Predominant Phenotype Research Articles

Risk factors for chronic obstructive pulmonary disease (COPD) in a tertiary health institution in Lagos, Nigeria.

To describe the clinical characteristics and identifiable risk factors for Chronic Obstructive Pulmonary Disease (COPD) in a real-world clinical setting. Cross-sectional study among patients with COPD. The Respiratory clinic of the Lagos University Teaching Hospital. Consecutive patients with spirometry confirmed COPD on follow-up for ≥3 months. There were 79 participants. None. COPD risk factors, disease severity, comorbidities, and the severity of airflow limitation. The mean age of the participants was 63.3± 12.4 years, and 47 (59.5) were male. There was a high symptom burden (73.4% had COPD assessment test (CAT) score >10), 33 (41.8%) and 4 (5.1%) had GOLD 3 and GOLD 4 airflow limitation, respectively. Risk factors were identified for 96.2% of the participants: history of asthma in 37 (46.8%), tobacco smoking 22 (27.8%), occupational exposure 15 (19%), biomass exposure 5 (6.6%), post-tuberculosis 3 (3.8%), old age (3.8%), and prematurity 1 (1.3%). Fifty-nine (74.7%) had Asthma COPD Overlap (ACO). There were no significant associations between the risk factors and disease severity. Participants with ACO had lower lung function and a high frequency of allergic rhinitis. Asthma was the most commonly identifiable risk factor for COPD, underscoring asthma risk reduction and management optimisation as priorities toward COPD burden mitigation. Future studies need to validate these findings and identify the predominant COPD phenotypes in our setting. None declared.

P06.19.A BEYOND T CELL TOXICITY - INTRATHECAL CXCL13 ELEVATION INDICATES B-CELL INVOLVEMENT IN NEUROLOGICAL IMMUNE-RELATED ADVERSE EVENTS FOLLOWING IMMUNE CHECKPOINT INHIBITION: 2 CASE OBSERVATIONS AND COMPREHENSIVE REVIEW

Abstract BACKGROUND Neurological immune-related adverse events (nirAE) can occur following cancer treatment with immune checkpoint inhibitors (ICI). Mainly attributed to autoreactive T-cells, nirAE usually respond to first line therapy with high-dose steroids (GC). Severe or fatal outcomes are rare & most frequently reported in clinically overlapping syndromes with accumulating evidence of B cell autoimmunity. MATERIAL AND METHODS We present 2 patients who developed grade 3-4 nirAE with evidence suggestive for B cell involvement. RESULTS Case 1: A 75y female with metastatic melanoma developed double vision & general weakness 2 weeks after the 1st cycle of ipilimumab & nivolumab. Diagnostic workup showed pleocytosis (27 cells/µl) with elevated CXCL13 (316 pg/ml) in cerebrospinal fluid (CSF). Increases of creatine kinase, troponin T, elevated levels of anti-acetylcholine receptor antibodies & positive anti-titin antibodies led to the diagnosis of myocarditis & myositis/myasthenia gravis overlap syndrome. The patient received pulsed high-dose GC with tapering. CSF flow cytometry revealed intrathecal recruitment of CXCL13-responsive B cell helper T cells of a predominant inflammatory phenotype & a highly increased pathological CD4/CD8 T cell ratio in peripheral blood. Clinically non-responding to GC, the patient received additional therapy with immunoglobulins (IVIG). 2 weeks later she was readmitted due to generalized myopathy with dropped head & received a second cycle of high-dose GC since she refused plasmapheresis. Further escalation with rituximab could not be realized because the patient rapidly deteriorated & deceased. Case 2: A 75y female with metastatic invasive enteric adenocarcinoma of the lung developed gait ataxia & ataxia of the lower limbs 5 months after pembrolizumab therapy. CSF analysis showed a pleocytosis (248 cells/µl) with plasma cells, pronounced CXCL13 elevation (>488 pg/ml) & positive screening for anti-neuronal cerebellar antibodies, suggesting ICI-mediated cerebellitis. The patient received high-dose GC & IVIG for 5 days each, was discharged but readmitted 5 months later due to subacute onset of spastic paraparesis. Magnetic resonance imaging of the spine revealed thoracic myelopathy & CSF showed mild pleocytosis (5 cells/µl), intrathecal immunoglobulin synthesis & mild CXCL13 elevation (33 pg/ml). The patient completed a second cycle of steroids followed by rituximab targeting B-cell involvement & currently 4 months later is clinically stable. CONCLUSION Intrathecal CXCL13 may serve as diagnostic tool of B cell involvement, here supported by intrathecal immunoglobulin synthesis, presence of plasma cells and/or severely altered immune cell compositions. Early treatment escalation with B cell depleting agents such as rituximab may help prevent fatal clinical courses.

The Classification of Suspected Predominant Nociplastic Pain in People with Moderate and Severe Haemophilia: A Secondary Exploratory Study.

In people with haemophilia (PwH), joint pain is a major comorbidity that is often overlooked and under-treated. It is believed that, to ensure the most successful outcome, pain management should be tailored to the predominant pain phenotype (i.e., nociceptive, neuropathic and nociplastic). The 2021 clinical criteria and grading system for nociplastic pain, established by the International Association for the Study of Pain (IASP), emphasize the necessity of early-stage identification and predominant pain type classification. Consistent with findings in other chronic musculoskeletal pain conditions, studies suggest that a subgroup of PwH suffers from nociplastic pain, i.e., pain arising from altered nociception rather than structural damage, but this has not yet been explored in PwH. This study aimed to identify PwH with "unlikely", "possible" and "probable" nociplastic pain and investigate differences in anthropometric, demographic and clinical characteristics and psychological factors between subgroups of PwH and healthy individuals.: The IASP clinical criteria and grading system were used to classify pain types in adult men with moderate or severe haemophilia recruited from two Belgian haemophilia treatment centres. Statistical analyses were applied to study between-subgroup differences. Of 94 PwH, 80 PwH (85%) were classified with "unlikely" and 14 (15%) with "at least possible" nociplastic pain (including 5 PwH (5%) with "possible" and 9 PwH (10%) with "probable" nociplastic pain). PwH in both the "unlikely" and "at least possible" nociplastic pain groups showed significantly higher levels of unhelpful psychological factors compared to healthy individuals. Additionally, age may partially account for the observed differences in body height and psychological factors. Larger sample sizes may be needed to detect more subtle between-group differences. study confirmed the presence of nociplastic pain in haemophilia, categorising a notable subgroup as individuals who experience at least possible nociplastic pain. These exploratory insights may provide a starting point for future studies and the development of more effective and tailored pain management.

Revisiting anti-Hu paraneoplastic autoimmunity: phenotypic characterization and cancer diagnosis.

Anti-Hu are the most frequent antibodies in paraneoplastic neurological syndromes, mainly associated with an often limited stage small cell lung cancer. The clinical presentation is pleomorphic, frequently multifocal. Although the predominant phenotypes are well characterized, how different neurological syndromes associate is unclear. Likewise, no specific study assessed the performance of new-generation CT and PET scanners for cancer screening in these patients. Herein, we aimed to describe the clinical pattern and cancer screening in a retrospective cohort of 466 patients with anti-Hu autoimmunity from the French Reference Centre on Paraneoplastic Neurological Syndromes registry. Clinical presentation, cancer screening and diagnosis were analysed. Among the 466 patients, 220 (54%) had multifocal neurological involvement. A hierarchical cluster analysis grouped the patients into (i) mainly limbic encephalitis, (ii) predominantly peripheral neuropathy and (iii) broad involvement of the nervous system (mixed group). Compared with limbic encephalitis and mixed groups, patients in the neuropathy group more frequently had a chronic onset of symptoms (29 versus 13 and 17%), elevated CSF proteins (83 versus 47 and 67%) and died from cancer progression (67 versus 15 and 28%; all P < 0.05). No significant difference in overall survival was observed between groups. Dysautonomia and brainstem signs were associated with a higher risk of death from the neurological cause; cancer diagnosis was the main predictor of all-cause death, especially when diagnosed within 2 years from clinical onset (all P < 0.05). Three hundred and forty-nine (75%) patients had cancer: in 295 (84%) neurological symptoms preceded tumour diagnosis, being lung cancer in 262 (89%), thereof small cell lung cancer in 227 (87%). First CT scan revealed lung cancer in 205/241 (85%), and PET scan shortened the interval to diagnosis when the initial CT scan was negative [7 months (1-66) in 27 patients versus 14 months (2-45) in 6; P < 0.001]. Although cancer diagnosis mostly occurred within 2 years from clinical onset, 13/295 (4%) patients exceeded that threshold. Conversely, 33 patients (7%) were 'cancer-free' after 2 years of follow-up. However, 13/33 (39%) had initial suspicious imaging findings that spontaneously regressed. In conclusion, although anti-Hu autoimmunity clinical presentation is mostly multifocal, we observed patients with a predominant limbic syndrome or isolated sensory neuropathy. Early implementation of PET scan shortens the interval to cancer diagnosis, which was the strongest predictor of death, especially if diagnosed ≤2 years from clinical onset. As cancer was diagnosed >2 years after clinical onset in few patients, screening should be extended up to 5 years. In addition, tumour regression was suspected in a substantial proportion of 'cancer-free' patients.

Macrophage-Myofibroblast Transition Contributes to Myofibroblast Formation in Proliferative Vitreoretinal Disorders.

Inflammation and fibrosis are key features of proliferative vitreoretinal disorders. We aimed to define the macrophage phenotype and investigate the role of macrophage-myofibroblast transition (MMT) in the contribution to myofibroblast populations present in epiretinal membranes. Vitreous samples from proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR) and nondiabetic control patients, epiretinal fibrovascular membranes from PDR patients and fibrocellular membranes from PVR patients, human retinal Müller glial cells and human retinal microvascular endothelial cells (HRMECs) were studied by ELISA, immunohistochemistry and flow cytometry analysis. Myofibroblasts expressing α-SMA, fibroblast activation protein-α (FAP-α) and fibroblast-specific protein-1 (FSP-1) were present in all membranes. The majority of CD68+ monocytes/macrophages co-expressed the M2 macrophage marker CD206. In epiretinal membranes, cells undergoing MMT were identified by co-expression of the macrophage marker CD68 and myofibroblast markers α-SMA and FSP-1. Further analysis revealed that CD206+ M2 macrophages co-expressed α-SMA, FSP-1, FAP-α and ß-catenin. Soluble (s) CD206 and sFAP-α levels were significantly higher in vitreous samples from PDR and PVR patients than in nondiabetic control patients. The proinflammatory cytokine TNF-α and the hypoxia mimetic agent cobalt chloride induced upregulation of sFAP-α in culture media of Müller cells but not of HRMECs. The NF-ĸß inhibitor BAY11-7085 significantly attenuated TNF-α-induced upregulation of sFAP-α in Müller cells. Our findings suggest that the process of MMT might contribute to myofibroblast formation in epiretinal membranes, and this transition involved macrophages with a predominant M2 phenotype. In addition, sFAP-α as a vitreous biomarker may be derived from M2 macrophages transitioned to myofibroblasts and from Müller cells.

Microbiological Investigation and Virulence Factor Characterization of Chronic Suppurative Otitis Media in A Nigerian Tertiary Hospital

Background: Chronic suppurative otitis media (CSOM) is a common cause of hearing loss with the attendant poor academic performance and low productivity in workplaces. Objectives: This study investigated the microbial aetiology and associated virulence mechanisms of CSOM in a Nigerian tertiary hospital. Methods: This was a prospective study of 52 patients diagnosed with CSOM in either one or both ears who had not taken any antibiotics for at least the last seven (7) days. Ear swabs were taken by an otolaryngologist and sent to the Microbiology Department for processing. The specimens were cultured within 30 min of collection and the isolates identified using standard microbiological techniques. Selected virulence properties were characterised. Results: The most common organism isolated was Staphylococcus aureus 18 (34.6%) followed by Pseudomonas aeruginosa 14 (26.9%). Fungal isolates were recovered from 6 11.5%) of specimens; in 11 (21.15%) of cases no microbe was detected. Age did not significantly affect incidence of CSOM of microbial origin (p = 0.1742) although most cases were in the age 31-40 years group. Male and female patients were almost equally affected (M: F = 1:1.08), DNase followed by biofilm formation were the predominant virulence phenotypes identified while coagulase, followed by haemolysin production, were least common. Conclusion: Staphylococcus aureus and Pseudomonas aeruginosa were the most common organisms among CSOM cases and recovered from all age-groups. Early detection and infection control are key to reducing incidence of CSOM.

Study of the gut microbiome in Egyptian patients with Parkinson’s Disease

BackgroundRecently, an important relationship between Parkinson’s disease and the gut microbiota, through the brain-gut axis interactions, has been established. Previous studies have declared that alterations in the gut microbiota have a great impact on the pathogenesis and clinical picture of Parkinson’s disease (PD). The present study aimed to identify the gut microbiome that is likely related to Parkinson’s disease as well as their possible relation to clinical phenotypes.MethodsThirty patients with Parkinson’s disease, who presented to the Parkinson’s disease Neurology Clinic of Alexandria University Hospital were enrolled in our study. A cross-matching control group of 35 healthy subjects of similar age and sex were included. Stool specimens were taken from each. Quantitative SYBR Green Real-Time PCR was done for the identification and quantitation of selected bacterial phyla, genera and/or species.ResultsThere was a significant increase in Bacteroides and a significant decrease of Firmicutes and Firmicutes / Bacteroidetes ratio and Bifidobacteria in PD patients. Although Prevotella was decreased among PD patients relative to the healthy control, the difference was not statistically significant. Comparing the PD clinical phenotypes with the control group, the Mixed phenotype had significantly higher Bacteroides, Tremors predominant had lower Firmicutes and Firmicutes / Bacteroidetes ratio, and both tremors and postural instability and gait disability (PIGD) phenotypes had lower Bifidobacteria. However, there was no statistically significant difference between these phenotypes. Furthermore, when comparing tremors and non-tremors predominant phenotypes; Lactobacilli showed a significant decrease in non-tremors predominant phenotypes.ConclusionsThe current study showed evidence of changes in the gut microbiome of Parkinson’s disease patients compared to the healthy controls. These observations may highlight the importance of the identification of microbiome and specific bacterial changes that can be targeted for the treatment of Parkinson’s disease.

Autoimmune bullous dermatoses in cancer patients treated by immunotherapy: a literature review and Italian multicentric experience.

Cutaneous immune-related adverse events are frequently associated with immune checkpoint inhibitors (ICIs) administration in cancer patients. In fact, these monoclonal antibodies bind the cytotoxic T-lymphocyte antigen-4 and programmed cell death-1/ligand 1 leading to a non-specific activation of the immune system against both tumoral cells and self-antigens. The skin is the most frequently affected organ system appearing involved especially by inflammatory manifestations such as maculopapular, lichenoid, psoriatic, and eczematous eruptions. Although less common, ICI-induced autoimmune blistering diseases have also been reported, with an estimated overall incidence of less than 5%. Bullous pemphigoid-like eruption is the predominant phenotype, while lichen planus pemphigoides, pemphigus vulgaris, and mucous membrane pemphigoid have been described anecdotally. Overall, they have a wide range of clinical presentations and often overlap with each other leading to a delayed diagnosis. Achieving adequate control of skin toxicity in these cases often requires immunosuppressive systemic therapies and/or interruption of ICI treatment, presenting a therapeutic challenge in the context of cancer management. In this study, we present a case series from Italy based on a multicenter, retrospective, observational study, which included 45 patients treated with ICIs who developed ICI-induced bullous pemphigoid. In addition, we performed a comprehensive review to identify the cases reported in the literature on ICI-induced autoimmune bullous diseases. Several theories seeking their underlying pathogenesis have been reported and this work aims to better understand what is known so far on this issue.

Disturbance in the reconstitution of distinct T-cell subsets and the incidence of GvHD following allo-HSCT in pediatric patients with non-malignant hematological disorders

BackgroundThe reconstitution of different T-cell subsets following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is critical for efficient pathogen protection and the prevention of graft-versus-host disease (GvHD). In particular, studies have highlighted the importance of balanced ratios of regulatory T-cells (Tregs) and distinct functionally T-cells in preventing acute and chronic GvHD. MethodsWe evaluated the regeneration of CD4 and CD8 T-cell subpopulations in nine pediatric patients with non-malignant disorders following allo-HSCT from a fully HLA-identical donor. ResultsCD4 and CD8 T-cells were higher 12 months after the transplant but still lower than in healthy controls and pre-transplant. However, we found after allo-HSCT, central memory and effector memory cell subsets were the predominant phenotypes in the CD4 and CD8 T-cell populations, respectively. In patients who had developed acute GvHD, there was an increase in the frequency of TEMRA (effector memory T cells that re-express CD45RA) cells within the CD4 T-cell population. Meanwhile, in patients with chronic GvHD, we observed a decrease in Th1 cells in CD4 T-cells and effector memory cells within the CD8 T-cell population. In addition, we found decreased TEMRA cell subsets in CD4 and CD8 T-cell populations in chronic GvHD. ConclusionOur findings suggest a possible relationship between the influence of acute GvHD and its prevention on delayed CD4 T-cell reconstitution and, reciprocally, unbalanced regeneration of CD4 and CD8 T-cell subsets in the development of chronic GvHD.

Alternative splicing variants involved in pyroptosis and cuproptosis contribute to phenotypic remodeling of the tumor microenvironment in cervical cancer.

Cervical cancer (CC) remains a prevalent gynecological malignancy, posing a significant health burden among women worldwide. With the remarkable discoveries of cellular pyroptosis and cuproptosis, there has been a growing focus on exploring the intricate relationship between these two forms of cell death and their impact on tumor progression. In recent years, alternative splicing has emerged as a significant field in cancer research. Thus, the integration of alternative splicing, pyroptosis, and cuproptosis holds immense value in studying their collective impact on the occurrence and progression of cervical cancer. In this study, alternative splicing data of pyroptosis- and cuproptosis-associated genes were integrated with public databases, including TCGA, to establish a prognostic model for cervical cancer based on COX regression modeling. Subsequently, the tumor microenvironment (TME) phenotypes in the high-risk and low-risk patient groups were characterized through a comprehensive bioinformatics analysis. The findings of this study revealed that the low-risk group exhibited a predominant immune-active TME phenotype, while the high-risk group displayed a tumor-favoring metabolic phenotype. These results indicate that the alternative splicing of pyroptosis- and cuproptosis-associated genes plays a pivotal role in remodeling the phenotypic landscape of the cervical cancer TME by modulating immune responses and metabolic pathways. This study provides valuable insights into the interplay between alternative splicing variants involved in pyroptosis and cuproptosis and the TME, contributing to a deeper understanding of cervical cancer pathogenesis and potential therapeutic avenues.

The impact of upper and lower motor neuron burden on diagnostic certainty, and clinical course of spinal-onset amyotrophic lateral sclerosis: a cluster-based approach.

Upper motor neuron (UMN) and lower motor neuron (LMN) involvement represent the core clinical features of amyotrophic lateral sclerosis (ALS). Several studies divided patients into prevalent UMN and LMN impairment phenotypes to investigate the association between motor systems impairments and ALS clinical course. However, this distinction was somehow heterogeneous and significantly affected the comparability across studies. This study aimed to investigate whether patients spontaneously segregate based on the extent of UMN and LMN involvement without a-priori categorization and to identify potential clinical and prognostic features of different clusters. Eighty-eight consecutive spinal-onset ALS patients were referred to an ALS tertiary center between 2015 and 2022. UMN and LMN burden was assessed with the Penn Upper Motor Neuron scale (PUMNS) and the Devine score, respectively. PUMNS and LMN scores were normalized into 0-1 and analyzed using a two-step cluster analysis and the Euclidean distance measure. The Bayesian Information Criterion was used to determine the cluster number. Demographic and clinical variables were tested for differences among the clusters. Three distinct clusters emerged at cluster analysis. Patients in "cluster-1" showed moderate UMN and severe LMN involvement, corresponding to the typical ALS phenotype. Patients in "cluster-2" showed mild LMN and severe UMN damage, corresponding to a predominant UMN phenotype, while "cluster-3" patients showed mild UMN and moderate LMN damage, corresponding to a predominant LMN phenotype. Patients in "cluster-1" and "cluster-2" showed a higher prevalence of definite ALS than those in "cluster-3" (61% and 46 vs 9%, p < 0.001). "Cluster-1" patients had a lower median ALSFRS-r score compared to both "cluster-2" and 3 patients (27 vs 40 and 35, < 0.001). "Cluster-1" (HR: 8.5; 95% CI 2.1-35.1 and p = 0.003) and 3 (HR: 3.2; 95% CI 1.1-9.1; p = 0.03) were associated with shorter survival than those in "cluster-2". Spinal-onset ALS can be categorized into three groups according to LMN and UMN burden. The UMN burden is related to higher diagnostic certainty and broader disease spread, while LMN involvement is associated with higher disease severity and shorter survival.

Carpal Tunnel Syndrome: Neuropathic Pain Associated or Not with a Nociplastic Condition.

Carpal tunnel syndrome (CTS) has been traditionally classified as primarily a neuropathic condition with or without pain. Precision medicine refers to an evidence-based method of grouping patients based on their susceptibility to biology, prognosis of a particular disease, or in their response to a specific treatment, and tailoring specific treatments accordingly. In 2021, the International Association for the Study of Pain (IASP) proposed a grading system for classifying patients into nociceptive, neuropathic, or nociplastic phenotypes. This position paper presents data supporting the possibility of subgrouping individuals with specific CTS related-pain into nociceptive, neuropathic, nociplastic or mixed-type phenotypes. Carpal tunnel syndrome is a neuropathic condition but can also be comorbid with a nociplastic pain condition. The presence of extra-median symptoms and the development of facilitated pain processing seem to be signs suggesting that specific CTS cases can be classified as the nociplastic pain phenotype. The clinical responses of therapeutic approaches for the management of CTS are inconclusive. Accordingly, the ability to identify the predominant pain phenotype in patients with CTS could likely be problematic for producing efficient treatment outcomes. In fact, the presence of a nociplastic or mixed-type pain phenotype would explain the lack of clinical effect of treatment interventions targeting the carpal tunnel area selectively. We propose a clinical decision tree by using the 2021 IASP classification criteria for identifying the predominant pain phenotype in people with CTS-related pain, albeit CTS being a priori a neuropathic pain condition. The identification of a nociplastic-associated condition requires a more nuanced multimodal treatment approach to achieve better treatment outcomes.

Predictors of Pulmonary Hypertension and Right Ventricular Dysfunction in Patients with Hypersensitivity Pneumonitis.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) that occurs in susceptible individuals in response to various inhaled antigens. The fibrotic phenotype of HP is characterized by disease progression and can lead to pulmonary hypertension (PH). The aim of this study was to estimate the prevalence of PH and to identify predictors of PH in patients with chronic HP. We conducted an observational longitudinal study that included 85 patients with an established diagnosis of HP. Clinical examination, quality of life questionnaires, high-resolution computed tomography (HRCT) of the chest, arterial blood gases analyses, six-minute walking test (6-MWT), pulmonary function tests, and echocardiography were performed. Patients were divided into groups with fibrotic (71.8%) and nonfibrotic phenotype (28.2%). PH was detected in 41 (48.2%) patients. Patients with PH had the predominant fibrotic phenotype of HP, were older, more symptomatic, and had a higher FVC/DLco ratio. The most significant predictors of PH were CT signs of fibrosis, finger clubbing, FVC/DLco, decreased distance, and SpO2 at the end of 6-MWT, as well as the presence of cardiovascular diseases. PH is a common condition in patients with chronic HP, especially with the fibrotic phenotype. Early detection of the PH predictors is necessary for the timely diagnosis of this complication of HP.

BODY COMPOSITION AS A FUNCTION OF COAT COLOR, SEX AND AGE IN LOCAL KIDS FROM NORTHERN MEXICO

The aim was to evaluate the effect of coat color, sex and age on body composition in local kids from northern Mexico. Eighty-three local kids between 1 and 30 days of age were selected. They were assigned to groups according to coat color (dark and light), sex (males and females) and age (1=1 to 10; 2=11 to 20 and 3=21 to 30 days). Pigmentation of skin, hooves, mucous membranes, morphostructural characteristics, live weight and 14 zoomometric measurements were evaluated. A predominant phenotype was found of animals without mammels, beards, without pigment in the skin and hooves, with horns, horizontal ears and pigmented mucous membranes. The highest values (p &lt; 0.05) for live weight (PV), neck length and width (LCue, ACue), chest circumference (CPe) and flank depth (PFl) were found in dark kids. The highest value (p &lt; 0.05) in ear length (LO) was observed in light-colored kids. When considering sex, the highest values (p &lt; 0.05) were observed in males for all traits, except for length and width of face (LCa, ACa) and width of ears (AO), height at withers (ACruz), PFl and sacrolumbar height (ASL), which were not different (p &gt; 0.05). When considering age, the highest values were found in all traits for group 3. All variables were positively and significantly correlated. The variables showing the greatest magnitude of change in the first 20 days of age are PV (+40 %), LCa, LCor, CPe (+15 %) and LCue, ACruz, PFl, leg length (+10 %), while between 20 and 30 days of age the magnitude of change generally decreases. It is concluded that coat color, sex and age significantly influence the body composition of local kids from northern Mexico, which may have implications in the selection and marketing thereof.

Retrospective Cohort Study of Shear-Wave Elastography and Computed Tomography Enterography in Crohn's Disease.

Distinguishing between inflammatory and fibrotic lesions drastically influences treatment decision-making regarding Crohn's disease. However, it is challenging to distinguish these two phenotypes before surgery. This study investigates the diagnostic yield of shear-wave elastography and computed tomography enterography to distinguish intestinal phenotypes in Crohn's disease. Thirty-seven patients (mean age, 29.51 ± 11.52; 31 men) were evaluated with average value of shear-wave elastography (Emean) and computed tomography enterography (CTE) scores. The results demonstrated that a positive correlation between the Emean and fibrosis (Spearman's r = 0.653, p = 0.000). The cut-off value for fibrotic lesions was 21.30 KPa (AUC: 0.877, sensitivity: 88.90%, specificity: 89.50%, 95% CI:0.755~0.999, p = 0.000). The CTE score showed a positive correlation with inflammation (Spearman's r = 0.479, p = 0.003), and a 4.5-point grading system was the optimal cut-off value for inflammatory lesions (AUC: 0.766, sensitivity: 73.70%, specificity: 77.80%, 95% CI: 0.596~0.936, p = 0.006). Combining these two metrics improved the diagnostic performance and specificity (AUC: 0.918, specificity: 94.70%, 95% CI: 0.806~1.000, p = 0.000). In conclusion, shear-wave elastography can be used to help detect fibrotic lesions and the computed tomography enterography score emerged as a feasible predictor of inflammatory lesions. The combination of these two imaging techniques is proposed to distinguish intestinal predominant phenotypes.

Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19.

The role of adaptive SARS-CoV-2 specific immunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although a growing population of convalescent COVID-19 patients with manifestation of PASC is observed. We analyzed the SARS-CoV-2-specific immune response, via pseudovirus neutralizing assay and multiparametric flow cytometry in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors. Although frequencies of SARS-CoV-2-reactive CD4+ T cells were similar between the studied cohorts, a stronger SARS-CoV-2 reactive CD8+ T cell response, characterized by IFNγ production and predominant TEMRA phenotype but low functional TCR avidity was detected in PASC patients compared to controls. Of interest, high avidity SARS-CoV-2-reactive CD4+ and CD8+ T cells were comparable between the groups demonstrating sufficient cellular antiviral response in PASC. In line with the cellular immunity, neutralizing capacity in PASC patients was not inferior compared to controls. In conclusion, our data suggest that PASC may be driven by an inflammatory response triggered by an expanded population of low avidity SARS-CoV-2 reactive pro-inflammatory CD8+ T cells. These pro-inflammatory T cells with TEMRA phenotype are known to be activated by a low or even without TCR stimulation and lead to a tissue damage. Further studies including animal models are required for a better understanding of underlying immunopathogensis. Summary: A CD8+ driven persistent inflammatory response triggered by SARS-CoV-2 may be responsible for the observed sequelae in PASC patients.

Healthcare resource utilization of patients with mitochondrial disease in an outpatient hospital setting

Background and objectivesMitochondrial diseases present as multi-system disorders requiring a comprehensive multidisciplinary approach. The data on healthcare resource utilization associated with mitochondrial diseases and the clinical drivers of these costs are limited including for the out-patient setting where the majority of the clinical care for mitochondrial disease patients occurs. We performed a cross-sectional retrospective study of out-patient healthcare resource utilization and costs for patients with a confirmed diagnosis of mitochondrial disease.MethodsWe recruited participants from the Mitochondrial Disease Clinic in Sydney and stratified them into three groups: those with mitochondrial DNA (mtDNA) mutations (Group 1), those with nuclear DNA (nDNA) mutations and the predominant phenotype of chronic progressive external ophthalmoplegia (CPEO) or optic atrophy (Group 2) and those without a confirmed genetic diagnosis but clinical criteria and muscle biopsy findings supportive of a diagnosis of mitochondrial disease (Group 3). Data was collected through retrospective chart review and out-patient costs were calculated using the Medicare Benefits Schedule.ResultsWe analyzed the data from 91 participants and found that Group 1 had the greatest average out-patient costs per person per annum ($838.02; SD 809.72). Neurological investigations were the largest driver of outpatient healthcare costs in all groups (average costs per person per annum:—Group 1: $364.11; SD 340.93, Group 2: $247.83; SD 113.86 and Group 3: $239.57; SD 145.69) consistent with the high frequency (94.5%) of neurological symptoms. Gastroenterological and cardiac-related out-patient costs were also major contributors to out-patient healthcare resource utilization in Groups 1 and 3. In Group 2, ophthalmology was the second-most resource intensive specialty ($136.85; SD 173.35). The Group 3 had the greatest average healthcare resource utilization per person over the entire duration of out-patient clinic care ($5815.86; SD 3520.40) most likely due to the lack of a molecular diagnosis and a less customized management approach.ConclusionThe drivers of healthcare resource utilization are dependent on the phenotype–genotype characteristics. Neurological, cardiac, and gastroenterological costs were the top three drivers in the out-patient clinics unless the patient had nDNA mutations with predominant phenotype of CPEO and/or optic atrophy wherein ophthalmological-related costs were the second most resource intensive driver.

Sex differences in Cardiorenal Syndrome: Insights from CARDIOREN Registry.

Although sex-specific differences in heart failure (HF) or kidney disease (KD) have been analyzed separately, the predominant cardiorenal phenotype by sex has not been described. This study aims to explore the sex-related differences in cardiorenal syndrome (CRS) in a contemporary cohort of outpatients with HF. An analysis of the Cardiorenal Spanish registry (CARDIOREN) was performed. CARDIOREN Registry is a prospective multicenter observational registry including 1107 chronic ambulatory HF patients (37% females) from 13 Spanish HF clinics. Estimated Glomerular Filtration Rate (eGFR) < 60ml/min/1.73 m2 was present in 59.1% of the overall HF population, being this prevalence higher in the female population (63.2% vs. 56.6%, p = 0.032, median age: 81years old, IQR:74-86). Among those with kidney dysfunction, women displayed higher odds of showing HF with preserved ejection fraction (HFpEF) (odds ratio [OR] = 4.07; confidence interval [CI] 95%: 2.65-6.25, p < 0.001), prior valvular heart disease (OR = 1.76; CI 95%:1.13-2.75, p = 0.014), anemia (OR: 2.02; CI 95%:1.30-3.14, p = 0.002), more advanced kidney disease (OR for CKD stage 3: 1.81; CI 95%:1.04-3.13, p = 0.034; OR for CKD stage 4: 2.49, CI 95%:1.31-4.70, p = 0.004) and clinical features of congestion (OR:1.51; CI 95%: 1.02-2.25, p = 0.039). On the contrary, males with cardiorenal disease showed higher odds of presenting HF with reduced ejection fraction (HFrEF) (OR:3.13; CI 95%: 1.90-5.16, p < 0.005), ischemic cardiomyopathy (OR:2.17; CI 95%: 1.31-3.61, p = 0.003), hypertension (OR = 2.11; CI 95%:1.18-3.78, p = 0.009), atrial fibrillation (OR:1.71; CI 95%: 1.06-2.75, p = 0.025), and hyperkalemia (OR:2.43, CI 95%: 1.31-4.50, p = 0.005). In this contemporary registry of chronic ambulatory HF patients, we observed sex-related differences in patients with combined heart and kidney disease. The emerging cardiorenal phenotype characterized by advanced CKD, congestion, and HFpEF was predominantly observed in women, whereas HFrEF, ischemic etiology, hypertension, hyperkalemia, and atrial fibrillation were more frequently observed in men.

Novel DPAGT1 Gene Mutation in Two Twins with Congenital Myasthenic Syndrome and a Review of the Literature.

Congenital myasthenic syndromes (CMS) are rare diseases caused by mutation in genes coding for proteins involved in neuromuscular junction structure and function. DPAGT1 gene mutations are a rare cause of CMS whose clinical evolution and pathophysiological mechanisms have not been clarified completely. We present the case of two twins displaying an infancy-onset predominant limb-girdle phenotype and carrying a novel DPAGT1 mutation associated with unusual histological and clinical findings. CMS can mimic paediatric and adult limb-girdle phenotype, hence neurophysiology plays a fundamental role in the differential diagnosis.

Inflammatory response-based subtyping and potential therapeutic strategies for triple-negative breast cancer

Objective: Inflammatory response plays a crucial role in the development and treatment of cancer. However, the role of inflammatory response in triple-negative breast cancer (TNBC) remains unclear. Based on the heterogeneity of the inflammatory response, we classified TNBC, elucidated its subtype features, and revealed potential therapeutic strategies. Methods: We established inflammatory response subtyping based on the RNA sequencing data of TNBCs derived from a cohort at the Fudan University Shanghai Cancer Center (FUSCC). Next, we explored the features and potential therapeutic strategies for each subgroup by analyzing transcriptome data. Using a machine-learning method, we validated and generalized the TNBC inflammatory response subtypes in an external dataset. Results: A total of 360 TNBC samples and 88 normal tissues were collected from a cohort at FUSCC. Patients with TNBC were divided into four inflammatory response groups (IRGs) based on the expression of inflammatory response genes: high inflammatory response gene expression with pronounced pyroptosis phenotype and high immune cell infiltration (IRG 1), low inflammatory response gene expression and low immune cell infiltration (IRG 2), ITGB8 specific inflammatory response with a predominant proliferation phenotype (IRG 3), and low M1/M2 ratio with a marked angiogenesis phenotype (IRG 4). Relapse-free survival (RFS) was better in IRG 1 and 2 and worse in IRG 3 and 4. Owing to their poor prognosis, we mainly focused on IRG 3 and IRG 4 to investigate potential treatment strategies. ITGB8 was highly expressed in IRG 3; thus, targeting ITGB8 may be a potential therapeutic strategy for patients in IRG 3. IRG 4 had a lower M1/M2 ratio and a marked angiogenesis phenotype; therefore, therapeutic strategies, such as anti-angiogenesis or M2 to M1 repolarization of macrophages, could be recommended for these patients. Additionally, we validated and generalized the TNBC inflammatory response subtyping in an external dataset using a machine-learning method. Conclusion: TNBC patients with different inflammatory response subtypes have different characteristics and may need subtype-specific treatment strategies.