Phenotypic Groups Research Articles

Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion.

Prolonged cytopenias after chimeric antigen receptor (CAR) T cell therapy are a significant clinical problem and the underlying pathophysiology remains poorly understood. Here, we investigated how (CAR) T cell expansion dynamics and serum proteomics affect neutrophil recovery phenotypes after CD19-directed CAR T cell therapy. Survival favored patients with "intermittent" neutrophil recovery (e.g., recurrent neutrophil dips) compared to either "quick" or "aplastic" recovery. While intermittent patients displayed increased CAR T cell expansion, aplastic patients exhibited an unfavorable relationship between expansion and tumor burden. Proteomics of patient serum collected at baseline and in the first month after CAR-T therapy revealed higher markers of endothelial dysfunction, inflammatory cytokines, macrophage activation, and T cell suppression in the aplastic phenotype group. Prolonged neutrophil aplasia thus occurs in patients with systemic immune dysregulation at baseline with subsequently impaired CAR-T expansion and myeloid-related inflammatory changes. The association between neutrophil recovery and survival outcomes highlights critical interactions between host hematopoiesis and the immune state stimulated by CAR-T infusion.

Machine learning-based prediction of in-hospital death for patients with takotsubo syndrome: The InterTAK-ML model.

Takotsubo syndrome (TTS) is associated with a substantial rate of adverse events. We sought to design a machine learning (ML)-based model to predict the risk of in-hospital death and to perform a clustering of TTS patients to identify different risk profiles. A ridge logistic regression-based ML model for predicting in-hospital death was developed on 3482 TTS patients from the International Takotsubo (InterTAK) Registry, randomly split in a train and an internal validation cohort (75% and 25% of the sample size, respectively) and evaluated in an external validation cohort (1037 patients). Thirty-one clinically relevant variables were included in the prediction model. Model performance represented the primary endpoint and was assessed according to area under the curve (AUC), sensitivity and specificity. As secondary endpoint, a K-medoids clustering algorithm was designed to stratify patients into phenotypic groups based on the 10 most relevant features emerging from the main model. The overall incidence of in-hospital death was 5.2%. The InterTAK-ML model showed an AUC of 0.89 (0.85-0.92), a sensitivity of 0.85 (0.78-0.95) and a specificity of 0.76 (0.74-0.79) in the internal validation cohort and an AUC of 0.82 (0.73-0.91), a sensitivity of 0.74 (0.61-0.87) and a specificity of 0.79 (0.77-0.81) in the external cohort for in-hospital death prediction. By exploiting the 10 variables showing the highest feature importance, TTS patients were clustered into six groups associated with different risks of in-hospital death (28.8% vs. 15.5% vs. 5.4% vs. 1.0.8% vs. 0.5%) which were consistent also in the external cohort. A ML-based approach for the identification of TTS patients at risk of adverse short-term prognosis is feasible and effective. The InterTAK-ML model showed unprecedented discriminative capability for the prediction of in-hospital death.

Differential sensitivity of the 2020 revised comprehensive diagnostic criteria and the 2019 ACR/EULAR classification criteria across IgG4-related disease phenotypes: results from a Norwegian cohort

BackgroundWe investigated sensitivity of the 2020 Revised Comprehensive Diagnostic Criteria (RCD) and the 2019 ACR/EULAR classification criteria across the four identified IgG4-related disease (IgG4-RD) phenotypes: “Pancreato-Hepato-Biliary”, “Retroperitoneum and Aorta”, “Head and Neck-limited” and “Mikulicz’ and Systemic” in a well-characterized patient cohort.MethodsWe included adult patients diagnosed with IgG4-RD after comprehensive clinical assessment at Oslo University Hospital in Norway. We assigned patients to IgG4-RD phenotypes based on pattern of organ involvement and assessed fulfillment of RCD and 2019 ACR/EULAR classification criteria. Differences between phenotype groups were analyzed using one-way ANOVA for continuous variables, and contingency tables for categorical variables.ResultsThe study cohort included 79 IgG4-RD patients assigned to the “Pancreato-Hepato-Biliary” (22.8%), Retroperitoneum and Aorta” (22.8%) “Head and Neck-limited” (29.1%), and “Mikulicz’ and Systemic” (25.3%) phenotype groups, respectively. While 72/79 (91.1%) patients in total fulfilled the RCD, proportion differed across phenotype groups and was lowest in the “Retroperitoneum and Aorta” group (66.7%, p < 0.001). Among the 57 (72.2%) patients meeting the 2019 ACR/EULAR classification criteria, proportion was again lowest in the “Retroperitoneum and Aorta” group (27.8%, p < 0.001).ConclusionThe results from this study indicate that IgG4-RD patients having the “Retroperitoneum and Aorta” phenotype less often fulfill diagnostic criteria and classification criteria than patients with other IgG4-RD phenotypes. Accordingly, this phenotype is at risk of being systematically selected against in observational studies and randomized clinical trials, with potential implications for patients, caregivers and future definitions of IgG4-RD.

Clinical heterogeneity of polish patients with KAT6B-related disorder.

Say-Barber-Biesecker-Young-Simpson (SBBYSS) variant of Ohdo syndrome is a rare, autosomal dominant and clinically heterogenous disorder, caused by pathogenic variants in the KAT6B gene located on chromosome 10q22.2. KAT6B encodes a highly conserved histone acetyltransferase belonging to the MYST family. Currently, diseases caused by pathogenic variants in KAT6B (KAT6B-related disorders) comprise two allelic entities: SBBYSS variant of Ohdo syndrome and genitopatellar syndrome (GPS). Increase in the number of cases with overlapping GPS/SBBYSS phenotype which makes it necessary to redefine this group of phenotypes as KAT6B-related disorders or KAT6B spectrum disorders. Individuals with SBBYSS usually present with facial abnormalities, hypotonia, joint laxity, feeding problems, and long thumbs/great toes. This syndrome also typically involves skeletal problems including patellar hypoplasia/agenesis. Here we report six SBBYS syndrome patients with the same dysmorphic features but a different course of the disease. One known and five novel KATB6 pathogenic variants were identified by molecular diagnostics using Next Generation Sequencing (NGS). We present a detailed phenotypic analysis of six individuals with KAT6B-related disorders, in whom a heterozygous pathogenic variant in KAT6B gene was found. In all of our patients facial dysmorphism as well as developmental and speech delay were present. Additionally, all but one patients presented with hypotonia, ocular abnormalities and long thumbs. Most of our probands showed blepharophimosis and skeletal (mainly knee) defects. Contrary to previously reported severe patellar defects (hypoplasia/agenesis) anomalies presented by our patients were less severe (dysplasia, habitual dislocation, subluxation) referring to KAT6B-related disorders. While most of the anomalies found in our patients comply with SBBYSS criteria, phenotypic differences in our probands support a broader spectrum of the disease phenotype. To establish the range of this spectrum, a detailed analysis of clinical variability among patients with SBBYSS requires further investigation.

Alzheimer's disease phenotype based upon the carrier status of the apolipoprotein E ɛ4 allele.

The apolipoprotein E ɛ4 allele (APOE4) is universally acknowledged as the most potent genetic risk factor for Alzheimer's disease (AD). APOE4 promotes the initiation and progression of AD. Although the underlying mechanisms are unclearly understood, differences in lipid-bound affinity among the three APOE isoforms may constitute the basis. The protein APOE4 isoform has a high affinity with triglycerides and cholesterol. A distinction in lipid metabolism extensively impacts neurons, microglia, and astrocytes. APOE4 carriers exhibit phenotypic differences from non-carriers in clinical examinations and respond differently to multiple treatments. Therefore, we hypothesized that phenotypic classification of AD patients according to the status of APOE4 carrier will help specify research and promote its use in diagnosing and treating AD. Recent reviews have mainly evaluated the differences between APOE4 allele carriers and non-carriers from gene to protein structures, clinical features, neuroimaging, pathology, the neural network, and the response to various treatments, and have provided the feasibility of phenotypic group classification based on APOE4 carrier status. This review will facilitate the application of APOE phenomics concept in clinical practice and promote further medical research on AD.

The Relationship Between Time-Varying Achieved HbA1c and Risk of Coronary Events Depends on Haptoglobin Phenotype Among White and Black ACCORD Participants.

Intensive glycemic therapy reduced coronary artery disease (CAD) events among White participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study with the haptoglobin (Hp)2-2 phenotype, while participants without the Hp2-2 phenotype had no CAD benefit. The association between achieved glycated hemoglobin (HbA1c) and CAD for each Hp phenotype remains unknown. Achieved HbA1c was similar in each phenotype throughout the study. Prospectively collected HbA1c data (categorized as <6.0%, 6.0-6.5%, 6.6-6.9%, or ≥8.0% compared with 7.0-7.9%) from the ACCORD study, updated every 4 months over a median of 4.7 years, were analyzed in relation to CAD in the Hp2-2 (n = 3,322) and non-Hp2-2 (n = 5,949) phenotypes separately overall, and within White (63%, 37% Hp2-2) and Black (19%, 26% Hp2-2) participants using Cox proportional hazards regression with time-varying covariables. Compared with HbA1c of 7.0-7.9%, having HbA1c ≥8.0% was associated with CAD risk among White (adjusted HR [aHR] 1.43, 95% CI 1.03-1.98) and Black (2.86, 1.09-7.51) participants with the Hp2-2 phenotype, but not when all Hp2-2 participants were combined overall (1.30, 0.99-1.70), and not among participants without the Hp2-2 phenotype. HbA1c <7.0% was not associated with a lower risk of CAD for any Hp phenotype. Achieving HbA1c >8.0% compared with 7.0-7.9% was consistently associated with incident CAD risk among White and Black ACCORD participants with the Hp2-2 phenotype, while no association was observed among participants without the Hp2-2 phenotype. We found no evidence that HbA1c concentration <7.0% prevents CAD in either Hp phenotype group.

Characterization of circulating microRNA profiles of postpartum dairy cows with persistent subclinical endometritis

Subclinical endometritis (SCE) is an unresolved inflammation of the endometrium of postpartum dairy cows, seriously affecting fertility. Current diagnosis, which relies on uterine cytology or even more invasive biopsy sampling, would benefit from the identification of blood-based diagnostic biomarkers. Due to the known role of microRNAs (miRNAs) in other diseases, this case-control study evaluated the cell-free circulating miRNA profiles of SCE cows, and the network of transcripts predicted to interact with those miRNAs, previously identified as differentially expressed genes (DEG) in the endometrium of the same cows. Healthy (H, n = 6) and persistent SCE (n = 11) cows characterized by endometrial cytology and biopsy were blood sampled at 21 and 44 d postpartum (DPP). Following extraction of cell-free plasma miRNAs and RNA-seq analysis, differential abundance analysis of miRNAs was performed with the DESeq2 R package (adjusted p-value of 0.05), and in silico prediction of miRNA-interacting genes on a sequence complementary basis was conducted using the miRWalk database. The principal component analysis showed a clear clustering between groups of uterine health phenotypes (H vs. SCE), although the clustering between groups was less pronounced at 44 DPP than at 21 DPP. No effect of the stage (21 vs. 44 DPP) was observed. A total of 799 known circulating miRNAs were identified, from which 34 demonstrated differential abundance between H and SCE cows (12 less abundant and 22 more abundant in SCE than in H cows). These 34 miRNAs are predicted to interact with 10,104 transcripts, among which 43, 81, and 147 were previously identified as differentially expressed in, respectively, endometrial luminal epithelial, glandular epithelial, and stromal cells of the same cows. This accounts for approximately half of the DEG identified between those H and SCE cows, including genes involved in endometrial cell proliferation, angiogenesis and immune response, whose dysregulation in SCE cows may impair pregnancy establishment. From 219 miRNAs with mean normalized read counts above 100, the presence and abundance of miR-425-3p and miR-2285z had the highest discriminatory level to differentiate SCE from H cows. In conclusion, despite apparent confinement to the endometrium, SCE is associated with a distinct circulating miRNA profile, which may represent a link between the systemic changes associated with disease and the endometrial immune response. The validation of a miRNA panel consisting of circulating cell-free miR-425-3p and miR-2285z may prove a relevant advancement for the noninvasive diagnosis of persistent SCE.

Unravelling the diversity in water usage among wild banana species in response to vapour pressure deficit.

The rise in global temperature is not only affecting plant functioning directly, but is also increasing air vapour pressure deficit (VPD). The yield of banana is heavily affected by water deficit but so far breeding programs have never addressed the issue of water deficit caused by high VPD. A reduction in transpiration at high VPD has been suggested as a key drought tolerance breeding trait to avoid excessive water loss, hydraulic failure and to increase water use efficiency. In this study, stomatal and transpiration responses under increasing VPD at the leaf and whole-plant level of 8 wild banana (sub)species were evaluated, displaying significant differences in stomatal reactivity. Three different phenotypic groups were identified under increasing VPD. While (sub)species of group III maintained high transpiration rates under increasing VPD, M. acuminata ssp. errans (group I), M. acuminata ssp. zebrina (group II) and M. balbisiana (group II) showed the highest transpiration rate limitations to increasing VPD. In contrast to group I, group II only showed strong reductions at high VPD levels, limiting the cost of reduced photosynthesis and strongly increasing their water use efficiency. M. acuminata ssp. zebrina and M. balbisiana thus show the most favourable responses. This study provides a basis for the identification of potential parent material in gene banks for breeding future-proof bananas that cope better with lack of water.

PhenoScore quantifies phenotypic variation for rare genetic diseases by combining facial analysis with other clinical features using a machine-learning framework.

Several molecular and phenotypic algorithms exist that establish genotype-phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore's ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants of unknown significance and enables sophisticated genotype-phenotype studies by testing hypotheses on possible phenotypic (sub)groups. PhenoScore confirmed previously known phenotypic subgroups caused by variants in the same gene for SATB1, SETBP1 and DEAF1 and provides objective clinical evidence for two distinct ADNP-related phenotypes, already established functionally.

Influence of behavioural and morphological group composition on pigeon flocking dynamics.

Animals rely on movement to explore and exploit resources in their environment. While movement can provide energetic benefits, it also comes with energetic costs. This study examines how group phenotypic composition individual speed and energy expenditure during group travel in homing pigeons. We manipulated the composition of pigeon groups based on body mass and leadership rank. Our findings indicate that groups of leader phenotypes show faster speeds and greater cohesion than follower phenotype groups. Additionally, we show that groups of homogenous mass composition, whether all heavy or all light, were faster and expended less energy over the course of a whole flight than flocks composed of a mixture of heavy and light individuals. We highlight the importance of considering individual-level variation in social-level studies, and the interaction between individual and group-level traits in governing speed and the cost of travel.

Advantage of precision metagenomics for urinary tract infection diagnostics.

Urinary tract infections (UTIs) remain a diagnostic challenge and often promote antibiotic overuse. Despite urine culture being the gold standard for UTI diagnosis, some uropathogens may lead to false-negative or inconclusive results. Although PCR testing is fast and highly sensitive, its diagnostic yield is limited to targeted microorganisms. Metagenomic next-generation sequencing (mNGS) is a hypothesis-free approach with potential of deciphering the urobiome. However, clinically relevant information is often buried in the enormous amount of sequencing data. Precision metagenomics (PM) is a hybridization capture-based method with potential of enhanced discovery power and better diagnostic yield without diluting clinically relevant information. We collected 47 urine samples of clinically suspected UTI and in parallel tested each sample by microbial culture, PCR, and PM; then, we comparatively analyzed the results. Next, we phenotypically classified the cumulative microbial population using the Explify® data analysis platform for potential pathogenicity. Results revealed 100% positive predictive agreement (PPA) with culture results, which identified only 13 different microorganisms, compared to 19 and 62 organisms identified by PCR and PM, respectively. All identified organisms were classified into phenotypic groups (0-3) with increasing pathogenic potential and clinical relevance. This PM can simultaneously quantify and phenotypically classify the organisms readily through bioinformatic platforms like Explify®, essentially providing dissected and quantitative results for timely and accurate empiric UTI treatment. PM offers potential for building effective diagnostic models beyond usual care testing in complex UTI diseases. Future studies should assess the impact of PM-guided UTI management on clinical outcomes.

Associations of Culprit Vessel Size and Plaque Characteristics in Patients with ST-Segment Elevation Myocardial Infarction.

Small vessel disease (SVD) widely exists in patients with acute coronary syndrome. However, the plaque characteristic of SVD has not been investigated. Optical coherence tomography (OCT) of culprit lesion was examined in 576 patients with ST-segment elevation myocardial infarction (STEMI) and finally 404 patients with qualified images were analysed of plaque phenotypes and microstructure. The cohort was divided into three groups according to vessel diameters of culprit lesion which were measured by OCT. Major adverse cardiac events (MACEs) were recorded of each patient and compared among patients with different vessel diameters and plaque phenotypes. Gender, age and body mass index (BMI) were significantly different among patients with different diameters of culprit vessels (98.4% vs. 85.7% vs.71.4%, p 0.001; 40.0 7.0 vs. 54.9 6.6 vs. 68.9 5.8, p 0.001; 28.4 4.0 vs. 25.8 2.9 vs. 25.2 3.0, p 0.001, respectively). Moreover, patients with diameters of culprit lesion 3 mm presented with more incidence of plaque rupture and macrophage (57.7% vs. 42.1% vs. 46.2%, p = 0.015, 55.1% vs. 41.0% vs. 36.9%, p = 0.010). Total MACE did not differ among groups of different vessel diameters and plaque phenotypes. Vessel size of culprit lesion is significantly associated with plaque phenotype in patients with STEMI. However, patients with different diameters and plaque phenotypes showed no significant difference of clinical outcomes. NCT03593928.

Spectrum and Outcome of Prenatally Diagnosed Fetal Primary Cardiomyopathies-A Twenty-Year Overview.

to assess the course and outcome of fetuses affected by primary cardiomyopathy (CM). Retrospective study of 21 cases with prenatal diagnosis of a primary CM in one tertiary center over a period of 20 years. Charts were reviewed for echocardiographic findings, pregnancy outcome, and postnatal course. The utility of prenatal evaluation was discussed. The mean gestational age (GA) at diagnosis was 26.7 (±5.1) weeks. A total of 33.3% (7/21) had associated anomalies. Genetic etiology was confirmed in 50.0% (10/20, with one case lost to follow up). The overall survival rate of the entire study population was 40% (8/20) including termination of pregnancy in 20% (4/20) and an intrauterine mortality rate of 5% (1/20). Of the initial survivors (n = 15), a neonatal and early infant mortality rate of 46.7% (7/15) was calculated. Prenatal isolated right ventricular involvement was the only identified significant parameter for survival (p = 0.035). Four phenotypical groups were identified: 42.9% (9/21) hypertrophic (HCM), 38.1% (8/21) dilated (DCM), 14.3% (3/21) isolated noncompaction (NCCM), and 4.8% (1/21) restrictive CM (RCM). Fetuses assigned to isolated NCCM revealed a 100% survival rate. Prenatal detection is feasible but needs to a introduce classification method for better consulting and management practices. A poor outcome is still observed in many cases, but an increase in examiners' awareness may influence optimal multispecialized care.

Mapping and Identifying Candidate Genes Enabling Cadmium Accumulation in Brassica napus Revealed by Combined BSA-Seq and RNA-Seq Analysis.

Rapeseed has the ability to absorb cadmium in the roots and transfer it to aboveground organs, making it a potential species for remediating soil cadmium (Cd) pollution. However, the genetic and molecular mechanisms underlying this phenomenon in rapeseed are still unclear. In this study, a 'cadmium-enriched' parent, 'P1', with high cadmium transport and accumulation in the shoot (cadmium root: shoot transfer ratio of 153.75%), and a low-cadmium-accumulation parent, 'P2', (with a cadmium transfer ratio of 48.72%) were assessed for Cd concentration using inductively coupled plasma mass spectrometry (ICP-MS). An F2 genetic population was constructed by crossing 'P1' with 'P2' to map QTL intervals and underlying genes associated with cadmium enrichment. Fifty extremely cadmium-enriched F2 individuals and fifty extremely low-accumulation F2 individuals were selected based on cadmium content and cadmium transfer ratio and used for bulk segregant analysis (BSA) in combination with whole genome resequencing. This generated a total of 3,660,999 SNPs and 787,034 InDels between these two segregated phenotypic groups. Based on the delta SNP index (the difference in SNP frequency between the two bulked pools), nine candidate Quantitative trait loci (QTLs) from five chromosomes were identified, and four intervals were validated. RNA sequencing of 'P1' and 'P2' in response to cadmium was also performed and identified 3502 differentially expressed genes (DEGs) between 'P1' and 'P2' under Cd treatment. Finally, 32 candidate DEGs were identified within 9 significant mapping intervals, including genes encoding a glutathione S-transferase (GST), a molecular chaperone (DnaJ), and a phosphoglycerate kinase (PGK), among others. These genes are strong candidates for playing an active role in helping rapeseed cope with cadmium stress. Therefore, this study not only sheds new light on the molecular mechanisms of Cd accumulation in rapeseed but could also be useful for rapeseed breeding programs targeting this trait.

Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy

A genetic contribution to preeclampsia susceptibility has been established but is still incompletely understood. To disentangle the underlying genetic architecture of preeclampsia and preeclampsia or other maternal hypertension during pregnancy with a genome-wide association study (GWAS) of hypertensive disorders of pregnancy. This GWAS included meta-analyses in maternal preeclampsia and a combination phenotype encompassing maternal preeclampsia and preeclampsia or other maternal hypertensive disorders. Two overlapping phenotype groups were selected for examination, namely, preeclampsia and preeclampsia or other maternal hypertension during pregnancy. Data from the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC, 1990-2011), Finnish FinnGen project (1964-2019), Estonian Biobank (1997-2019), and the previously published InterPregGen consortium GWAS were combined. Individuals with preeclampsia or other maternal hypertension during pregnancy and control individuals were selected from the cohorts based on relevant International Classification of Diseases codes. Data were analyzed from July 2020 to February 2023. The association of a genome-wide set of genetic variants and clinical risk factors was analyzed for the 2 phenotypes. A total of 16 743 women with prior preeclampsia and 15 200 with preeclampsia or other maternal hypertension during pregnancy were obtained from FINNPEC, FinnGen, Estonian Biobank, and the InterPregGen consortium study (respective mean [SD] ages at diagnosis: 30.3 [5.5], 28.7 [5.6], 29.7 [7.0], and 28 [not available] years). The analysis found 19 genome-wide significant associations, 13 of which were novel. Seven of the novel loci harbor genes previously associated with blood pressure traits (NPPA, NPR3, PLCE1, TNS2, FURIN, RGL3, and PREX1). In line with this, the 2 study phenotypes showed genetic correlation with blood pressure traits. In addition, novel risk loci were identified in the proximity of genes involved in the development of placenta (PGR, TRPC6, ACTN4, and PZP), remodeling of uterine spiral arteries (NPPA, NPPB, NPR3, and ACTN4), kidney function (PLCE1, TNS2, ACTN4, and TRPC6), and maintenance of proteostasis in pregnancy serum (PZP). The findings indicate that genes related to blood pressure traits are associated with preeclampsia, but many of these genes have additional pleiotropic effects on cardiometabolic, endothelial, and placental function. Furthermore, several of the associated loci have no known connection with cardiovascular disease but instead harbor genes contributing to maintenance of successful pregnancy, with dysfunctions leading to preeclampsialike symptoms.

Clinical and biochemical changes and their correction in patients with metabolic phenotype of osteoarthritis and insomnia

BACKGROUND: Currently, OA is considered a polyetiological disease, where several phenotypes are distinguished based on the leading role of a specific risk factor. It is assumed that each clinical phenotype corresponds to its own fundamental changes in various organs and systems. Modern experimental evidence of chondro-osteogenic activity allows us to consider melatonin as a potential drug for various types of osteoarticular pathology.AIM: To study clinical and biochemical changes and effects of melatonin in the metabolic phenotype of OA and insomnia.MATERIALS AND METHODS: The study involved patients with a metabolic phenotype of OA and healthy volunteers. The subjects were collected complaints and anamnesis, as well as general clinical and orthopedic examination. In the blood serum, markers of bone and cartilage metabolism were determined. Patients were asked to answer the questions of clinical scales to assess the quality of sleep, the functional state of the joints and quality of life.RESULTS: The study involved 36 patients. Participants were divided into 3 groups: group health patients — patients without articular pathology, sleep quality disorders and normal body mass index; control group- patients with metabolic phenotype of OA, insomnia and basic treatment for 30 days; experimental group — patients with a metabolic phenotype of OA and insomnia, whose basic treatment included melatonin (Melaxen®) at a dosage of 3 mg for 30 days. Statistically significant differences were observed between the initial levels of acid phosphatase (AP), bone isoenzyme alkaline phosphatase (ALP) and calcium (Ca) in the control and experimental groups. According to the results of screening for the detection of insomnia among patients with the metabolic phenotype of, there were statistically significant insomnological disorders compared to the group health patients, as well as significant differences in terms of pain, symptoms, activity and quality of life in general according to the KOOS and SF-36 scales. Correlation analysis showed moderate correlations with biochemical parameters in patients with OA metabolic phenotype groups. After the treatment there was a certain increase in the level of Ca and a decrease in the activity of ALP and АP in patients of experimental group in comparison with patients of control groups. There was a positive trend in the range of criteria of the KOOS and SF-36 scale in experimental groups, pronounced decrease in pain syndrome (P), symptoms (S) and an increase in the levels of daily activity (A) and the total indicator (Sum) in comparison with patients of control groups. Also as improved sleep quality on all scales in comparison with the control group. In control group, problems with the quality and quantity of sleep remained at the same level.CONCLUSION: In patients with the most pronounced indicators of clinical manifestations of OA, more active processes of bone remodeling. The higher the level of bone resorption markers, the greater the severity of the clinical course in patients with osteoarthritis, and the worse the quality of sleep in general. The addition of melatonin to the treatment regimen was associated with a decrease in serum activity of the bone isoenzyme of alkaline phosphatase, acid phosphatase, an increase in calcium levels, as well as with an improvement in sleep and clinical symptoms ОА.

Follicular fluid redox balance and DNA damage according to PCOS phenotype.

Classification of polycystic ovary syndrome (PCOS) according to their phenotypes is important in terms of understanding which parameter has clinical and laboratory implications. This study was designed to measure the follicular fluid total oxidant capacity (TOC) and total antioxidant capacity (TAC) and DNA degradation products of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in patients with different PCOS phenotypes undergoing In-Vitro Fertilization/Intra-Cytoplasmic Sperm Injection (IVF/ICSI). Thirty women who were diagnosed with PCOS and twenty infertile patients who did not have the clinical and laboratory findings of PCOS were included. Women carrying at least two of the three parameters below were considered to have PCOS. (1) Biochemical or clinical manifestations of hyperandrogenism (HA); (2) Ovulatory dysfunction (OD); (3) Polycystic ovarian morphology (PCOM). Patients were then classified into four different PCOS phenotypes: (1) Phenotype A is also known as classical PCOS and meets all three criteria (HA/OD/PCOM). (2) Phenotype B has two criteria, HA and OD. (3) Phenotype C consists of HA and PCOM criteria. (4) Phenotype D is the non-hyperandrogenic form and consists of OD and PCOM criteria. Antagonist protocol was used in both PCOS and control groups. During oocyte pick-up, follicular fluid of the dominant follicle was collected. TAC and TOC levels, which are redox balance markers, and 8-OHdG levels, which are DNA degradation products, were measured in follicular fluid samples (FF). Follicular fluid 8-OHdG levels of all four types of phenotypes were significantly higher than the control group. When the phenotype groups were evaluated among themselves, FF-8-OHdG levels of each group were found to be similar. Serum TOC levels of each phenotype group were found to be significantly higher than the control group. TAC levels of the patients in the control group were significantly higher than the other four phenotype groups. Oxidative stress index (OSI) values were significantly higher in all four phenotype groups compared to the control group. OSI values of phenotype B and D groups were significantly higher than phenotypes A and C. In each phenotype of PCOS, TOC and OSI increased while TAC decreased. Increased OSI leads to DNA degradation and an increase in the level of 8-OHdG. The cumulative effect of oxidative stress and DNA degradation may be the main mechanism of PCOS-related subfertility.

SEVERE HEMATOLOGICAL TOXICITY FOLLOWING CD19 CAR‐T FOR RELAPSED/REFRACTORY LBCL IS ASSOCIATED WITH SUPPRESSIVE IMMUNE DYSREGULATION AND LIMITED CAR‐T EXPANSION

Background: Hematological toxicity represents the most frequent high-grade toxicity of CD19 CAR-T, but remains poorly understood. We recently proposed a classification system for CAR-T-related hematotoxicity, defining three unique phenotypes of neutrophil recovery: quick [“Q”] versus intermittent [“I”] versus aplastic [“A”]. Quick: sustained neutrophil recovery without a second dip below an ANC <1000/µL. Intermittent: neutrophil recovery (ANC > 1500/µL) followed by a second dip with an ANC < 1000/µL after day 21. Aplastic: continuous severe neutropenia (ANC < 500/µL) ≥14 days. Multivariable binary logistic regression was applied to analyze clinical metadata. CAR T-cell expansion dynamics were studied during the first 4 months post-CAR-T infusion. The plasma proteome was explored in 58 patients across four time points (day 0, 4, 14, 28) using a 92-protein multiplex proximity extension assay (Olink Bioscience). Progression-free (PFS) and overall survival (OS) were studied via Kaplan-Meier estimates. Results: The distribution of phenotypes was 18%, 42%, and 40% (A vs. I vs. Q). As expected, ‘aplastic’ patients displayed prolonged severe neutropenia (A vs. I vs. Q: 28 vs. 10 vs. 5 days, p < 0.001) and a higher rate of severe infections (40% vs. 22% vs. 18%). On multivariable regression of baseline risk factors (n = 344), the aplastic phenotype was independently associated with the presence of BM infiltration (p = 0.004), low ANC (p = 0.002), and increased ferritin (p = 0.039). When comparing CAR-T expansion among phenotypes, ‘intermittent’ patients displayed the greatest CAR T-cell expansion over time (Figure 1A). Conversely, ‘aplastic’ patients displayed low expansion with an unfavorable relationship between CAR-T expansion and baseline tumor burden (Figure 1B). Serum proteomics revealed higher markers of T-cell suppression, endothelial dysfunction, inflammatory cytokines, and macrophage activation in the ‘aplastic’ phenotype group (Figure 1C). Notably, both PFS and OS was poor in the ’aplastic’patients (1-yr PFS 26%, 1-yr OS 46%). On the other hand, the ‘intermittent’ phenotype, characterized by recurrent neutrophil dips, was associated with superior survival outcomes (1-yr PFS 51%, 1-yr OS 46%). Keywords: aggressive B-cell non-Hodgkin lymphoma, cellular therapies, basic and translational science – Basic and Translational Science - Other Conflicts of interests pertinent to the abstract K. Rejeski Consultant or advisory role: BMS/CELGENE Honoraria: Novartis, BMS/CELGENE Research funding: Kite/Gilead Travel grants: Kite/Gilead

Healthy eating index and bone health markers in adults with metabolically healthy and unhealthy obese phenotypes.

The Healthy Eating Index (HEI) estimates the diet quality, and low HEI scores are associated with adverse bone outcomes. However, the relationship between HEI scores and bone health in individuals who are obese but otherwise healthy or obese with comorbidities remains unclear. We aimed to evaluate the association of HEI scores with bone mineral density (BMD), bone regulating hormones and bone turnover markers in individuals with metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) phenotypes. This was a cross-sectional analysis of 122 adults who were overweight or obese. A questionnaire was completed to obtain demographic data. Body composition and BMD were assessed by a Dual Energy X-Ray Absorptiometry (DXA) exam. The HEI scores and dietary components were calculated using a 24-h dietary recall. Blood samples were collected for the analysis of serum 25-hydroxyvitamin D (s25OHD), total osteocalcin (OC), parathyroid hormone (PTH), and C-terminal telopeptide (CTx) concentrations. The MHO and MUO phenotypes were classified according to the absence or presence of metabolic abnormalities. The sample mean age was 37.91 ± 12.66 years, 50.8% were men, mean body mass index (BMI) was 30.01 ± 4.63 kg/m2, and 45.9% were classified as the MUO phenotype. The mean HEI scores were 54.42 ± 16.25 and 61.48% had low-diet quality. HEI scores were positively associated with s25OHD in the MUO phenotype group (β = 0.194, 95%CI = 0.038-0.350, p = 0.016). Certain dietary score components, such as fruits, seafood and plant protein, added sugars, whole grains, and fatty acids were also associated with bone health markers. However, HEI scores were not associated with BMD measures, neither with other bone regulating hormones and turnover markers. There was a positive association between HEI scores and s25OHD in adults who were overweight or obese with MUO phenotype. Additionally, the adequate consumption of specific food groups may benefit bone mass and metabolism. These results emphasize the importance of lifestyle interventions encouraging healthy eating habits to prevent s25OHD deficiency, poor bone health, and cardiometabolic complications.

Association between thyroid function and obesity phenotypes in healthy euthyroid individuals: an investigation based on Tehran Thyroid Study

AimsWe investigated whether thyroid function could be associated with obesity phenotypes amongst euthyroid individuals.Materials and methodsA cross-sectional analysis was conducted among healthy, euthyroid subjects. The study participants were chosen from the Tehran Thyroid Study (TTS). We analyzed 2988 euthyroid adults and classified them into four obesity phenotype groups: metabolically healthy normal weight (MHNW), metabolically healthy obese (MHO), metabolically unhealthy normal weight (MUNW), and metabolically unhealthy obese (MUO). The statistical differences between thyroid hormones between various obesity phenotypes according to age and sex was compared using analysis of covariance (ANCOVA).ResultsIt was found that MHNW participants had higher levels of FT4 when compared with metabolically healthy or unhealthy obese subjects (P < 0.001), even after adjustment for the confounding variables. No difference was observed in the levels of TSH (P = 0.260) among obesity phenotypes. In the subgroup analysis according to the age, a significant difference was observed in the level of FT4 only in subjects with age < 55 years (P = 0.001). However, analyzing men and women separately did not show a significant difference in the FT4 level among obesity phenotypes (P > 0.05).Conclusion“Metabolically abnormality” was independently related to low normal FT4 levels in overweight/obese euthyroid individuals. There is a need for further research to understand how low FT4 levels are linked to metabolically unhealthy states in euthyroid individuals.