Manifestations Of Disease Research Articles

E072 The psoriatic arthritis disease activity score demonstrates excellent test-retest reliability in early, untreated psoriatic arthritis

Abstract Background/Aims Psoriatic arthritis (PsA) is a chronic inflammatory arthritis characterised by heterogenous clinical features including peripheral arthritis, spondylitis, enthesitis, dactylitis, skin and nail disease. Historically, outcome measures in PsA trials focused on the articular manifestations of disease, with a recent emphasis in composite tools. The Psoriatic Arthritis Disease Activity Score (PASDAS) is a validated, composite measure with defined cut-off and excellent responsiveness when compared with other PsA-specific and non-specific composite measures. Although PASDAS is one of the recommended GRAPPA measures for research trials, data on its test-retest reliability are limited particularly in PsA of short disease duration. Aims and Objectives - To assess the test-retest reliability of the PASDAS composite index in a cohort of early, untreated PsA patients. Methods Data were collected from a subset of participants recruited to the GOLMePsA clinical trial (EudraCT Number: 2013-004122-28), after a minor protocol amendment enabling additional data collection at the screening visit. The test-retest reliability of PASDAS was performed by calculating the intraclass correlation coefficient (ICC) between measurements collected at screening and baseline time-points (maximum 4 weeks apart, by protocol). Table 1 details the sample size calculation. Baseline variables collected in the GOLMePsA trial were described by absolute numbers, percentages, means, medians, absolute and inter-quartile ranges (IQR). Results The PASDAS test-retest reliability was assessed in 37 consecutive participants. Average time between the two time-points was 1.9 weeks (range 0.4 to 4.0). Baseline characteristics of test-retest subset compared to all GOLMePsA participants were similar (table 1). The ICC was 0.85 (95% confidence interval 0.73-0.92). The observed ICC was identical to the value assumed in the sample size calculation for this analysis, yielding an acceptably narrow confidence interval around the estimate. There was no substantial correlation between the means of the two measurements and the differences between them (Pearson’s r=-0.26). The Bland-Altman limits of agreement were -0.11 ± 1.24 (-1.35 to 1.13). Conclusion These results confirm the excellent test-retest reliability of PASDAS in early, untreated PsA, supporting its use as an outcome measure in interventional studies in newly diagnosed disease of short-duration. Disclosure G. De Marco: Consultancies; Janssen, Novartis. E.M.A. Hensor: None. D.G. McGonagle: Consultancies; AbbVie, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, UCB. Grants/research support; AbbVie, BMS, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, UCB. A. Tan: None. L.C. Coates: Consultancies; AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Moonlake, Novartis, Pfizer and UCB. Honoraria; AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Medac, Novartis, Pfizer and UCB. Grants/research support; AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer and UCB. P. Emery: None. P.S. Helliwell: None. H. Marzo Ortega: Consultancies; AbbVie, Celgene, Eli-Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB. Grants/research support; Janssen, Novartis and UCB.

E064 Identifying patients with pulmonary disease in a mixed connective tissue disease cohort

Abstract Background/Aims Respiratory involvement specifically interstitial lung disease (ILD) is a recognised complication of mixed connective tissue disease (MCTD), with a reported prevalence ranging from 40-78%. Surveillance for ILD in other connective tissue diseases such as systemic sclerosis is established clinical practice. Using guidelines recently published by the American College of Rheumatology (2023) we undertook a service evaluation to evaluate current practice for patients in our centre. Methods Electronic case notes were searched using key terms ‘mixed connective tissue disease’, ‘MCTD’ and ‘anti-RNP positive’ to identify patients seen between January 2021-2023. Patients identified were then compared against three MCTD classification criteria (Sharp et al, Alarcon-Sergovia et al and Kasukawa et al). To ensure a robust diagnosis, only those meeting the classification threshold on two or more criterion were included. Results 56 patients were identified however only 44 met two classification criteria and were subsequently included. Mean age was 47.3 years with 40/44 (91%) female. 28/44 (64%) had previous CT chest imaging. In the remaining 16/44 (46%), none had reported symptoms suggestive of ILD in preceding two years. 34/44 (77%) patients had previous pulmonary function testing. In those without, 1/10 had recently reported dyspnoea. 9/44 (20%) had identified MCTD-ILD of which 7/9 (30%) were on immunosuppression, 3/9 for predominant lung disease. Of those with ILD, 7/9 (78%) had had PFTs in the last year. No patients with ILD had undergone assessment for ambulatory desaturation. 7/9 (78%) patients with ILD had received specialist respiratory input, 1 had been seen in a general respiratory clinic, and in 1 case it was unknown. All patients with identified ILD who met established criteria for treatment were receiving immunosuppression. No patient met criteria for progressive fibrotic ILD. No specific disease characteristics (utilising clinical criterion from classification criteria) were demonstrated to have association with ILD (statistical analysis performed using the chi-squared test). No association was demonstrated in patients displaying anti- Ro52 and Ro60 positivity and ILD. Conclusion This evaluation has highlighted that patients with identified MCTD-ILD are being treated and monitored well. However further surveillance for pulmonary involvement both at baseline and then subsequent interval pulmonary function testing needs to improve. This may account for the lower prevalence of ILD in our MCTD cohort in comparison to the literature. Surveillance of pulmonary involvement should take place regardless of clinical disease manifestations displayed. We need to establish feasibility for ambulatory desaturation testing in those with ILD within our outpatient setting. With increasing immunomodulatory treatment available identifying patients with MCTD-ILD is imperative. Disclosure R. Benson: None. K. Mashida: None. M. Ahmad: None. L.G. Spencer: None. Z. McLaren: None. T. Barnes: None.

Ophthalmic vascular manifestations in eosinophil-associated diseases: a comprehensive analysis of 57 patients from the CEREO and EESG networks and a literature review.

Eosinophils have widespread procoagulant effects. In daily practice, eosinophil-related cardiovascular toxicity consists of endomyocardial damage, eosinophilic vasculitis and arterial or venous thrombosis. Here we aim to report on the clinical features and treatment outcomes of patients with unexplained ophthalmic vascular manifestations and eosinophilia. We conducted a retrospective, multicenter, observational study and a literature review of patients with eosinophilia (≥0.5 x109/L) and concomitant ophthalmic vascular manifestations independent of the underlying eosinophilic disease but with no alternative cause for ophthalmic manifestations. Fifty-seven patients were included (20 from the observational study and 37 from the literature review). Ophthalmic vascular features were the initial manifestation of eosinophil-related disease in 34 (59%) patients and consisted of 29 central retinal artery occlusions, six branch retinal artery occlusions, five central retinal vein occlusions, two branch retinal vein occlusions, seven retinal vasculitides, two retinal vasospasms, 12 Purtscher's retinopathies, 13 anterior ischemic optic neuropathies and two posterior ischemic optic neuropathies. The median [IQR] absolute eosinophil count at onset of ophthalmic vascular manifestations was 3.5 [1.7-7.8] x109/L. Underlying eosinophil-related diseases included eosinophilic granulomatosis with polyangiitis (n=32), clonal hypereosinophilic syndrome (HES) (n=1), idiopathic HES (n=13), lymphocytic HES (n=2), adverse drug reactions (n=3), parasitosis (n=2), polyarteritis nodosa (n=1), IgG4-related disease (n=1), eosinophilic fasciitis (n=1) and primary sclerosing cholangitis (n=1). Other extra-ophthalmologic arterial or venous thromboses related to eosinophilia were reported in four (7%) and nine (16%) patients, respectively. Visual prognosis was poor: only eight (10%) patients achieved full recovery of ophthalmologic symptoms. After a median follow-up of 10.5 [1-18] months, one patient (3%) had a recurrence of an ophthalmic vascular manifestation, and three patients (10%) had a recurrence of other vascular symptoms (deep vein thrombosis in two and pulmonary embolism in one patient). At the time of recurrence, absolute eosinophil counts were above 0.5 x109/L in all cases (n=4). This study broadens the spectrum of vascular manifestations associated with hypereosinophilia by adding ophthalmic vascular manifestations. In patients with ophthalmological vascular manifestations and hypereosinophilia, aggressive treatment of the underlying pathology (and normalization of blood count) should be implemented.

Editor’s Pick: Correlation of Cutaneous Manifestations with the Severity of Disease in Patients with Chronic Kidney Disease and Effect of Hemodialysis: An Observational Study

Aim: Chronic kidney disease is a non-communicable disease, and is the sixth fastest growing contributor of morbidity and mortality. Hemodialysis is one of the important therapeutic modalities that can improve survival in these patients, and can increase their life expectancy, but the cutaneous disorder can precede or follow the initiation of hemodialysis. Methods: This is a retrospective, observational study with a sample size of 250 patients, with a glomerular filtration rate <60 mL/min/1.73 m2 for a minimum duration of 3 months or more, undergoing hemodialysis. Patients post-renal transplant, HIV-positive cases, and pregnant patients were excluded from the study. Studied cases were recruited equally into two groups: the dialytic group (Group A) and non-dialytic group (Group B). Results: In the authors’ study, the prevalence of dermatological manifestations was 79% in the dialytic group and 75% in the non-dialytic group. The most common finding overall was xerosis (58%), which was more common in the dialytic (66%) group, both in number of patients and severity. The second most common finding was pallor (55%), which was seen more in the dialytic group (60%). Other major findings were pruritus (49%) and hyperpigmentation (37%). The intensity of pruritus was higher in non-dialytic patients. Specific cutaneous manifestations, such as Kyrle’s disease, were seen only in eight patients. Skin infections were seen in 17% of patients overall, and there was no major difference seen in both groups. The prevalence of nail findings, mucosal changes, and hair changes was also high in the dialytic group. Other specific cutaneous manifestations, like calciphylaxis, uremic frost, and nephrogenic fibrosing dermopathy, were not seen in the authors’ study. Hemodialysis has increased the life expectancy of patients with end-stage renal disease and has also brought about a rise in the number of manifestations, by giving time for these changes to occur. The severity of symptoms was also higher in patients on dialysis. This could be because of the higher mean duration of disease in the dialytic group compared to the non-dialytic group. Conclusion: Dermatological manifestations of chronic kidney disease were significantly associated with the mean duration of disease, which was higher in patients on dialysis. There was a higher prevalence of non-specific dermatological findings, such as xerosis, hyperpigmentation, nail findings, hair, and mucosal changes in the dialytic group, except pruritus. Any such cutaneous marker in the absence of a primary dermatological problem warrants a thorough search, including blood, urine, and radiological investigations, to rule out kidney disease.

A machine learning approach for predicting textbook outcome after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Peritoneal carcinomatosis is considered a late-stage manifestation of neoplastic diseases. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) can be an effective treatment for these patients. However, the procedure is associated with significant morbidity. Our aim was to develop a machine learning model to predict the probability of achieving textbook outcome (TO) after CRS-HIPEC using only preoperatively known variables. Adult patients with peritoneal carcinomatosis and who underwent CRS-HIPEC were included from a large, single-center, prospectively maintained dataset (2001-2020). TO was defined as a hospital length of stay ≤14days and no postoperative adverse events including any complications, reoperation, readmission, and mortality within 90days. Four models (logistic regression, neural network, random forest, and XGBoost) were trained, validated, and a user-friendly risk calculator was then developed. A total of 1954 CRS-HIPEC procedures for peritoneal carcinomatosis were included. Overall, 13% (n=258) achieved TO following CRS-HIPEC procedure. XGBoost and logistic regression had the highest area under the curve (AUC) (0.76) after model optimization, followed by random forest (AUC 0.75) and neural network (AUC 0.74). The top preoperative variables associated with achieving a TO were lower peritoneal cancer index scores, not undergoing proctectomy, splenectomy, or partial colectomy and being asymptomatic from peritoneal metastases prior to surgery. This is a data-driven study to predict the probability of achieving TO after CRS-HIPEC. The proposed pipeline has the potential to not only identify patients for whom surgery is not associated with prohibitive risk, but also aid surgeons in communicating this risk to patients.

THE LEVEL OF EXTRACELLULAR DNA AS AN INDICATOR OF THE ACTIVITY OF INFLAMMATORY REACTIONS IN PATIENTS WITH RHEUMATOID ARTHRITIS AND ASTHMA

A clinical and laboratory examination of patients with rheumatoid arthritis and bronchial asthma was performed. The choice of nosologies was made to study changes in extracellular DNA (cfDNA) in the blood during immunopathological processes, based on generally accepted views on the role of helper balance in the pathogenesis of these diseases. The severity of disease manifestations in rheumatoid arthritis depends mainly on the severity of inflammatory changes in the joints and, therefore, is closely associated with a shift in the balance of helpers towards the Th1. According to today’s concepts the pathogenesis of asthma is determined by the intensive production of specific antibodies, which is controlled by activated Th2 lymphocytes. Patients have been indicators of the activity of neutrophil granulocytes and their ability to netosis were determined in addition to measuring standard laboratory indicators. The aim was to compare these parameters with changes in the level of extracellular DNA in pathological conditions depending on fluctuations in the Th1/Th2 balance. It has been shown that a significant difference between the studied immunopathological conditions is a significant decrease in the level of cfDNA in the blood plasma in patients with asthma, which sharply contrasts with its increase in arthritis. Laboratory parameters confirm the presence of local inflammation in patients with asthma in the absence of obvious symptoms of a systemic inflammatory response, while in patients with arthritis, inflammatory changes in the joints are accompanied by an increase in level of C-reactive protein, indicating a systemic reaction of the body in response to inflammatory stimuli. Thus, it can be assumed that the state of Th1/Th2 balance is one of the significant regulators that determines the concentration of cfDNA in the blood. According to the proposed hypothesis the shift in this ratio towards the predominance of Th1 cells should promote the development of inflammatory processes in the body and increase the amount of cfDNA, while a shift in the balance of helpers towards the dominance of Th2 lymphocytes should suppress these processes and lead to a decrease in cfDNA in the blood.

One gene to rule them all - clinical perspectives of a potent suppressor of cytokine signaling - SOCS1.

The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences.

Fecal microbiota is associated with extraintestinal manifestations in inflammatory bowel disease

Introduction A large proportion of patients with inflammatory bowel disease (IBD) experience IBD-related inflammatory conditions outside of the gastrointestinal tract, termed extraintestinal manifestations (EIMs) which further decreases quality of life and, in extreme cases, can be life threatening. The pathogenesis of EIMs remains unknown, and although gut microbiota alterations are a well-known characteristic of patients with IBD, its relationship with EIMs remains sparsely investigated. This study aimed to compare the gut microbiota of patients with IBD with and without EIMs. Methods A total of 131 Danish patients with IBD were included in the study, of whom 86 had a history of EIMs (IBD-EIM) and 45 did not (IBD-C). Stool samples underwent 16S rRNA sequencing. Amplicon sequence variants (ASVs) were mapped to the Silva database. Diversity indices and distance matrices were compared between IBD-EIM and IBD-C. Differentially abundant ASVs were identified using a custom multiple model statistical analysis approach, and modules of co-associated bacteria were identified using sparse correlations for compositional data (SparCC) and related to patient EIM status. Results Patients with IBD and EIMs exhibited increased disease activity, body mass index, increased fecal calprotectin levels and circulating monocytes and neutrophils. Microbiologically, IBD-EIM exhibited lower fecal microbial diversity than IBD-C (Mann–Whitney’s test, p = .01) and distinct fecal microbiota composition (permutational multivariate analysis of variance; weighted UniFrac, R 2 = 0.018, p = .01). A total of 26 ASVs exhibited differential relative abundances between IBD-EIM and IBD-C, including decreased Agathobacter and Blautia and increased Eggerthella lenta in the IBD-EIM group. SparCC analysis identified 27 bacterial co-association modules, three of which were negatively related to EIM (logistic regression, p < .05) and included important health-associated bacteria, such as Agathobacter and Faecalibacterium. Conclusions The fecal microbiota in IBD patients with EIMs is distinct from that in IBD patients without EIM and could be important for EIM pathogenesis.

Cardiac tamponade: Rare manifestation of Castleman's disease.

Cardiac tamponade: Rare manifestation of Castleman's disease.

Differentially co-expressed myofibre transcripts associated with abnormal myofibre proportion in chronic obstructive pulmonary disease.

Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD. Forty-six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre-type distribution and cross-sectional area via immunofluorescence microscopy and RNA-sequenced to generate transcriptome-wide gene expression data. Sex-stratified k-means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co-expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype. Abnormal myofibre proportion was defined in males with COPD (n=29) as <18% type I and/or >22% type IIx/IIax fibres and in females with COPD (n=17) as <36% type I and/or >12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0kg, P=0.022), 6-min walk distance (300 vs. 353m, P=0.039) and forced expiratory volume in 1s-to-forced vital capacity ratio (0.42 vs. 0.48, P=0.041) compared with participants with COPD and normal myofibre proportions. Twenty-nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co-expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co-expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density. Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co-expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.

“Quality of Life in Epidermolysis Bullosa” and “Epidermolysis Bullosa Burden of Disease”: Italian translation, cultural adaptation, and pilot testing of two disease-specific questionnaires

BackgroundInherited epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of skin fragility disorders characterized by blister formation following minor trauma. Four major types are distinguished based on the level of cleavage within the skin. Most EB forms present severely disabling cutaneous and systemic signs and symptoms. Management relies on daily time-consuming and distressing topical medications, and symptomatic treatment of systemic findings. Disease manifestations, symptoms, and daily care strongly affect patient and caregiver quality of life (QoL). To date, there are two validated EB-specific questionnaires, the “Quality of Life in Epidermolysis Bullosa” (QOLEB) and the “Epidermolysis Bullosa Burden of Disease” (EB-BoD) for the evaluation of patient and family disease burden, respectively. The aim of our study was to develop an Italian translation of the two questionnaires and to pilot-test them.MethodsThe guidelines for translation and cross-cultural adaptation of health-related QoL measures were followed. Initially, two separate translations were generated for each questionnaire, and subsequently reconciled by an expert committee. This was followed by a back-translation process. The original texts and all translations underwent revision by the expert committee, resulting in definitive versions. The final versions were then tested in a pilot study involving cognitive debriefing in a group of 17 families, representative of all EB major types.ResultsThe translation and reconciliation process led to minor changes to obtain semantic/idiomatic/cultural equivalence of the Italian versions with the original ones and to reconcile the questions with the answer options. The cognitive debriefing process showed a good understanding and did not require text modifications.ConclusionsThe Italian versions of the QOLEB and EB-BoD provide valuable tools in everyday clinical practice of reference centers, and they allow the participation in multicenter international real-life observational studies as well as in controlled clinical trials. They enable the identification of disease-specific psychological and socioeconomic challenges for EB patients and their families, guiding targeted interventions to ensure appropriate and timely care.

Atypical and Unpredictable Superficial Mycosis Presentations: A Narrative Review.

While typically exhibiting characteristic features, fungal infections can sometimes present in an unusual context, having improbable localization (eyelid, face, or joint); mimicking other skin diseases such as eczema, psoriasis, or mycosis fungoides; and appearing with unexpected color, shape, or distribution. The emergence of such a challenging clinical picture is attributed to the complex interplay of host characteristics (hygiene and aging population), environment (climate change), advances in medical procedures, and agent factors (fungal resistance and species emergence). We aim to provide a better understanding of unusual epidemiological contexts and atypical manifestations of fungal superficial diseases, knowing that there is no pre-established clinical guide for these conditions. Thus, a literature examination was performed to provide a comprehensive analysis on rare and atypical superficial mycosis as well as an update on certain fungal clinical manifestations and their significance. The research and standard data extraction were performed using PubMed, Medline, Scopus, and EMBASE databases, and a total of 222 articles were identified. This review covers published research findings for the past six months.

Multilocus pathogenic variants contribute to intrafamilial clinical heterogeneity: a retrospective study of sibling pairs with neurodevelopmental disorders

BackgroundMultilocus pathogenic variants (MPVs) are genetic changes that affect multiple gene loci or regions of the genome, collectively leading to multiple molecular diagnoses. MPVs may also contribute to intrafamilial phenotypic variability between affected individuals within a nuclear family. In this study, we aim to gain further insights into the influence of MPVs on a disease manifestation in individual research subjects and explore the complexities of the human genome within a familial context.MethodsWe conducted a systematic reanalysis of exome sequencing data and runs of homozygosity (ROH) regions of 47 sibling pairs previously diagnosed with various neurodevelopmental disorders (NDD).ResultsWe found siblings with MPVs driven by long ROH regions in 8.5% of families (4/47). The patients with MPVs exhibited significantly higher FROH values (p-value = 1.4e-2) and larger total ROH length (p-value = 1.8e-2). Long ROH regions mainly contribute to this pattern; the siblings with MPVs have a larger total size of long ROH regions than their siblings in all families (p-value = 6.9e-3). Whereas the short ROH regions in the siblings with MPVs are lower in total size compared to their sibling pairs with single locus pathogenic variants (p-value = 0.029), and there are no statistically significant differences in medium ROH regions between sibling pairs (p-value = 0.52).ConclusionThis study sheds light on the significance of considering MPVs in families with affected sibling pairs and the role of ROH as an adjuvant tool in explaining clinical variability within families. Identifying individuals carrying MPVs may have implications for disease management, identification of possible disease risks to different family members, genetic counseling and exploring personalized treatment approaches.

Interventional inflammatory bowel disease: current and future practice.

Inflammatory bowel diseases (IBD) are associated with several well described neoplastic and structural complications. Increasing disease prevalence, healthcare barriers, and medication refractory phenotypes contribute to ongoing complications despite significant strides in medical management. Enhancements in endoscopic technology and techniques have allowed a minimally invasive approach for what has historically required surgery. In this article, we review the current and future landscape of endoscopic IBD intervention. Endoscopic resection is the first line for managing conventional and complex colitis-associated dysplasia. Evidence supporting endoscopic submucosal dissection is mounting, yet there is a paucity of studies evaluating modified endoscopic mucosal resection techniques or hybrid endoscopic submucosal dissection. We also have more clarity in how best to approach fibrostenotic disease, as we learn how to position endoscopic stricturotomy and stenting, relative to balloon dilation. Finally, applications in managing penetrating and postsurgical complications have been described, but still require further study. While important knowledge gaps still exist, the application of endoscopic therapies in IBD is more refined, especially within the management of colitis-associated dysplasia and strictures. The indications for endoscopy in perianal disease and other penetrating manifestations of Crohn's disease presents exciting opportunities for growth.

Spinal Manifestation of Sickle Cell Disease. A Report On 35 Patients with Literature Review

Background: Sickle cell disease is a hereditary hemoglobinopathy affecting the spine in a wide range of pathology. Despite the several pathological involvements, some patients remain asymptomatic even with positive imaging findings. Objectives: Theme of this study is to report the various pathological disorders involving the spine of patients with sickle cell disease in Basra “south of Iraq” Patients and method: 35 Homozygous and heterozygous sickle cell patients were included in this study. 22 Males and 13 females, their age range from 6 to 69 years they were evaluated clinically, and also by laboratory imaging studies like plain radiography, computerized tomography, magnetic resonance imaging and mineral bone density “DEXA scan “ Results: 54% of the patients were homozygous, and the remaining were heterozygous, 66% of them were asymptomatic, back pain was the complaint in 60% while spine tenderness was reported in 40%, 31% had tenderness in the sacroiliac region and only 6% had neurological claudication and focal neurological deficit. Biconcave vertebra was confirmed in 72% of the patients and mainly localized in the lumbar Spine, MRI findings of vertebral infarction were observed in 58% of the studied patients while sacroiliac joint changes appeared in 60%, 60% of those who had DEXA scan showed low mineral bone density in the lumbar spine Conclusion: Sickle cell disease involve the whole Spine in a wide range of pathological process, some show clinical symptoms, and some remain asymptomatic in spite of changes. The structural changes are more obvious in the homozygous group (55) the lumber spine is dominantly involved, disc prolapse, and neurological deficit is rare while the low mineral changes is common. We did not report a case of spondylodiscitis in this series, though it is very much expected, so routine screening of the spine in sticklers is mandatory

Genetic variants of unknown significance in alpha-galactosidase A: Cellular delineation from Fabry disease.

Fabry disease (FD) is an X-linked multiorgan disorder caused by variants in the alpha-galactosidase A gene (GLA). Depending on the variant, disease phenotypes range from benign to life-threatening. More than 1000 GLA variants are known, but a link between genotype and phenotype in FD has not yet been established for all. p.A143T, p.D313Y, and p.S126G are frequent examples of variants of unknown significance (VUS). We have investigated the potential pathogenicity of these VUS combining clinical data with data obtained in human cellular in vitro systems. We have analyzed four different male subject-derived cell types for alpha-galactosidase A enzyme (GLA) activity and intracellular Gb3 load. Additionally, Gb3 load in skin tissue as well as clinical data were studied for correlates of disease manifestations. A reduction of GLA activity was observed in cells carrying p.A143T compared with controls (p < 0.05). In cells carrying the p.D313Y variant, a reduced GLA activity was found only in endothelial cells (p < 0.01) compared with controls. No pathological changes were observed in cells carrying the p.S126G variant. None of the VUS investigated caused intracellular Gb3 accumulation in any cell type. Our data of aberrant GLA activity in cells of p.A143T hemizygotes and overall normal cellular phenotypes in cells of p.D313Y and p.S126G hemizygotes contribute a basic science perspective to the clinically highly relevant discussion on VUS in GLA.

Clinical and genetic features of dominant Essential Tremor in Tuscany, Italy: FUS, CAMTA1, ATXN1 and beyond

ObjectiveEssential Tremor (ET) is one of the most common neurological disorders. In most instances ET is inherited as an autosomal dominant trait with age-related penetrance (virtually complete in advanced age); however, ET genetics remains elusive. The current study aims to identify possibly pathogenic genetic variants in a group of well-characterized ET families. Methods34 individuals from 14 families with dominant ET were clinically evaluated and studied by whole exome sequencing studies (after excluding trinucleotide expansion disorders). ResultsMost patients had pure ET. In 4 families, exome studies could identify a genetic variant potentially able to significantly alter the protein structure (CADD >20, REVEL score > 0.25), shared by all the affected individuals (in CAMTA1, FUS, MYH14, SGCE genes). In another family there were two variants in dominant genes (PCDH9 and SQSTM1). Moreover, an interrupted “intermediate” trinucleotide expansion in ATXN1 (“SCA1”) was identified in a further family with pure ET. ConclusionCombining our observations together with earlier reports, we can conclude that ET genes confirmed in at least two families to date include CAMTA1 and FUS (reported here), as well as CACNA1G, NOTCH2NLC and TENM4. Most cases of familial ET, inherited with an autosomal dominant inheritance, may result from “mild” variants of many different genes that, when affected by more harmful genetic variants, lead to more severe neurological syndromes (still autosomal dominant). Thus, ET phenotype may be the “mild”, incomplete manifestation of many other dominant neurogenetic diseases. These findings further support evidence of genetic heterogeneity for such disease(s).Author's keywords: cerebellar ataxias, movement disorders, neurogenetics, rare neurological disorders, tremor.

COVID-19 acts like a stress test, uncovering the vulnerable part of the human body: a retrospective study of 1640 cases in China.

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection exhibits multi-organ damage with diverse complications, the correlation between age, gender, medical history and clinical manifestations of novel coronavirus disease 2019 (COVID-19) patients was investigated. 1640 patients who were infected with SARS-CoV-2 and hospitalized at the First Affiliated Hospital of Ningbo University from 22 December 2022 to 1 March 2023 were categorized and analysed. Normal distribution test and variance homogeneity test were performed. Based on the test results, one-way analysis of variance, Pearson's chi-squared test and logistic regression analysis were conducted in the study. According to the ANOVA, there was a significant difference in the age distribution (P = .001) between different clinical presentations, while gender did not (P = .06). And regression analysis showed that age, hypertension, atherosclerosis and cancer were significant hazard factors for the development of predominant clinical manifestations in patients hospitalized with novel COVID-19. Additionally, infection with SARS-CoV-2 has the potential to exacerbate the burden on specific diseased or related organs. The elderly who are infected with SARS-CoV-2 ought to be treated with emphasis not only on antiviral therapy but also on individualized treatment that takes their medical history and comorbidities into account.

Hormones and B-cell development in health and autoimmunity.

The development of B cells into antibody-secreting plasma cells is central to the adaptive immune system as they induce protective and specific antibody responses against invading pathogens. Various studies have shown that, during this process, hormones can play important roles in the lymphopoiesis, activation, proliferation, and differentiation of B cells, and depending on the signal given by the receptor of each hormone, they can have a positive or negative effect. In autoimmune diseases, hormonal deregulation has been reported to be related to the survival, activation and/or differentiation of autoreactive clones of B cells, thus promoting the development of autoimmunity. Clinical manifestations of autoimmune diseases have been associated with estrogens, prolactin (PRL), and growth hormone (GH) levels. However, androgens, such as testosterone and progesterone (P4), could have a protective effect. The objective of this review is to highlight the links between different hormones and the immune response mediated by B cells in the etiopathogenesis of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). The data collected provide insights into the role of hormones in the cellular, molecular and/or epigenetic mechanisms that modulate the B-cell response in health and disease.

The prevalence of developmental defects of enamel in people with cystic fibrosis: a systematic review

BackgroundOral health impacts systemic health, individual well-being, and quality of life. It is important to identify conditions that may exacerbate oral disease to aid public health and policy development and promote targeted patient treatment strategies. Developmental defects can increase an individual’s risk of dental caries, hypersensitivity, premature tooth wear, erosion, and poor aesthetics. As part of an ongoing study assessing oral health in adults with cystic fibrosis at Cork University Dental School and Hospital, a systematic review of available literature was conducted to assess the prevalence of enamel defects in people with cystic fibrosis.AimsTo critically evaluate the literature to determine if the prevalence of developmental defects of enamel is higher in people with cystic fibrosis (PwCF).MethodsData Sources: Three online databases were searched Embase, Scopus, and Web of Science Core Collection. Studies that examined an association between cystic fibrosis and developmental defects of enamel were included in this systematic review.ResultsThe initial search identified 116 publications from the following databases Embase, Web of Science Core Collection, and Scopus. Eleven studies were included for qualitative analysis. Nine studies concluded that PwCF had a higher prevalence of enamel defects than control people and one study found no difference in cystic fibrosis (CF) status. All studies had a risk of bias that may influence study results and their interpretation.ConclusionsThe results of the systematic review show a consistent pattern that PwCF have a higher prevalence of DDE than people without CF. Genetic dysfunction, chronic systemic infections, and long-term antibiotic use are possible aetiological causes. This review highlights the need for future studies to investigate if DDEs are caused by the underlying CFTR mutation or as a consequence of disease manifestations and/or management.