89 (83%) isolates were MDRSE]. FOF inhibited all isolates except one, which had an MIC > 256 mg/L. The commercial AD panel demonstrated good overall performance but tended to overestimate the MIC, resulting in 84% essential agreement with the gold standard. Genomic analysis with publically available tools for whole-genome sequencing (WGS) data suggested genotypic FOF resistance in all isolates, but in-depth analysis revealed that fosB , associated with FOF resistance, was only present in the phenotypically resistant isolate. No other genes or gene variants associated with FOF resistance were detected. Conclusions Phenotypic resistance to FOF and presence of fosB were rare in this collection, indicating FOF's potential as a treatment option for S. epidermidis. The commercial AD panel demonstrated high reproducibility, but EA with the reference method was less than optimal. Findings of genotypic FOF resistance using common tools for WGS data should be critically evaluated and appropriately verified with relevant fosB references for S. epidermidis. [ABSTRACT FROM AUTHOR]

ObjectiveMethodsResultsSignificanceTo investigate phenotypes of comorbidity before and after an epilepsy diagnosis in a national cohort of post‐9/11 Service Members and Veterans and explore phenotypic associations with mortality.Among a longitudinal cohort of Service Members and Veterans receiving care in the Veterans Health Administration (VHA) from 2002 to 2018, annual diagnoses for 26 conditions associated with epilepsy were collected over 5 years, ranging from 2 years prior to 2 years after the year of first epilepsy diagnosis. Latent class analysis (LCA) was used to identify probabilistic comorbidity phenotypes with distinct health trajectories. Descriptive statistics were used to describe the characteristics of each phenotype. Fine and Gray cause‐specific survival models were used to measure mortality outcomes for each phenotype up to 2021.Six distinct phenotypes were identified: (1) relatively healthy, (2) post‐traumatic stress disorder, (3) anxiety and depression, (4) chronic disease, (5) bipolar/substance use disorder, and (6) polytrauma. Accidents were the most common cause of death overall, followed by suicide/mental health and cancer, respectively. Each phenotype exhibited unique associations with mortality and cause of death, highlighting the differential impact of comorbidity patterns on patient outcomes.By delineating clinically meaningful epilepsy comorbidity phenotypes, this study offers a framework for clinicians to tailor interventions. Moreover, these data support systems of care that facilitate treatment of epilepsy and comorbidities within an interdisciplinary health team that allows continuity of care. Targeting treatment toward patients with epilepsy who present with specific heightened risks could help mitigate adverse outcomes and enhance overall patient care. [ABSTRACT FROM AUTHOR]

With increasing life expectancy and prevalence of thalassaemia, it has led to a greater need for safe blood, yet the current supply from voluntary donors is insufficient to meet this demand. Thalassaemia recipients face a significant risk of alloimmunization because of repeated exposure to foreign red cell antigens. Study aims to determine high prevalent Rh antigen negative donors in western India donor population along with what percentage of these donors are willing to become dedicated voluntary donors for thalassaemia patients. Study also aims to examine factors influencing their willingness and challenges faced in mobilizing dedicated donors. 700 whole blood donors from western India, following screening for inclusion & exclusion criteria as per Drugs and Cosmetic Act (DCA) 2020 amendment guidelines & were sero-negative for transfusion transmitted infections were enrolled for the study. Red cell phenotyping was performed using Conventional Tube Technique (CTT) for "D", "C", "E", "c", "e" and "K" antigen using known antisera. Donors that were "C" AND/OR "e" antigen negative were contacted telephonically and were counseled and motivated for becoming voluntary blood donors. Statistical analysis assessed correlation between donation frequency, donor's occupation and education. Among 700 donors, 96.6% (n = 676) were males and 3.4% (n = 24) were females. The most predominant blood group was B > O > A > AB. Rh(D) antigen was present in 91.44% (n = 640) and absent in 8.6% (n = 60). Prevalence of other Rh antigens is as follows: "e" (99%) > "C" (85.4%) > "c" (59.1%) > "E" (18.0%). Only 1.15% had "K" antigen positive. The commonest Rh phenotype R 1 R 1 (DCe/DCe) was expressed by 40.57% (n = 283), and the least common r″r (cE/ce), r″r″ (cE/cE) and r′r′ (Ce/Ce) was found in 0.14% (n = 1), respectively. 'C' negative, 'e' negative, 'C' and 'e' antigen negative donors constituted 14.8% (n = 104) with 93.2% (n = 97) C-antigen negative, 1.92% (n = 2) e-antigen negative and 4.8% (n = 5) both "C" and "e" antigen negative donors. The commonest phenotypes among C-antigen and e-antigen negative donors were rr (50%) and R z R 2 (1.94%) respectively. Likewise, the most common phenotype amongst both C- and e-antigens negative donors was R 2 R 2 (3.84%). 61.5% of the donors agreed to enroll for voluntary blood donation following telephonic invitation, while 6.8% of them refused permanently. Approximately, 3.9% of the blood donors were willing to donate blood only when needed and 27.8% of them could not be contacted. Creating a database of voluntary donors with known phenotype, especially who lack very common antigens like "C" and "e" and are willing to become dedicated, regular voluntary donors for thalassemic patients can ensure timely administration of safe blood. One of the major challenges for this noble initiative was lack of awareness which can be circumvent effectively with proper counseling efforts. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by the malfunction of motile cilia and a specific etiology of adult bronchiectasis of unknown prevalence. A better understanding of the clinical phenotype of adults with PCD is needed to identify individuals for referral to diagnostic testing. What is the frequency of PCD among adults with bronchiectasis; how do people with PCD differ from those with other etiologies; and which clinical characteristics are independently associated with PCD? We investigated the proportion of PCD among the participants of the Prospective German Non-CF-Bronchiectasis Registry (PROGNOSIS) study; applied multiple imputation to account for missing data in 64 (FEV 1), 58 (breathlessness), 26 (pulmonary exacerbations), and two patients (BMI), respectively; and identified predictive variables from baseline data using multivariate logistic regression analysis. We consecutively recruited 1,000 patients from 38 centers across all levels of the German health care system. Overall, PCD was the fifth most common etiology of bronchiectasis in 87 patients (9%) after idiopathic, postinfective, COPD, and asthma. People with PCD showed a distinct clinical phenotype. In multivariate regression analysis, the chance of PCD being the etiology of bronchiectasis increased with the presence of upper airway disease (chronic rhinosinusitis and/or nasal polyps; adjusted OR [aOR], 6.3; 95% CI, 3.3-11.9; P <.001), age < 53 years (aOR, 5.3; 95% CI, 2.7-10.4; P <.001), radiologic involvement of any middle and lower lobe (aOR, 3.7; 95% CI, 1.3-10.8; P =.016), duration of bronchiectasis > 15 years (aOR, 3.6; 95% CI, 1.9-6.9; P <.001), and a history of Pseudomonas aeruginosa isolation from respiratory specimen (aOR, 2.4; 95% CI, 1.3-4.5; P =.007). Within our nationally representative cohort, PCD was a common etiology of bronchiectasis. We identified few easy-to-assess phenotypic features, which may promote awareness for PCD among adults with bronchiectasis. ClinicalTrials.gov; No.: NCT02574143 ; URL: www.clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous disease characterized by multiple phenotypes with varying risk factors and therapeutic responses. This Commentary describes research on biomarkers for T2-"high" and T2-"low" inflammation, a hallmark of the disease. Patients with asthma who exhibit an increase in airway T2 inflammation are classified as having T2-high asthma. In this endotype, Type 2 cytokines interleukins (IL)-4, IL-5, and IL-13, plus other inflammatory mediators, lead to increased eosinophilic inflammation and elevated fractional exhaled nitric oxide (FeNO). In contrast, T2-low asthma has no clear definition. Biomarkers are considered valuable tools as they can help identify various phenotypes and endotypes, as well as treatment response to standard treatment or potential therapeutic targets, particularly for biologics. As our knowledge of phenotypes and endotypes expands, biologics are increasingly integrated into treatment strategies for severe asthma. These treatments block specific inflammatory pathways or single mediators. While single or composite biomarkers may help to identify subsets of patients who might benefit from these treatments, only a few inflammatory biomarkers have been validated for clinical application. One example is sputum eosinophilia, a particularly useful biomarker, as it may suggest corticosteroid responsiveness or reflect non-compliance to inhaled corticosteroids. As knowledge develops, a meaningful goal would be to provide individualized care to patients with asthma. [ABSTRACT FROM AUTHOR]

A growing number of genes have been identified in individuals with cerebral palsy (CP); however, many of these studies have poor compliance with the cerebral palsy clinical description. This systematic review aimed to assess the quality of the cerebral palsy clinical description/phenotype in cerebral palsy genetic studies published between 2010 and 2024 and report clinically relevant genes based on the quality of the cerebral palsy phenotype. An expert panel developed 6 criteria to review the reported cerebral palsy phenotype/description for each included study. Clinically relevant genes were extracted from each study and stratified into 2 tiers based on the quality. Eighteen studies were included. There was high confidence in the reported cerebral palsy description/phenotype from 8 studies. Of the initial 373 clinically relevant genes, 85 were tier II genes. Individual cerebral palsy motor disorder and phenotype data were absent for 349 of these individuals, limiting further analysis. The tier I gene list was composed of 6 genes: ATL1, COL4A1, GNAO1, KIF1A, SPAST, and TUBA1A. Bilateral spasticity was the most common motor disorder reported in individuals with variants in all 6 genes, and most individuals had accompanying conditions. Prioritizing the accurate reporting of motor and nonmotor phenotypes is crucial for future cerebral palsy genetic studies to further understand the underlying neurobiology. [ABSTRACT FROM AUTHOR]

Inflammation is a complex biological process protecting the body from diverse external threats. Effectively performing this task requires an intricate, well‐regulated interplay of different cells and tissues. Furthermore, several cells participating in inflammation can assume diverse phenotypes. A classic and relatively well‐studied example of phenotypic diversity in inflammation is macrophage polarization. Based on the TH1/TH2 phenotypes of T helper cells, this scheme has proinflammatory "classical/M1" activation contrasted with the anti‐inflammatory and healing‐promoting "alternative/M2" phenotype. Some authors have extended the concept into an M17 phenotype induced by the classic TH17 cytokine IL‐17. Phenotypic changes in chondrocytes have also been studied especially in the context of osteoarthritis (OA), and there are indications that these cells can also assume polarized phenotypes at least partly analogous to those of TH cells and macrophages. The therapeutic success of biological agents targeting TH1/TH2/TH17 inductor and/or effector cytokines displays the utility of the concept of polarization. The aim of this focused review is to survey the internal and external factors affecting macrophage and chondrocyte phenotypes (such as inflammatory cytokines, widely used medications and natural products) and to explore the possibility of ameliorating pathological states by modulating these phenotypes. [ABSTRACT FROM AUTHOR]

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of severe fluoropyrimidine-related toxicities. The best strategy for identifying DPD-deficient patients is still not defined. The EMA recommends targeted DPYD genotyping or uracilemia (U) testing. We analyzed the concordance between both approaches. This study included 19,376 consecutive French patients with pre-treatment plasma U, UH2 and targeted DPYD genotyping (*2A, *13, D949V, *7) analyzed at Eurofins Biomnis (2015–2022). Mean U was 9.9 ± 10.1 ng/mL (median 8.7, range 1.6–856). According to French recommendations, 7.3 % of patients were partially deficient (U 16–150 ng/mL) and 0.02 % completely deficient (U≥150 ng/mL). DPYD variant frequencies were *2A: 0.83 %, *13: 0.17 %, D949V: 1.16 %, *7: 0.05 % (2 homozygous patients with U at 22 and 856 ng/mL). Variant carriers exhibited higher U (median 13.8 vs. 8.6 ng/mL), and lower UH2/U (median 7.2 vs. 11.8) and UH2/U2 (median 0.54 vs. 1.37) relative to wild-type patients (p<0.00001). Sixty-six% of variant carriers exhibited uracilemia <16 ng/mL, challenging correct identification of DPD deficiency based on U. The sensitivity (% patients with a deficient phenotype among variant carriers) of U threshold at 16 ng/mL was 34 %. The best discriminant marker for identifying variant carriers was UH2/U2. UH2/U2<0.942 (29.7 % of patients) showed enhanced sensitivity (81 %) in identifying deleterious genotypes across different variants compared to 16 ng/mL U. These results reaffirm the poor concordance between DPD phenotyping and genotyping, suggesting that both approaches may be complementary and that targeted DPYD genotyping is not sufficiently reliable to identify all patients with complete deficiency. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment affects 40–65% of MS patients, encompassing all disease stages and types of clinical courses. This estimation is based on different instruments used and population normative data. Objective: This study aims to assess the cognitive function in a hospital-based cohort of Portuguese MS patients, to allow estimating the prevalence of cognitive impairment in different phenotypes. Methods: Three hundred and thirteen patients with Multiple Sclerosis (MS) underwent neuropsychological assessment with the brief repeatable battery of neuropsychological tests (BRBN-T) and the brief international cognitive assessment for multiple sclerosis (BICAMS). Results: Differences were observed in the cognitive impairment profile of different disease phenotypes and of the different disease severity stages. RRMS patients performed better in the cognitive test of the BRBN-T and BICAMS than those with progressive disease phenotypes. Relationships between cognitive impairment and disability and professional status were relevant. Although similarities could be observed in the cognitive profile of the MS phenotypes, with predominant involvement of verbal memory, verbal fluency, and information processing speed, the latter was found to be more frequent as the disease progressed. Conclusion: This study contributes to improve knowledge about the cognitive profile of the different MS phenotypes and understand the cognitive characteristics of Portuguese patients. [ABSTRACT FROM AUTHOR]

Although vitamin D deficiency is common in critically ill patients, randomized controlled trials fail to demonstrate benefits of supplementation. We aimed to identify distinct vitamin D 3 responsive metabolic phenotypes prior to trial intervention of high-dose vitamin D 3 by applying machine learning clustering method to metabolomics data from the Correction of Vitamin D Deficiency in Critically Ill Patients (VITdAL-ICU) trial. In the randomized, placebo-controlled VITdAL-ICU trial, critically ill adults received placebo or high-dose vitamin D 3. To distinguish vitamin D 3 responsive metabolic phenotypes prior to intervention, we implemented consensus clustering with partitioning around medoids algorithm to the plasma metabolome data before randomization. Individual metabolite differences were determined utilizing linear mixed-effects regression models stratified for metabolomic phenotypes with false discovery rate adjustment. The association between vitamin D 3 supplementation and 180-day mortality was evaluated in each metabolic phenotype, applying multivariable logistic regression analysis. In 453 critically ill adults, the study identified 4 distinct metabolic phenotypes (clusters A. N = 134; B. N = 123; C. N = 92; D. N = 104). We found differential metabolic pathway patterns in the four clusters. Specifically, branched chain amino acid catabolic metabolites, long-chain acylcarnitines and diacylglycerol species are significantly increased in a specific metabolic phenotype (cluster D) following high-dose vitamin D 3. Further, in cluster D high-dose vitamin D 3 supplementation had a significantly lower adjusted odds of 180-day mortality after controlling age, sex, Simplified Acute Physiology Score II, admission diagnosis, and baseline 25-hydroxyvitamin D (OR 0.28 (95%CI, 0.09–0.89); P = 0.03). In metabotype A, B, and C, high-dose vitamin D 3 supplementation was not significantly associated with lower 180-day mortality following multivariable adjustment. In this post-hoc cohort study of the VITdAL-ICU trial, the clustering analysis of plasma metabolome data identified biologically distinct metabolic phenotypes. Among clusters, we found the different associations between high-dose vitamin D 3 supplementation and specific metabolite pathways as well as 180-day mortality. Our findings facilitate further research to validate metabolic phenotype-targeted strategies for critical illness treatments. [Display omitted] [ABSTRACT FROM AUTHOR]

The impact of patient sex on the presentation of inflammatory bowel disease (IBD) has been poorly evaluated. Our aims were to assess potential disparities in IBD phenotype and progression between sexes. We performed an observational multicenter study that included patients with Crohn's disease (CD) or ulcerative colitis from the Spanish Estudio Nacional en Enfermedad Inflamatoria intestinal sobre Determinantes genéticos y Ambientales registry. Data extraction was conducted in July 2021. A total of 51,595 patients with IBD were included, 52% were males and 25,947 had CD. The median follow-up period after diagnosis was 9 years in males and 10 years in females. In CD, female sex was an independent risk factor for medium disease onset (age, 17–40 y) (relative risk ratio, 1.45; 95% CI, 1.31–1.62), later disease onset (age, >40 y) (relative risk ratio, 1.55; 95% CI, 1.38–1.73), exclusive colonic involvement (odds ratio, 1.24; 95% CI, 1.14–1.34), inflammatory behavior (odds ratio, 1.14; 95% CI, 1.07–1.21), and extraintestinal manifestations (odds ratio, 1.48; 95% CI, 1.38–1.59). However, female sex was a protective factor for upper gastrointestinal involvement (odds ratio, 0.84; 95% CI, 0.79–0.90), penetrating behavior (odds ratio, 0.76; 95% CI, 0.70–0.82), perianal disease (odds ratio, 0.77; 95% CI, 0.71–0.82), and complications (odds ratio, 0.73; 95% CI, 0.66–0.80). In ulcerative colitis, female sex was an independent risk factor for extraintestinal manifestations (odds ratio, 1.48; 95% CI, 1.26–1.61). However, female sex was an independent protective factor for disease onset from age 40 onward (relative risk ratio, 0.76; 95% CI, 0.66–0.87), left-sided colonic involvement (relative risk ratio, 0.72; 95% CI, 0.67–0.78), extensive colonic involvement (relative risk ratio, 0.59; 95% CI, 0.55–0.64), and abdominal surgery (odds ratio, 0.78; 95% CI, 0.69–0.88). There is sexual dimorphism in IBD. The patient's sex should be taken into account in the clinical management of the disease. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims: Tooth agenesis (TA) is common in Down syndrome (DS). It is unknown whether this agenesis occurs in specific patterns, which is important regarding treatment planning and aetiological research. This study aimed to aggregate and analyze patterns of TA, excluding third molars, in individuals with DS using the tooth agenesis code (TAC). Methods and results: The study was designed as a secondary analysis, following STROSA guidelines. The search (MEDLINE‐PubMed) and selection process resulted in six included studies encompassing 241 individuals with DS. TA data were systematically converted into TACs and analyzed per dentition, per jaw, and per tooth type. Symmetry was evaluated. The prediction was calculated for oligodontia. In the 155 cases with TA 86 distinct Overall‐TAC patterns were identified. The most common patterns were bilateral maxillary lateral incisor agenesis (TAC002.002.000.000;10.3%), bilateral mandibular second premolar agenesis (TAC000.000.016.016;5.8%), and unilateral left maxillary lateral incisor agenesis (TAC000.002.000.000;5.2%). Symmetry in TA patterns was observed in 49.6% of TA cases in the maxilla and 52.3% in the mandible. The simultaneous absence of both mandibular central incisors had a large predictive value for oligodontia (OR12.44;95% CI:4.97–31.84; p <.001). Conclusion: Predominant TA patterns exist in DS. Observation of mandibular central incisor agenesis can promote early diagnosis of oligodontia in DS. [ABSTRACT FROM AUTHOR]

This study evaluates the preferences of dentists regarding the interdisciplinary treatment of patients with gingival recession (GR) and a thin periodontal phenotype, based on their specialization. A cross-sectional study was conducted among Polish dentists, between May and October 2022, using an online survey. The dentists were first asked to provide details regarding their specialization and the length of their professional career. In the second part of the survey, they responded to questions about the preferred timing of a consultation and soft tissue augmentation in patients who planned to undertake orthodontic treatment (OT). Moreover, factors undermining the decision-making process regarding soft tissue augmentation and the methods used for the evaluation of periodontal tissues were assessed. In total, 554 dentists completed the survey, among whom 328 were orthodontists and 226 were periodontists/oral surgeons. A third of the surveyed periodontists/oral surgeons (33%) reported that they receive referrals from orthodontists prior to OT and 39% of orthodontists indicated that they refer patients for soft tissue augmentation before commencing OT. The majority of periodontists/oral surgeons (51%) and the most significant proportion of orthodontists (45%) agreed that the ideal timing of soft tissue augmentation is dependent on each specific case. Both groups of surveyed dentists considered "planned tooth movement" as the most important factor in clinical decision-making. Among the periodontists/oral surgeons, the most popular methods to assess periodontal tissues were: 3D radiological examination, the visual method, and gingival transparency with the use of a periodontal probe. On the other hand, the surveyed orthodontists preferred the visual method, followed by 2D radiological examination, and then by 3D radiological examination. The majority of surveyed periodontists/oral surgeons and orthodontists agreed that the ideal timing of soft tissue augmentation in patients undertaking orthodontic treatment should be decided on a case-by-case basis, with planned tooth movement being the determining factor. [ABSTRACT FROM AUTHOR]

Understanding the maintenance and shift in reproductive strategies is a fundamental question in evolutionary research. Although many efforts have been made to compare different reproductive strategies, the association between reproductive strategies and lineage divergence is largely unknown. To explore the impact of different reproductive strategies on lineage divergence, we investigated the evolution of clonality in Saxifraga sect. Irregulares+Heterisia. By integrating several lines of evidence, we found that the loss of clonality in Irregulares+Heterisia was associated with a progressive increase in diversification rate and intraspecific morphological diversity but with a reduction in species distribution range. Our findings provide insights into the ecological and evolutionary effects of different reproductive strategies, suggesting the necessity of integrating clonality into ecological and evolutional research. [ABSTRACT FROM AUTHOR]

MUTYH-Associated Polyposis (MAP) is caused by biallelic pathogenic germline variants in the MUTYH gene. However, individuals harboring monoallelic MUTYH pathogenic variants in the presence of a positive family history have been reported to have a twofold increased risk of colorectal cancer (CRC) and extra colonic cancers. Our aim was to characterize the spectrum of monoallelic and biallelic germline MUTYH pathogenic variants in Latin American patients and to describe their clinical and genetic characteristics. Patients were identified from eight high-risk genetic cancer centers of five Latin American countries. Statistical analysis was performed using the two-sided P test using the Vassarstats statistical tools. Statistical significance was set at a p value ≤ 0.05. Of the 105 unrelated patients with cancer or colorectal polyposis, 84.8% and 15.2% carried pathogenic monoallelic and biallelic MUTYH variants, respectively. The most common pathogenic variants were p.Gly396Asp and p.Tyr179Cys (55% and 23%, respectively). The mean age at first diagnosis was 48.29 years (range 31–71) and 49.90 years (range 27–87) in biallelic and monoallelic MUTYH patients, respectively. CRC was the only cancer diagnosed in patients with biallelic MUTYH pathogenic variants (75%), while breast cancer (46.1%) was more common than CRC (24.7%) in individuals with monoallelic MUTYH pathogenic variants. We reported a high frequency of European founder variants in our diverse population. Some phenotypic differences from current studies were identified, such as a higher breast cancer burden in monoallelic carriers and a complete absence of extra-colon tumors in biallelic patients. [ABSTRACT FROM AUTHOR]

Objectives: To determine the inflammatory profile of CRSwNP in Brazil and characterize the subgroups of CRSwNP patients in this population through cluster analysis. Study Design: Multicenter cross‐sectional study involving 15 centers representing different regions of Brazil. Subjects and Methods: Clinical data of 166 patients and 80 controls, aged 18 to 70 years old, number of surgeries for CRS, history of asthma and aspirin sensitivity, and Lund‐Mackay scores on CT scans. During nasal endoscopy, we obtained the Lund‐Kennedy scores and collected 2 samples of nasal polyps: one for eosinophil and neutrophil tissue counts and one to quantify different cytokines. Results: 79.6% of our patients had 10 or more eosinophils/HPF. CRSwNP groups exhibited significantly lower concentrations of TNF‐alpha and significantly higher concentrations of IFN‐gamma, CCL11/Eotaxin, CCL24/Eotaxin‐2/MPIF‐2, and CCL26/Eotaxin‐3 versus the control group (Kruskal‐Wallis test). Comparison between CRSwNP groups (≥10 vs <10 eosinophils/HPF) showed no difference in cytokine concentration (Mann‐Whitney test). Hierarchical clustering and PCA according to cytokine concentrations revealed 2 main Clusters, with a significantly higher concentration of all cytokines in Cluster 1 (n = 35) than in Cluster 2 (n = 121), except IL‐6 and IL‐33 (Mann‐Whitney test). According to ROC curve analysis the best cut‐off to differentiate the 2 clusters was 43 eosinophils/HPF. The group with ≥43 presented a higher prevalence of men and a higher Lund‐Mackay score (Mann‐Whitney test). Conclusions: CRSwNP patients in Brazil present mixed inflammation, with 2 distinct groups (high and low inflammatory pattern) that can be distinguished by tissue eosinophilia of ≥43 eosinophils/HPF cut‐off in nasal polyps. [ABSTRACT FROM AUTHOR]

Genetic testing is recommended for all patients with pheochromocytomas and paragangliomas (PPGL) to establish genotype–phenotype associations. We investigated germline mutations in 59 patients with PPGL at six Korean university hospitals using next-generation sequencing (NGS) targeting 38 PPGL-associated genes, including those recommended by the Korean PPGL Task Force. Germline mutations were identified in 13 patients (22%), and affected four genes: RET, NF1, VHL, and SDHD. Germline mutations were significantly associated with a family history of PPGL, smaller tumor size, and the presence of other types of tumors. Using 95 Korean PPGL cases with germline mutations identified through a literature review and 13 cases from our cohort, we characterized genotype–phenotype correlations. Mutation hotspots were identified in specific codons of RET (codons 631 and 634), VHL (157 and 167), and SDHB (131 and 253). NF1 mutations varied, indicating the absence of common hotspots. These findings highlight the efficacy of the recommended NGS panel for Korean patients with PPGL and the importance of genetic testing in establishing clinical management and personalized therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objectives: High rate of alloimmunization in sickle cell disease (SCD) patients poses a significant challenge in finding compatible blood unit. Accurate determination of the blood group genotype of them can help reduce the alloimmunization risk. Tetra ARMS PCR is a novel method that has been utilized recently to investigate SNPs in diseases in a fast and reliable way. Methods: Our study included 104 SCD and sickle thalassemia (Sβ) patients referred to Baghaei-2-Hospital of Ahvaz in 2019 using a nonrandom sampling method. Blood samples were collected for serological and molecular tests. Rh genotyping was performed using Tetra ARMS PCR and compared with the serological results. Results: Based on the Tetra ARMS PCR method, out of 104 patients, 7 (6.7%) were d/d, 40 (38.5%) were D/d, 57 (54.8%) were D/D, 25 (24%) were C/C, 59 (56.7%) were C/c, 20 (19.3%) were c/c, 4 (3.8%) were E/E, 25 (24%) were E/e, and patients 75 (72.2%) were e/e. There were discrepancies in the serological and molecular results for 11 patients. Conclusion: Use of Tetra ARMS PCR in combination with serological methods for determining the Rh blood group system in donors and transfusion-dependent patients represents a remarkable transformation in the field of immunohematology. [ABSTRACT FROM AUTHOR]

Introduction: Parashorea chinensis is a rare monodominant species in southwest China known for its production of high-quality timber, is facing decline due to its narrow distribution, human interference and habitat destruction. However, there are no reports on genetic diversity and geographical variation of phenotypic traits of P. chinensis. Methods: In this study, phenotypic characters and genetic diversity of 15 germplasms resources from five provenances in southwest China were investigated, and their relationships with geographical and environmental factors was discussed. Results: Our results revealed a rich phenotypic diversity among the germplasms, with variation coefficients ranging from 3.63% to 45.49%. Among the studied germplasms, NP03 from Napo and ML02 from Mengla region exhibited superior phenotypic traits. Notably, NP03 also demonstrated the highest genetic diversity. Genetic differentiation analyses including genetic differentiation coefficient (0.6264) and gene flow (0.3736) illustrated that genetic variation was most prevalent among populations. Furthermore, redundancy analysis showed that temperature related factors (maximum air temperature, annual mean temperature and minimum air temperature) significantly affected phenotypic variation. Similarly, altitude, longitude, latitude, annual mean precipitation and the minimum air temperature significantly impacted the level of genetic diversity. The molecular variation of the natural population of P. chinensis followed a certain geographical pattern. Discussion: Our finding indicated abundant phenotypic variation among P. chinensis germplasms. However, populations exhibited low levels of genetic diversity alongside high genetic differentiation, potentially contributing to the species' rarity. Based on our results, NP03 and ML02 germplasm could be used as the parents for breeding superior germplasm of P. chinensis. Overall, this study provides valuable insights into germplasm diversity and conservation, genetic improvement, and utilization of P. chinensis. [ABSTRACT FROM AUTHOR]

Objective: Yao syndrome (YAOS) is formerly called nucleotide-binding oligomerization domain containing 2 (NOD2)-associated autoinflammatory disease.We report a large cohort of YAOS. Methods: We conducted a retrospective analysis of a cohort of adult patients with systemic autoinflammatory diseases (SAIDs). All patients underwent testing for a periodic fever syndrome gene panel. Results: A total of 194 patients carried NOD2 variants, 152 patients were diagnosed with YAOS, and 42 had mixed autoinflammatory diseases with combined variants in NOD2 and other SAID-associated genes. Demographic, clinical and molecular data were summaried. In sub-group analysis of the 194 patients, individual patients were often identified to carry two or more variants that usually included IVS8 + 158/R702W, IVS8 + 158/L1007fs, IVS8 + 158/V955I, IVS8 + 158/other, or NOD2/variants in other SAID genes. Ninety-nine patients carried single variants. Taken together, these variants contribute to the disease in combination or individually. Conclusion: This largest cohort has provided comprehensive clinical and genotyping data in YAOS. Variants in the NOD2 gene can give rise to a spectrum from inflammatory bowel disease to autoinflammatory disease.This report further raises awareness of the underdiagnosed disease in the medical community. [ABSTRACT FROM AUTHOR]

Background: Genetic factors, including the Hedgehog Interacting Protein (HHIP) gene, play a crucial role in Chronic Obstructive Pulmonary Disease (COPD) susceptibility. This study examines the association between HHIP gene polymorphisms and COPD susceptibility, phenotypes, and serum IL-17 and IL-18 levels in a Han Chinese population. Methods: A case-control study was conducted with 300 COPD patients and 300 healthy controls in Chinese Han population. Participants underwent genotyping for HHIP gene polymorphisms, pulmonary function tests, and quantitative CT scans. DNA samples were sequenced using a custom chip targeting the HHIP gene. Serum IL-17 and IL-18 levels were measured by enzyme-linked immunosorbent assay. Associations between SNPs, COPD susceptibility, and phenotypes were analyzed using logistic and multiple linear regression models, adjusting for confounders. Results: Our study identified the rs11100865 polymorphism in the HHIP gene as significantly associated with COPD susceptibility (OR 2.479, 95% CI 1.527–4.024, P = 2.39E-04) after screening 114 SNPs through rigorous quality control. Stratified analyses further indicated this association was particularly in individuals aged 60 or older. Serum levels of IL-17 and IL-18 were significantly elevated in COPD patients compared to controls, with rs11100865 showing a notable association with IL-18 levels (B = 49.654, SE = 19.627, P = 0.012). However, no significant associations were observed between rs11100865 and serum IL-17 levels, COPD-related imaging parameters, or clinical phenotypes. Conclusion: This study identified a significant association between HHIP gene polymorphisms and COPD susceptibility in a Han Chinese population, with connections to inflammation, but found no significant associations between this SNP and COPD-related imaging or clinical phenotypes. Trial registration: www.chictr.org.cn ID: ChiCTR2300071579 2023-05-18. [ABSTRACT FROM AUTHOR]

Introduction: Rett syndrome (RTT) is a rare neurodevelopmental disorder with developmental impairments, comorbidities, and abnormal behaviours such as hand stereotypies and emotional features. The Rett Syndrome Behaviour Questionnaire (RSBQ) was developed to describe the behavioural and emotional features of RTT. Little is known how RSBQ scores are associated with genetic and clinical characteristics in RTT. This study investigated relationships between genotype, age, walking, hand function, sleep, and RSBQ total and subscale scores in RTT. Methods: This is a cross-sectional analysis of data collected in the Australian Rett Syndrome Database and the International Rett Syndrome Phenotype Database. Parent caregivers completed the RSBQ and Sleep Disturbance Scale for Children [subscales for disorders of initiating and maintaining sleep (DIMS), disorders of excessive somnolence (DOES)], and provided information on age, variant type, functional abilities (mobility, hand function), seizure frequency and gastrointestinal problems. Associations between the RSBQ scores and the independent variables were modelled using linear regression. Results: Data were available for 365 individuals with RTT [median (range) age 17.8 (2.9–51.9) years, 2 males]. Compared to adults, 2- to 12-year-old children had higher mean Total, Night-time Behaviour and Fear/Anxiety scores. Compared to individuals with a C-terminal deletion, individuals with the p.Arg255* variant had higher mean Total and Night-time Behaviours scores, whereas the p.Arg294* variant had higher mean Mood scores. Individuals with intermediate mobility and hand function abilities had a higher mean Total score. Total RSBQ and subscale scores were similar across categories for seizures, constipation, and reflux, but were higher with abnormal DIMS and abnormal DOES scores. Conclusion: Except for associations with sleep, the RSBQ measures the behavioural phenotype rather than clinical severity in RTT, as traditionally conceptualised in terms of functional abilities and comorbidities. When designing clinical trials, the RSBQ needs to be complemented by other outcome measures to assess specific core functions and associated comorbidities in RTT. [ABSTRACT FROM AUTHOR]

Background/Objective: SeptiCyte RAPID is a transcriptional host response assay that discriminates between sepsis and non-infectious systemic inflammation (SIRS) with a one-hour turnaround time. The overall performance of this test in a cohort of 419 patients has recently been described [Balk et al., J Clin Med 2024, 13, 1194]. In this study, we present the results from a detailed stratification analysis in which SeptiCyte RAPID performance was evaluated in the same cohort across patient groups and subgroups encompassing different demographics, comorbidities and disease, sources and types of pathogens, interventional treatments, and clinically defined phenotypes. The aims were to identify variables that might affect the ability of SeptiCyte RAPID to discriminate between sepsis and SIRS and to determine if any patient subgroups appeared to present a diagnostic challenge for the test. Methods: (1) Subgroup analysis, with subgroups defined by individual demographic or clinical variables, using conventional statistical comparison tests. (2) Principal component analysis and k-means clustering analysis to investigate phenotypic subgroups defined by unique combinations of demographic and clinical variables. Results: No significant differences in SeptiCyte RAPID performance were observed between most groups and subgroups. One notable exception involved an enhanced SeptiCyte RAPID performance for a phenotypic subgroup defined by a combination of clinical variables suggesting a septic shock response. Conclusions: We conclude that for this patient cohort, SeptiCyte RAPID performance was largely unaffected by key variables associated with heterogeneity in patients suspected of sepsis. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, characterized by considerable changes in peripheral lymphocyte structure and function, that plays a critical role in commencing and reviving the inflammatory and immune signaling pathways. In healthy individuals, B lymphocytes have a major role in guiding and directing defense mechanisms against pathogens. Certain changes in B lymphocyte phenotype, including alterations in surface and endosomal receptors, occur in the presence of SLE and lead to dysregulation of peripheral B lymphocyte subpopulations. Functional changes are characterized by loss of self-tolerance, intra- and extrafollicular activation, and increased cytokine and autoantibody production. T lymphocytes seem to have a supporting, rather than a leading, role in the disease pathogenesis. Substantial aberrations in peripheral T lymphocyte subsets are evident, and include a reduction of cytotoxic, regulatory, and advanced differentiated subtypes, together with an increase of activated and autoreactive forms and abnormalities in follicular T cells. Up-regulated subpopulations, such as central and effector memory T cells, produce pre-inflammatory cytokines, activate B lymphocytes, and stimulate cell signaling pathways. This review explores the pivotal roles of B and T lymphocytes in the pathogenesis of SLE and Lupus Nephritis, emphasizing the multifaceted mechanisms and interactions and their phenotypic and functional dysregulations. [ABSTRACT FROM AUTHOR]

Background: Collagen VI‐related disorder (COLVI‐RD) is one of the most common congenital muscular dystrophies. However, data is limited in China. Methods: We conducted a retrospective study at two tertiary centers. Clinical presentations, lab findings (including serum creatine kinase levels), muscle biopsy, and molecular test results for patients diagnosed with definite COLVI‐RD were collected. Results: A total of 82 patients were enrolled in the study, including 4 with early–severe Ullrich congenital muscular dystrophy (E–S UCMD) (4.8%), 45 with moderate–progressive Ullrich congenital muscular dystrophy (M–P UCMD, 54.9%), 19 with mild UCMD (23.2%), and 14 with Bethlem myopathy (BM, 17.1%). Feeding difficulty, DDH, and neurogenic damage were more common in E–S and M–P UCMD, while contracture of distal joints, atrophic scars, and hyperkeratosis was more prominent in mild UCMD and BM. Seventy patients harbored 64 pathogenic mutations in COLVI‐related genes: 28 patients in COL6A1 gene, 25 patients in the COL6A2 gene, and 17 patients in the COL6A3 gene, among which 33 mutations were novel. Missense and splicing mutations were predominant for COL6A1 and COL6A3 genes, which were mostly located in N‐terminus of THD, in a dominant pattern, while mutations in the COL6A2 gene were much more polymorphic, which spread throughout the whole length of the gene, in a dominant or recessive pattern. Immunofluorescence dual labeling of Collagen VI/IV in 44 patients showed complete deficiency of Collagen VI in 10 patients (22.7%), sarcolemma‐specific Collagen VI deficiency in 25 patients (56.8%), and normal Collagen VI staining in 9 patients (20.5%). Conclusion: Our study reported the largest cohort of COLVI‐RD in China, which showed M–P UCMD was the most common phenotype, followed by mild UCMD and BM. We identified 30 novel mutations and expanded the genetic spectrum. Missense and splicing mutations were predominant for COL6A1 and COL6A3 genes, while mutations in the COL6A2 gene were much more polymorphic. For severe phenotypes, most mutations are sporadic, while some are AD or recessive inherited. For milder phenotypes, sporadic and AD inherited were both common, while only 1 patient with recessive mutations was observed. [ABSTRACT FROM AUTHOR]

Introduction: Normal oral fibroblasts (NOFs) are located in the connective tissue of the oral mucosa. The NOFs play an important role in wound healing, tumor progression, and metastasis. They are subjected to influence by external and internal stimuli, among them extracellular vesicles (EVs), that are considered as important players in cell to cell communication, especially in carcinogenesis and metastatic processes. During tumorigenesis, stromal NOFs may undergo activation into cancer-associated fibroblasts (CAFs) that modify their phenotype to provide pro-oncogenic signals that in turn facilitate tumor initiation, progression, and metastasis. The aim of the study was to reveal the effect of EVs derived from local (oral squamous cell carcinoma – OSCC) and distant (pancreatic adenocarcinoma – PDAC; malignant melanoma brain metastasis – MBM) cancer origin on NOFs and their possible change into a CAF-like direction. Methods: The effect of each of the cancer EV types on NOFs proliferation, viability, and migration was tested. Also, changes in gene expression of the wellestablished CAF biomarkers ACTA2, FAP, PDGFR, and two putative CAF biomarkers, the Ca2+- activated ion channels ANO1 and KCNMA, were studied. Results: Obtained results indicate that NOFs receive and process signals transmitted by EVs originating from both OSCC, PDAC, and MBM. The fibroblast response was dependent on EV origin and concentration, and duration of EV exposure. Conclusion: The present results indicate that the molecular cargo of the EVs direct NOFs towards a pro-tumorigenic phenotype. [ABSTRACT FROM AUTHOR]

Background: EYA4 variants are responsible for DFNA10 deafness. Due to its insidious onset and slow progression, hearing loss in autosomal dominant non-syndromic hearing loss (ADNSHL) is usually challenging to detect early in clinical settings, with limited intervention options. Genetic testing can aid in early detection of hearing loss, enabling timely intervention to reduce disability rates and improve the quality of life. Methods: In this study, we report the case of a Chinese family with postlingual and progressive hearing loss that was passed down for four generations. Whole-exome sequencing (WES) was performed on DNA samples from the proband. Candidate variants identified in the proband and family members were confirmed via Sanger sequencing. In silico prediction tools and co-segregation analyses were used to assess the pathogenicity of identified variants. A literature review of known EYA4 variants was performed, analysing variant frequency, distribution characteristics across different populations, and genotype-phenotype correlations. Results: We identified a novel EYA4 variant, c.1745_1748del (p.Glu582ValfsTer6), in a Chinese family with ADNSHL, and co-segregation with the family's phenotype was confirmed. The audiometry showed mid-to-high frequency downsloping hearing loss. To date, 52 pathogenic variants of EYA4 have been reported, with majority identified in Asian populations. Most observed are the missense and frameshift variants. Conclusions: A novel variant of EYA4 was identified in a Chinese family with postlingual hearing loss, contributing to the expanding spectrum of EYA4 variants. The audiological features of EYA4 variants are highly heterogeneous and often challenging to detect early in clinical settings. Our findings highlight the significance of genetic testing in patients presenting with postlingual hearing loss. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Capillary malformation–arteriovenous malformation (CM‐AVM) is a rare genetic disorder characterized by multiple small capillary malformations (CMs) and arteriovenous malformations (AVMs), which has been linked with pathogenic variants in RASA1 and EPHB4. However, more data are needed to explore the phenotypic characteristics and the association between genotypes and clinical phenotypes.Our aim was to investigate the phenotypic and genetic characteristics of CM‐AVM in East Asians, identify potential unique phenotypes, and conduct genotype–phenotype association analyses.This is a single‐center study prospectively collecting CM‐AVM patients' clinical data, with genetic data from blood or tissue samples.A total of 59 patients were enrolled. Thirty‐two individuals had a leading CM greater than Schobinger stage II. The trigeminal nerve branches and greater auricular, transverse cervical, and lesser occipital nerves' somatosensory innervation zones divided head and neck CMs into six zones: V1, V2, V3, GA, TC, and LO zones. GA, TC, and LO zones had a positive correlation with one another but a negative correlation with V2 zone involvement. The RASA1 and EPHB4 pathogenic variants were detected in 41 out of 59, which showed two types of variant allele frequency (VAF) distributions. VAF above 30% made RASA1 pathogenic variants more susceptible to multifocal CMs than those below 30%.Leading CMs in the head and neck exhibit two segmentation patterns, anterior and lateral, which may differ in ear involvement and progression. Germline RASA1 pathogenic variants increased multifocal CM risk more than the somatic variants. [ABSTRACT FROM AUTHOR]

AIM: To investigate the role of proviral integration site for Moloney murine leukemia virus 1 （PIM1） in the phenotypic switching of vascular smooth muscle cells （VSMCs） induced by oxidized low-density lipoprotein （oxLDL）, and to explore the underlying mechanisms. METHODS: Eighteen male ApoE-/- mice （8 weeks old） were randomly divided into general diet group and high-fat diet group, with 9 mice per group. After 16 weeks, aortic samples were analyzed using HE staining to observe plaque formation. In vitro, VSMCs were exposed to oxLDL to induce phenotypic transformation. Western blot and immunofluorescence were used to measure the protein expression levels of PIM1 and phenotypic markers including α-smooth muscle actin （α-SMA）, smooth muscle protein 22α （SM22α）, osteopontin （OPN）, and CD68. Glycolysis levels were assessed by detecting the expression of glycolytic enzymes 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase （PFKFB3） and hexokinase 2 （HK2） by Western blot, and lactate secretion was measured using a lactate test kit. The effects of SMI-4a（ a specific inhibitor of PIM1） and PIM1 small interfering RNA on oxLDL-induced phenotypic markers in VSMCs were evaluated. Moreover, the impact of 3-（3-pyridinyl）-1-（4-pyridinyl）-2-propen-1-one （3PO; a glycolysis inhibitor） on oxLDL-induced phenotypic switching and glycolysis in VSMCs was investigated. RESULTS: HE staining revealed atherosclerotic plaque formation in the aortas of ApoE-/- mice fed with high-fat diet. Immunofluorescence showed high accumulation of PIM1 and OPN in the tunica intima of atherosclerotic plaques. Compared with control group, aortic plaques exhibited significantly elevated levels of PIM1, OPN and CD68 proteins（ P<0. 01）, accompanied by reduced expression of contractile phenotype markers α-SMA and SM22α （P<0. 01）. In vitro, oxLDL treatment led to gradual decrease in α-SMA and SM22α expression（ P<0. 05 or P<0. 01）, while OPN and CD68 expression increased （P<0. 05 or P<0. 01）. Moreover, oxLDL significantly up-regulated the protein expression of PIM1, PFKFB3 and HK2, and increased lactate secretion in VSMCs （P<0. 05 or P<0. 01）. Knockdown of PIM1 or treatment with SMI-4a markedly attenuated these oxLDL-induced effects on VSMCs（ P<0. 05 or P<0. 01）. Treatment with 3PO also abolished oxLDL-induced phenotypic transformation and glycolysis in VSMCs （P<0. 05 or P<0. 01）. CONCLUSION: PIM1 highly accumulates in the atherosclerotic plaques of ApoE-/- mice. The phenotypic transformation of VSMCs was correlated with the expression of PIM1. PIM1 can regulate the phenotypic transformation of oxLDL-treated VSMCs by inducing glycolysis. [ABSTRACT FROM AUTHOR]

Background and Aims The size and shape of reproductive structures is especially relevant in evolution because these characters are directly related to the capacity for pollination and seed dispersal, a process that plays a basic role in evolutionary patterns. The evolutionary trajectories of reproductive phenotypes in gymnosperms have received special attention in terms of pollination and innovations related to the emergence of the spermatophytes. However, variability of reproductive structures, evolutionary trends and the role of environment in the evolution of cycad species have not been well documented and explored. This study considered this topic under an explicitly phylogenetic and evolutionary approach that included a broad sampling of reproductive structures in the genus Ceratozamia. Methods We sampled 1400 individuals of 36 Ceratozamia species to explore the evolutionary pattern and identify and evaluate factors that potentially drove their evolution. We analysed characters for both pollen and ovulate strobili within a phylogenetic framework using different methods and characters (i.e. molecular and both quantitative and qualitative morphological) to infer phylogenetic relationships. Using this phylogenetic framework, evolutionary models of trait evolution for strobilar size were evaluated. In addition, quantitative morphological variation and its relation to environmental variables across species were analysed. Key Results We found contrasting phylogenetic signals between characters of pollen and ovulate strobili. These structures exhibited high morphological disparity in several characters related to size. Results of analyses of evolutionary trajectories suggested a stabilizing selection model. With regard to phenotype–environment, the analysis produced mixed results and differences for groups in the vegetation type where the species occur; however, a positive relationship with climatic variables was found. Conclusions The integrated approach synthesized reproductive phenotypic variation with current phylogenetic hypotheses and provided explicit statements of character evolution. The characters of volume for ovulate strobili were the most informative, and could provide a reference for further study of the evolutionary complexity in Ceratozamia. Finally, heterogeneous environments, which are under changing weather conditions, promote variability of reproductive structures. [ABSTRACT FROM AUTHOR]

Infiltrative heart disease (InHD) is a group of diseases characterized by the deposition of abnormal substances in the heart tissue, causing diastolic, less often systolic, dysfunction of the ventricle(s). Their classification still does not exist. In 2013, the MOGE(S) classification of cardiomyopathies was published, taking into account, along with the morphological and functional characteristics of the heart, damage to other organs, the presence of genetic mutations, acquired causes (e.g., myocardial inflammation, autoimmune diseases, storage diseases, amyloidosis), etc. By analogy with it we offer the MORAL-STAGE classification for InHD. It includes ten features: morphofunctional characteristics (M), organ damage (O), risk of cardiac death (R), age of clinical presentation, age of disease-specific therapy initiation (A), localization of the infiltrative process (inside or outside the cell, L), information about the functional class heart failure and stage of infiltrative heart disease (S), treatment (T), abnormal rhythm or conduction (A), genetic or familial nature of inheritance (G), etiology of the process (E). This article summarizes the cornerstones of the MORAL-STAGE classification and its clinical relevance. In addition, new issues are discussed that can be considered in future versions of the MORAL-STAGE classification. [ABSTRACT FROM AUTHOR]