Phenotypic Groups Research Articles

Progressive Myoclonus Epilepsy and Beyond: A Systematic Review of SEMA6B-related Disorders.

Progressive myoclonus epilepsy (PME) is a rare, clinically and genetically heterogeneous epilepsy syndrome, and pathogenic variants in the semaphorin 6B (SEMA6B) gene have recently been reported to be among the causes of PME. Cases with pathogenic variants in the SEMA6B gene are extremely rare, only a limited number of cases have been reported in the literature. In this systematic review, we aimed to present a summary of a PME case in which a heterozygous nonsense variant of c.2086C > T p.(Gln696*) in the SEMA6B gene was detected in the etiology and other cases with SEMA6B pathogenic variant in the literature. Except for our case, 35 cases from 12 studies were included. The main clinical findings in these patients were cognitive problems, seizures, gait and speech disturbances, and cognitive and/or motor regression, and they had a wide spectrum of severity. Response to antiseizure medications was also highly variable, almost half of the patients had pharmacoresistant seizures. Patients were divided into four different phenotypic groups according to their clinical presentations: PME (18/36), developmental and epileptic encephalopathy (13/36), neurodevelopmental disorder (4/36), and epilepsy (1/36), respectively. In conclusion, although SEMA6B has been associated with PME, it may actually cause a much broader phenotypic spectrum. Due to their extreme rarity, our knowledge of SEMA6B-related disorders is limited. As with all other rare diseases, each new SEMA6B-related disorder case could contribute to a better understanding of the disease. A better understanding of the disease may allow the development of specific treatment options in the future.

Phenotype groups in atrial cardiomyopathy and their prognosis

Abstract Background Atrial cardiomyopathy (ACM) includes patients with heterogenous demographic characteristics and comorbidities. Defining phenotype groups with similar clinical characteristics is important for the effective treatment of these patients, and for their prognosis and prevention of ACM. Purpose To conduct a cluster analysis that could help us in phenotyping ACM and exploring the clinical complexity of this entity. Methods We performed a hierarchical cluster analysis based on Ward’s Method using 10 clinical binary variables (hypertension, diabetes mellitus, heart failure, obesity, chronic obstructive pulmonary disease, cancer, coronary artery disease, sinus node dysfunction or atrio-ventricular block, implanted pacemaker, and ischemic stroke), identifying the optimal number of clusters. We investigated differences in demographic, laboratory and echocardiographic parameters, and treatment between defined clusters, and assessed the impact of these factors on prognosis. Results Of 724 evaluated consecutive patients with dilated left atrium only 200 met the criteria for advanced atrial cardiomyopathy, defined as severely dilated left atrium with volume index (LAVI) ≥ 48 ml/m2, preserved left ventricular systolic function - ejection fraction ≥ 50%, without an overt valvular or ventricular disease, and were included in the analysis. Mean age of the studied population was 73.91 ± 9.74 years, 58 % of them were women. We identified 4 clusters: cluster 1 (n = 73, 36%) were younger overweight patients with paroxysmal atrial fibrillation (AF); cluster 2 (n = 56, 28%) - old patients with congestive heart failure (CHF) and low body mass index (BMI); cluster 3 (n = 34, 17%)- diabetic patients with obesity and CHF; and cluster 4 (n = 37, 19%) old patients with tachycardia-bradycardia syndrome, implanted pacemakers, and long -standing AF. Over a mean follow up of 20.6 months cluster 2 had the highest mortality rate (28.6%), followed by cluster 3 (20.6%), compared to the lower mortality rate of cluster 1 and 4 (11% and 10.8%, respectively, p=0.047). The presence of heart failure (HR 4.4, CI 1.5 ÷12.7, p=0.006), cancer (HR 3.3, CI 1.6 ÷ 6.9, p=0.002) and greater than moderate tricuspid regurgitation (HR 5.4, CI 2.6 ÷ 11.3, p<0.001) were predictors of poor outcome. Conclusion In patients with advanced atrial cardiomyopathy, four main clusters were identified, differentiated by distinct comorbidities. Both clinical and echocardiographic parameters were found to be associated with an increased risk of mortality.Phenotype clusters of ACMKaplan-Meier curves of clusters

Cognitive patterns according to mini-mental state examination domains in patients with AF and association with all-cause mortality: a cluster analysis from a contemporary prospective study

Abstract Background Atrial fibrillation (AF) is associated with cognitive impairment even in the absence of previous stroke. However, data on specific patterns of cognitive impairment and their association with outcomes are limited. Purpose We aimed to identify different phenotypic groups of AF patients stratified according to specific cognitive domains using cluster analysis and evaluate the association between identified clusters and adverse outcomes. Methods We used data from a prospective observational study on AF patients excluding those with previous clinically overt stroke. We performed a hierarchical cluster analysis based on Ward’s Method using data from the Mini-Mental State Examination (MMSE) administered during the enrollment. The MMSE includes 6 distinct cognitive domains. We normalized each domain’s score from 0 to 100 to preserve the ranking and the interpretability of the test. Patients’ clusters were identified by examining the distance between cluster coefficients and by visual inspection of the dendrogram. All-cause mortality was the primary endpoint. Results A total of 872 stroke-free AF patients were included. Three clusters based on MMSE domains were identified: Cluster 1 (n=494, 56.7%); Cluster 2 (n=243, 27.9%) and Cluster 3 (n=135, 15.5%). The clusters greatly differed according to the cognitive domains affected and baseline characteristics (Table). The use of oral anticoagulants did not differ among clusters and it was substantially high (88.6%). Cluster 2 had a higher prevalence of cognitive impairment (37.9% vs 35.6% for Cluster 3 and 1.0% for Cluster 1, p<0.001) with a lower mean MMSE score compared to other clusters. The analysis of MMSE domains showed substantial deficits in the orientation, attention/calculation, and recall domains with peculiar differences among the clusters. Cluster 2 showed the most significant impairment in the copying domain (100%) while Cluster 3 had a higher impairment in attention/calculation and recall domains. After a median follow-up of 629 days, all-cause mortality was 15.9% with a significantly higher prevalence in Cluster 2 (26.9% vs 10.0% and 15.5% for Cluster 1 and Cluster 3 respectively, p<0.001). At the adjusted Cox regression analysis, Cluster 2 was independently associated with a higher risk of all-cause mortality compared with Cluster 1 (HR 1.83, 95% CI 1.18-2.82) while Cluster 3 was not independently associated with the outcome (Figure). Conclusions In a prospective observational cohort of stroke-free AF patients, we identified three clusters showing different patterns of cognitive impairment, affecting specific MMSE domains and resulting in a different risk of mortality. Our findings highlight the clinical implications of cognitive impairment and stress the need for a more holistic approach to AF patients including a comprehensive cognitive assessment, as well as the need for studies on interventions able to positively affect cognitive impairment.Figure

Gene-echocardiography: unmasking the covert role of fatty acid metabolism gene mutations in adult cardiomyopathy

Abstract Background Although the role of fatty acid metabolic deficiencies in cardiomyopathy is established, the precise identity of causative genes and their respective phenotypes in adult cardiomyopathy remains unclear. Methods We implemented a combination of echocardiography and whole exome sequencing in clinically diagnosed cardiomyopathy patients to uncover this relationship. This involved recording cardiac phenotypes, identifying genes associated with disrupted fatty acid metabolism, and subsequently followed up with these patients. Results Out of 802 cardiomyopathy patients, 27 exhibited mutations in genes tied to fatty acid metabolism. Specifically, 16 patients demonstrated a hypertrophic cardiomyopathy (HCM) phenotype, and 11 showed a dilated cardiomyopathy (DCM) phenotype. The implicated genes were SLC22A5 (n=7), ACADVL (n=6), ACADS (n=4), ACADM (n=3), SLC25A20 (n=3), ACADL (n=2), HADH (n=1), and AGK (n=1), with a higher prevalence in males. Among these, the SLC22A5 mutation was predominant and correlated with HCM phenotype. Notably, compound mutations were frequently observed (16/27), leading to earlier disease onset and diminished aortic sinus dimension. Further investigation showed that smaller aortic sinus dimensions resulted from abnormal left ventricular myocardial work. HCM phenotype mutation carriers showed more consistent left ventricular hypertrophy and a higher probability of right ventricular hypertrophy, while DCM phenotype mutation carriers exhibited impaired contractile function across all left ventricle segments. After a 24-month follow-up, the DCM phenotype group demonstrated higher cardiovascular risk, including two fatalities. Conclusion Our investigation highlights the significant prevalence of mutations related to abnormal fatty acid metabolism in adult cardiomyopathy patients, underscoring the utility of a gene-echocardiography approach for diagnosis.

Nontargeted urine metabolomic analysis of acute intermittent porphyria reveals novel interactions between bile acids and heme metabolism: New promising biomarkers for the long-term management of patients.

Acute intermittent porphyria is an inherited error of heme synthesis. The underlying pathophysiology, involving mainly hepatic heme synthesis, is poorly understood despite its occurrence, and the severity of acute porphyria attack is still difficult to control. A better understanding of the interactions between heme synthesis and global metabolism would improve the management of AIP patients. An untargeted metabolomic analysis was performed on the urine of 114 patients with overt AIP and asymptomatic carriers using liquid chromatography coupled to high-resolution mass spectrometry. The collected data were analyzed by combining univariate and multivariate analyses. A total of 239 metabolites were annotated in urine samples by matching chromatographic and mass spectral characteristics with those from our chemical library. Twenty-six metabolites, including porphyrin precursors, intermediates of tryptophan or glycine metabolism and, unexpectedly, bile acids, showed significant concentration differences between the phenotypic groups. Dysregulation of bile acid metabolism was confirmed by targeted quantitative analysis, which revealed an imbalance in favor of hydrophobic bile acids associated with changes in conjugation, which was more pronounced in the severe phenotype. Using a random forest model, the cholic acid/chenodeoxycholic acid ratio enables the differential classification of severe patients from other patients with a diagnostic accuracy of 84%. The analysis of urine samples revealed significant modifications in the metabolome of AIP patients. Alteration in bile acids provides new insights into the pathophysiology of chronic complications, such as primary liver cancer, while also providing new biomarker candidates for predicting the most severe phenotypes.

Distinct Phenotypic Groups and Related Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder with varying risks of clinical outcomes, including sudden cardiac death (SCD). We aimed to identify distinct phenotypes among patients with HCM in relation to SCD risk factors, interpret their clinical characteristics, and examine their outcomes. This retrospective study analyzed 1231 consecutive patients with HCM from 2 tertiary hospitals. We performed latent class analysis to categorize patients into phenotypic groups. Three distinct phenotypic groups were identified using latent class analysis. Group 1 (n=554) consisted of young patients with HCM with minimal SCD risk factors and favorable cardiac remodeling. Group 2 (n=114) comprised young patients with HCM and a high prevalence of SCD risk factors, whereas Group 3 (n=563) included older patients (median age, 68 years). Over a median 6.5-year follow-up, 34 SCD-related events, 131 cardiovascular events, 133 all-cause mortality events, and 70 noncardiovascular mortality events were observed. Group 2 exhibited the highest rate of SCD-related events (5-year SCD rate: Group 1 versus 2 versus 3: 0.8% versus 8.2% versus 4.0%, respectively, P<0.001), and cardiovascular events were more frequent in Groups 2 and 3 compared with Group 1. All-cause and noncardiovascular mortality were the most frequent in Group 3. A simplified decision tree was developed for the straightforward assignment of phenotypic group membership, demonstrating fair concordance. This study identified 3 distinct clinical phenotypes in patients with HCM, each associated with different SCD risks and outcomes. Data-driven phenotyping of patients with HCM offers effective risk stratification and may optimize patient management.

In vitro activity assessment of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp., including β-lactam nonsusceptible molecularly characterized isolates, collected from 2020 to 2021 in the United States and European hospitals.

This study reports the activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp. isolates collected from the United States and Europe, including Israel and Turkey, from 2020 to 2021. Among Enterobacterales, 2.8% were carbapenem nonsusceptible (CNSE); cefiderocol inhibited 96.6%/85.1% [Clinical Laboratory Standards Institute (CLSI)/European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints] of these isolates. Imipenem-relebactam, meropenem-vaborbactam, and ceftazidime-avibactam displayed susceptibilities lower than cefiderocol against CNSE isolates (67.4-84.6% susceptible, CLSI). Cefiderocol was the only agent active against CNSE isolates carrying metallo-β-lactamase (MBL) carbapenemase or multiple carbapenemase genes (84.6%-92.3% susceptible, CLSI). Approximately 18% of carbapenem-susceptible Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis carried extended-spectrum-β-lactamases and/or plasmid-borne AmpC-encoding genes; cefiderocol inhibited 99.8%-100.0% (CLSI) of these genotypic groups. Multi-drug resistance (MDR) phenotypes were observed in 16.9% and 52.5% of P. aeruginosa and A. baumannii-calcoaceticus isolates, respectively. Carbapenemase genes were rare (4.9%) among cephalosporin and/or carbapenem nonsusceptible P. aeruginosa, compared to 87.6% carriage in A. baumannii-calcoaceticus, respectively. Against the MDR and carbapenemase-carrying P. aeruginosa and A. baumannii-calcoaceticus subsets, cefiderocol was active against 98.6%/98.7% and 97.1%/97.4% (CLSI), respectively. Only 69 isolates (0.3%) across all species groups were identified as cefiderocol nonsusceptible per CLSI criteria (>4 mg/L). Cefiderocol was the most active agent in vitro against Enterobacterales, P. aeruginosa, and Acinetobacter spp., with uniform activity against all phenotypic- and genotypic-resistant subsets. Coupled with the low incidence of nonsusceptibility observed across species groups, these results demonstrate cefiderocol as an important option for treating infections caused by pathogens with diverse mechanisms of resistance in US and European hospitals.IMPORTANCEThe worldwide spread of multi-drug-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacterales and Acinetobacter spp. poses a serious challenge in healthcare settings as infections caused by these organisms are commonly refractory to many frontline therapeutic agents. Multiple global health organizations highlighted these pathogens as critical priorities for new antibiotic development, thus necessitating continued surveillance of the activities of currently available antimicrobial agents and circulating mechanisms of resistance. To meet this need, this study phenotypically and genotypically characterized priority Gram-negative pathogens collected from patients in US and European hospitals to examine the activity of cefiderocol and other currently available treatment options, including carbapenems and β-lactam-β-lactamase inhibitor combinations. The results presented here provide a detailed perspective to healthcare practitioners of cefiderocol's broad applicability, manifested in high activity and low nonsusceptibility rates, across phenotypic and genotypic organism groups relative to other agents and further support its use against the most intransigent infections.

Substance use and psychiatric phenotypes of youth experiencing homelessness: A cluster analysis.

Due to the complex interactions of psychopathology, psychosocial stressors, and risk behaviors, characterizing high-risk phenotypic groups of transitional-age youth experiencing homelessness (TAY-EH) for targeted interventions remains difficult. We aimed to uncover specific phenotypes of TAY-EH based upon psychiatric and substance use disorder (SUD) diagnoses, and to assess relationships between these phenotypes and negative outcomes including suicidality and high-risk behaviors. Participants (N = 140; 57% male, 54% Black) were individuals aged 16-25 years accessing support at a psychosocial agency in the U.S. Northeast. Data were gathered via structured assessment. Cluster analysis identified sub-groups of TAY-EH with differing diagnostic patterns. Bivariate analyses examined associations between cluster membership and target outcomes. A four-cluster solution was identified. Cluster 1 (Co-occurring; N = 33) was characterized by high levels of comorbidity (i.e., major depressive disorder (MDD), SUD, and notable levels of other diagnoses). Clusters 2 (MDD alone; N = 47) and 3 (SUD alone; N = 18) were characterized by single diagnoses. Cluster 4 (None; N = 42) was characterized by low levels of psychopathology. Clusters differed significantly on several variables including suicidality, adverse childhood experiences, and social connectedness. Comorbid MDD and SUD were most strongly associated with high-risk behaviors and suicidality. These results highlight the importance of diagnosis and targeted interventions for co-occurring MDD and SUD to address the crisis of early mortality and other negative outcomes among TAY-EH. This study is the first to identify specific high-risk psychiatric and psychosocial phenotypes among the highly complex group of TAY-EH based upon structured diagnostic assessments.

THE FIGHT INHERITED RETINAL BLINDNESS! PROJECT: A NEW TREATMENT OUTCOME AND NATURAL HISTORY REGISTRY FOR INHERITED RETINAL DISEASE.

To design and build a new disease registry to track the natural history and outcomes of approved gene therapy in patients with inherited retinal diseases (IRDs). A core committee of 6 members was convened to oversee the construction of the FIRB! module. A further 11 experts formed a steering committee, which discussed disease classification and variables to form minimum datasets via a consensus approach. The web-based FIRB! registry records baseline demographic, clinical and genetic data together with follow-up data. The Human Phenotype Ontology and Monarch Disease Ontology nomenclature were incorporated within the FIRB! architecture to standardise nomenclature. The registry software assigns individual diagnoses to one of 7 broad phenotypic groups, with minimum datasets dependent upon the broad phenotypic group. Additionally, minimum datasets were agreed upon for patients undergoing approved gene therapy with voretigene neparvovec (Luxturna). New patient entries can be completed in 5 minutes, and follow-up data can be entered in 2 minutes. Fight Inherited Retinal Blindness! (FIRB!) is an organized, web-based system that uses observational study methods to collect uniform data from IRD patients to track natural history and (uniquely) treatment outcomes. It is free to Users, who have control over their data.

The relationship between repeated measurements of HbA1c and risk of coronary events among the common haptoglobin phenotype groups: the Action for Health in Diabetes (Look AHEAD) study

BackgroundIn the ACCORD study, participants with the haptoglobin (Hp) 2–2 phenotype and glycated hemoglobin (HbA1c) ≥ 8.0% had a higher risk of coronary artery disease (CAD) compared to those with HbA1c 7.0–7.9%. However, this association was not observed in participants without the Hp2-2 phenotype. The optimal glycemic target for CAD prevention for the Hp phenotypes remains uncertain and may vary based on demographic and clinical factors.ObjectiveTo investigate how reaching clinically relevant HbA1c targets relates to the risk of CAD in different Hp phenotype groups among a diverse cohort of individuals with T2DM (the Look AHEAD study, HbA1c ≤ 11% at baseline).MethodsCox regression models with time-varying covariables were used to quantify the association between time-varying achieved HbA1c (< 6.5%, 6.5–6.9%, and ≥ 8.0% compared to 7.0-7.9%), updated at years 1–4, 6, 8, and 10, and incident CAD in the Hp2-2 (n = 1,587) and non-Hp2-2 (n = 2,944) phenotypes separately. Further pre-specified subgroup analyses by age, sex, history of cardiovascular disease (CVD), race, and diabetes duration were performed in each Hp phenotype group separately.ResultsCompared with HbA1c 7.0-7.9%, having HbA1c < 6.5% was associated with a 29% lower CAD risk among participants with the non-Hp2-2 phenotype (adjusted HR 0.71, 95% CI 0.55–0.90). In subgroup analyses, this association was present in participants with the non-Hp2-2 phenotype who were male (0.60, 0.44–0.83), who did not have a history of CVD (0.65, 0.47–0.90), who were aged ≥ 65 years (0.64, 0.44–0.94), who were White (0.68, 0.51–0.91), or who had diabetes duration > 10 years (0.58, 0.35–0.95). HbA1c ≥ 8.0% was associated with CAD risk only among participants with the Hp2-2 phenotype who had a history of CVD (1.79, 1.00-3.20). No associations were found between the other HbA1c targets and CAD risk when participants with the Hp2-2 phenotype were grouped together or divided into subgroups.ConclusionThe differences in our results compared to our previous findings may be due to variations in the study populations and factors associated with weight loss, making it difficult to draw definitive conclusions. Our current findings should be considered in the context of hypothesis generation, and ideally, will encourage additional research in this field.

Improving CYP2C19 phenotyping using stereoselective omeprazole and 5-hydroxy-omeprazole metabolic ratios.

Omeprazole (OME) is a CYP2C19 phenotyping probe, marketed as a racemic (S)/(R) mixture or as an S-enantiomer. Both CYP2C19 and CYP3A4 enzymes mediate (R)-OME hydroxylation to (R)-5-hydroxyomeprazole, while (S)-OME is exclusively hydroxylated via CYP2C19. This study investigates OME and its 5-hydroxymetabolite enantiomers' pharmacokinetics using data from two studies involving healthy volunteers. In Study A, volunteers received OME alone in Session 1, OME combined with voriconazole and fluvoxamine in Session 2 and finally OME with rifampicin in Session 3. In Study B, volunteers received OME alone in Session 1, OME combined with voriconazole in Session 2 and finally OME with fluvoxamine in Session 3. Despite low metabolic ratio values of (S)-OME, detectable modulation of CYP2C19 activity suggests both (R)- and (S)-OME isomers could effectively assess CYP2C19 activity. Further research is needed for precise cut-offs in different phenotype groups.

Evaluation of biocorrosion, biofouling, and health risks in the two study locations in danube alluvium

Within conducted research the results of microbiological investigations on specific metabolic (phenotypic) groups of bacteria that play crucial roles in the biogeochemical cycling of iron, manganese, nitrogen, sulfur, and carbon are presented. These bacteria are also involved in the development of biocorrosion and biofouling processes, with some posing risks to public health. Utilizing results from applied biological activity reaction tests (BART tests), processed using specialized software, potential risks for the development of microbiologically mediated corrosion, biofouling, and health risks were calculated for seven wells within two oxic sites in the Danube alluvium – Vinci and Veliko Gradište, Serbia. Moderate to high corrosion risk was determined for all seven wells at both sites (CR=5.4). Microbiological fouling risk was very high in three out of the seven investigated wells (PR=8.10). Among the seven sites studied, one site stood out based on the calculated high value of health risk coefficient (HR=8.10). The research results provide new insights into the microbiological role in aging wells in oxic groundwater of the Danube alluvium. It is demonstrated that the physicochemical composition and chemical species such as minerals, organic matter, and the specific composition of microbial communities in the studied groundwater have the potential to stimulate biocorrosion and the formation of deposits and biofilms within well structures. In addition to biochemical analyses, hydrogeological characteristics of the analyzed area are presented to define the geological stratigraphy, for which specific microbiological transformations would be expected based on the obtained results.

Characterization of systemic lupus erythematosus subtypes using cluster analysis: insights from lymphocyte subpopulations.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, in which lymphocyte subsets were dysregulated. Incorporating lymphocyte subpopulations in cluster analysis offers a pathway for personalized and precise treatment, targeting specific abnormalities for more effective management. We conducted Gaussian clustering analysis on clinical data, serological data, urine test results, and lymphocyte subpopulations for SLE patients hospitalized from September 2008 to December 2019. A total of 1863 SLE patients from Xi'Jing Hospital were included. After excluding those without complete assessments, 1281 patients underwent flow cytometry for lymphocyte subsets. Five SLE clusters emerged: Cluster 1 with severe kidney involvement, high SLEDAI scores, and infection rates, often accompanied by rashes and edema; cluster 2 with high urinary protein but better renal function; cluster 3 with normal lymphocyte count and low positive antibodies; cluster 4 with frequent psychiatric symptoms and pulmonary arterial hypertension (PAH); and cluster 5 with fever, arthritis, hematologic involvement, and high IgG levels despite decreased B cells. All enrolled SLE patients were ultimately categorized into five distinct clinical phenotype groups, with lymphocyte testing being meaningful for patient stratification. This finding shed light on the intricate heterogeneity of SLE, emphasizing the need for a personalized medicine approach. Targeting specific abnormalities in lymphocyte subsets holds promise for more effective and precise management of SLE. Key Points • A comprehensive analysis of SLE patients, including lymphocyte subpopulations, revealed five distinct clusters with varying clinical characteristics, emphasizing the heterogeneity of the disease. • This heterogeneity underscores the need for a personalized medicine approach in SLE management, targeting specific lymphocyte subset abnormalities for more effective and precise treatment.

The application of whole-exome sequencing in the early diagnosis of rare genetic diseases in children: a study from Southeastern China.

Genetic diseases exhibit significant clinical and genetic diversity, leading to a complex and challenging diagnostic process. Exploiting novel approaches is imperative for the molecular diagnosis of genetic diseases. In this study, we utilized whole-exome sequencing (WES) to facilitate early diagnosis in patients suspected of genetic disorders. This retrospective analysis included 144 patients diagnosed by singleton-WES Trio-WES between January 2021 and December 2023. We investigated the relevance of diagnosis rates with age, clinical presentation, and sample type. Among the 144 patients, 61 were diagnosed, yielding an overall diagnostic rate of 42.36%, with Trio-WES demonstrating a significantly higher diagnostic rate of 51.43% (36/70) compared to singleton-WES at 33.78% (25/74) (p < 0.05). Global developmental delay had a diagnosis rate of 67.39%, significantly higher than muscular hypotonia at 30.43% (p < 0.01) among different clinical phenotypic groups. Autosomal dominant disorders accounted for 70.49% (43/61) of positive cases, with autosomal abnormalities being fivefold more prevalent than sex chromosome abnormalities. Notably, sex chromosome abnormalities were more prevalent in males (80%, 8/10). Furthermore, 80.56% (29/36) of pathogenic variants were identified as de novo mutations through Trio-WES. These findings highlight the effectiveness of WES in identifying genetic variants, and elucidating the molecular basis of genetic diseases, ultimately enabling early diagnosis in affected children.

Cytokine Signature Differences in Major Phenotypic Groups of Behçet Disease.

Behçet disease (BD) has heterogeneous presentations, mainly mucocutaneous, vascular, and ocular manifestations. The mechanisms associated with different phenotypes have not been clarified. We aimed to investigate the expression of innate and adaptive immunity-related cytokines in these 3 main BD phenotypes in active and untreated states and remission after treatment to be able to develop a cytokine-based treatment algorithm. Serum samples were isolated from 41 patients with newly diagnosed active BD (aBD), which consisted of 19 mucocutaneous aBD, 11 ocular aBD (o-aBD), and 11 vascular aBD patients, 35 patients in remission (rBD), and 9 healthy controls (HC). Serum levels of each cytokine were measured with sandwich enzyme-linked immunosorbent assay and analyzed as both raw measurements and corrected levels for each 1 million white blood cells. The study included 41 aBD patients (female/male [F/M]: 9/32; median age, 29 years), 35 rBD patients (F/M: 9/26; median age, 29 years), and 9 HC (F/M: 3/6; median age, 28 years). The serum interferon γ level was significantly higher in the aBD group than in the rBD (116 vs. 92 pg/mL, p = 0.022). The serum interleukin 35 (IL-35) level was significantly higher in the HC group compared with aBD and rBD (p = 0.05). IL-17-related cytokines were lower in o-aBD. With treatment, they increased in o-aBD but decreased in mucocutaneous aBD and vascular aBD patients. This study supports the involvement of both innate and TH1-predominated adaptive immune responses across all BD phenotypes. The IL-17 and TH17-related immune responses appear less prominent in ocular BD, which may explain the ineffectiveness of IL-17 blockade in treating ocular BD. These findings support the need for further studies using comprehensive gene expression analyses to develop targeted treatment strategies for BD phenotypes.

Comparison of the production performance of some phenotypic groups and their crosses of quail birds

The study aimed to determine the production efficiency of local quail phenotypic groups with different feather colors (white, brown, and desert) and their crosses. The results showed significant differences between groups in average body weight at 2, 4, and 6 weeks of age, and in weight gain at 2 and 4 weeks of age in favor of the T6 cross followed by the T5 cross, while T1 recorded the lowest body weight and weight gain compared to other hybrids. Significant differences in feed consumption were observed at 2 and 6 weeks, with no significant differences at 4 weeks. The highest feed consumption was recorded at 6 weeks for hybrids compared to pure groups, and feed conversion efficiency improved at 2 weeks for T5 and T6. At 4 weeks of age, T5, T7, and T6 recorded the best feed conversion efficiency. Positive heterosis in weight at 4 weeks was observed in favor of T5, T6, and T7, while it was negative in T4. Body weight at 6 weeks increased in hybrids T5, T6, and T7 compared to their expected value in the parental groups, and feed conversion efficiency improved at 6 weeks in hybrids T4 and T7. We conclude that heterosis increases the economic value of hybrids, with T6 and T5 being the best hybrids.

Molecular Evaluation of Aminoglycoside Resistance and Biofilm Formation Potential in Escherichia coli Isolates Collected from Hospitalized Patients

Background: Resistance to antibiotics and the ability to develop biofilms, two main virulence determinants of Escherichia coli, play a crucial role in the persistence of infections. Objectives: The aim of this study was to evaluate aminoglycoside resistance and biofilm formation potential in E. coli isolates collected from hospitalized patients in the Southwest of Iran. Methods: A total of 70 E. coli clinical isolates from different specimens were collected from Ahvaz teaching hospitals affiliated with Ahvaz Jundishapur University of Medical Sciences. All the isolates were identified as E. coli using conventional microbiological tests. Susceptibility to antibiotics was determined using the Kirby–Bauer disk diffusion method. Biofilm formation was assessed using the microtiter plate method. Finally, PCR was conducted to detect virulence gene determinants, including fimbrial genes, aminoglycoside modifying enzymes (AMEs), and 16S rRNA methylase (RMTase) genes. Results: Among aminoglycoside antibiotics, E. coli isolates showed the highest and lowest resistance rates to tobramycin (TOB; 51.4%) and gentamicin (GEN; 24.2%), respectively. Simultaneous resistance to GEN, amikacin, and TOB was observed in 28.5% of the isolates, representing the most common antibiotic resistance pattern. The prevalence of strong biofilm producers was higher in the extensively drug-resistant (XDR) phenotype group compared to the multiple drug-resistant (MDR) group (76.1% vs. 23.8%). Among the 36 isolates resistant to at least one of the aminoglycoside antibiotics, 36.1% had AME-related genes, either alone or in various combinations. Most isolates harboring AME genes were also positive for the presence of biofilm-related genes, including ecpA and fimA. Conclusions: The most frequent AME-related genes were ant(2”)-Ia and aph(3’)-Ia, followed by aac(3’)-IIa. The findings of the present study provide probable evidence that GEN is an effective aminoglycoside against biofilm-producing and antibiotic-resistant E. coli isolates.

An International Retrospective Early Natural History Study of LAMA2-Related Dystrophies.

LAMA2-related dystrophies (LAMA2-RDs) represent one of the most common forms of congenital muscular dystrophy and have historically been classified into two subtypes: complete or partial deficiency of laminin-211 (merosin). Patients with LAMA2-RD with the typical congenital phenotype manifest severe muscle weakness, delayed motor milestones, joint contractures, failure to thrive, and progressive respiratory insufficiency. While a comprehensive prospective natural history study has been performed in LAMA2-RD patients over 5 years of age, the early natural history of patients with LAMA2-RD 5 years and younger has not been comprehensively characterized. We extracted retrospective data for patients with LAMA2-RD ages birth through 5 years via the Congenital Muscle Disease International Registry (CMDIR). We analyzed the data using a phenotypic classification based on maximal motor milestones to divide patients into two phenotypic groups: "Sit" for those patients who attained that ability to remain seated and "Walk" for those patients who attained the ability to walk independently by 3.5 years of age. Sixty patients with LAMA2-RD from 10 countries fulfilled the inclusion criteria. Twenty-four patients had initiated non-invasive ventilation by age 5 years. Hospitalizations during the first years of life were often related to respiratory insufficiency. Feeding/nutritional difficulties and orthopedic issues were commonly reported. Significant elevations of creatine kinase (CK) observed during the neonatal period declined rapidly within the first few months of life. This is the largest international retrospective early natural history study of LAMA2-RD to date, contributing essential data for understanding early clinical findings in LAMA2-RD which, along with the data being collected in international, prospective early natural history studies, will help to establish clinical trial readiness. Our proposed nomenclature of LAMA2-RD1 for patients who attain the ability to sit (remain seated) and LAMA2-RD2 for patients who attain the ability to walk independently is aimed at further improving LAMA2-RD classification.

Lack of Bridge to Recovery in Pediatric Dilated Cardiomyopathy With Left Ventricular Noncompaction

BackgroundThis study assessed the possibility of a bridge to recovery using the Berlin Heart EXCOR and the histologic characteristics of pediatric patients with dilated cardiomyopathy accompanied by a left ventricular noncompaction phenotype. MethodsOf the 17 pediatric patients with dilated cardiomyopathy who underwent Berlin Heart EXCOR implantation between 2013 and 2020, 6 were diagnosed with left ventricular noncompaction association. The patients were classified into 2 groups: the dilated cardiomyopathy group and dilated cardiomyopathy with the left ventricular noncompaction phenotype group. The histologic characteristics of the left ventricular myocardium and left ventricular function after Berlin Heart EXCOR implantation were compared. ResultsCardiac recovery was not observed in the dilated cardiomyopathy with left ventricular noncompaction group. In contrast, 6 patients (55%) in the dilated cardiomyopathy group achieved cardiac recovery, and the Berlin Heart EXCOR was explanted. The degree of myocardial fibrosis was significantly higher in the dilated cardiomyopathy with the left ventricular noncompaction phenotype group than in the dilated cardiomyopathy group (P < .05). The final follow-up left ventricular ejection fraction and end-diastolic diameter during Berlin Heart EXCOR support improved significantly compared with the preimplantation variables in the dilated cardiomyopathy group (both P < .001); the dilated cardiomyopathy with left ventricular noncompaction phenotype group showed no improvements (P = .84 and P = .37, respectively). ConclusionsThe left ventricular noncompaction phenotype associated with dilated cardiomyopathy may adversely affect the rate of cardiac recovery with Berlin Heart EXCOR.

Cell-specific gene networks and drivers in rheumatoid arthritis synovial tissues.

Rheumatoid arthritis (RA) is a common autoimmune and inflammatory disease characterized by inflammation and hyperplasia of the synovial tissues. RA pathogenesis involves multiple cell types, genes, transcription factors (TFs) and networks. Yet, little is known about the TFs, and key drivers and networks regulating cell function and disease at the synovial tissue level, which is the site of disease. In the present study, we used available RNA-seq databases generated from synovial tissues and developed a novel approach to elucidate cell type-specific regulatory networks on synovial tissue genes in RA. We leverage established computational methodologies to infer sample-specific gene regulatory networks and applied statistical methods to compare network properties across phenotypic groups (RA versus osteoarthritis). We developed computational approaches to rank TFs based on their contribution to the observed phenotypic differences between RA and controls across different cell types. We identified 18 (fibroblast-like synoviocyte), 16 (T cells), 19 (B cells) and 11 (monocyte) key regulators in RA synovial tissues. Interestingly, fibroblast-like synoviocyte (FLS) and B cells were driven by multiple independent co-regulatory TF clusters that included MITF, HLX, BACH1 (FLS) and KLF13, FOSB, FOSL1 (B cells). However, monocytes were collectively governed by a single cluster of TF drivers, responsible for the main phenotypic differences between RA and controls, which included RFX5, IRF9, CREB5. Among several cell subset and pathway changes, we also detected reduced presence of Natural killer T (NKT) cells and eosinophils in RA synovial tissues. Overall, our novel approach identified new and previously unsuspected Key driver genes (KDG), TF and networks and should help better understanding individual cell regulation and co-regulatory networks in RA pathogenesis, as well as potentially generate new targets for treatment.