Clinical Disease Research Articles

Autoreactive B cells remain active despite clinical disease control in rheumatoid arthritis

BackgroundAutoimmune diseases (AIDs) are frequently hallmarked by the presence of autoreactive B cell responses which are involved in disease pathogenesis. However, the dynamics of such responses and their relation to clinical disease activity in humans is poorly understood. Rheumatoid arthritis (RA), a prototypic chronic AID, is hallmarked by B cell responses directed against citrullinated proteins. ObjectiveTo determine the relation between the activity of the anti-citrullinated protein antibody (ACPA) B cell response and clinical disease activity in ACPA+ patients with RA. MethodsExpression of B cell activation markers by ACPA+, tetanus toxoid (TT)+ and ACPA− memory B cells (MBCs) from peripheral blood of ACPA+ RA patients receiving different treatments was analyzed by flow cytometry. Results were correlated to clinical disease activity. ResultsCompared to TT+ and ACPA− MBCs, ACPA+ MBCs displayed a highly activated phenotype as evidenced by increased expression of Ki-67, CD86, CD80, CD19 and CD20 and reduced expression of CD32. The activated phenotype of ACPA+ MBCs did not associate with clinical disease activity in a cross-sectional analysis of RA patients treated with various therapeutic agents. Also, in a longitudinal analysis of patients treated with Janus kinase (JAK) inhibitors, ACPA+ MBCs retained their activated phenotype despite effective control of inflammation and clinical disease. ConclusionACPA+ MBCs remain active despite clinical disease control in patients with RA across a range of interventions. This persistent activity indicates the absence of immunological remission and might explain why ACPA+ patients rarely reach sustained drug-free remission and frequently flare upon drug tapering.

Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).

Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene has recently been recognized as a common cause of late-onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4-aminopyridine in a cohort of 102 patients bearing GAA repeat expansions. We compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post-mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B. In our cohort of 102 patients with SCA27B, we found that SCA27B was a late-onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post-mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4-aminopyridine. Our study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024;96:1092-1103.

A Novel MYH14 Variant Presenting as a New Phenotype of MYH14-Associated Neuromuscular Disorders—Clinicohistologic Findings and Review of the Literature

Abstract Background: Pathogenic variants in the nonmuscle myosin, MYH14, have been associated with several pathologic conditions including a complex phenotype with peripheral neuropathy, myopathy, hoarseness, and hearing loss. Since its first description in a large Korean kindred, this rare neuromuscular disorder has further been characterized in 1 American and 1 Canadian pedigree. Case presentation: Here, we describe a German patient with atypical MYH14-related neuromuscular disorder. The clinical phenotype included signs of a distal myopathy with early respiratory involvement and a prominent hoarseness and peripheral neuropathy. In contrast to previous reports, no relevant deafness was identified. Muscle biopsy indicated a vacuolated myopathy with excessive autophagy, whereas histology of the sural nerve showed signs of a mixed axonal-demyelinating neuropathy. Next-generation sequencing revealed a loss-of-function variant not identified so far in the MYH14 gene (c.4510del, p.[Arg1504Glyfs*10]). Because of rapid disease progression with respiratory failure, the patient died at the age of 52. Conclusions: We present a novel MYH14 variant resulting in a severe and rapidly progressive MYH14-associated phenotype with predominantly distal myopathy, early respiratory failure, dysphagia, hoarseness, and peripheral neuropathy, without hearing loss. This case expands the clinical spectrum of MYH14-related neuromuscular disorders by providing a new clinical phenotype and disease course and histopathologic features.

Dental pulp stem cells promote malignant transformation of oral epithelial cells through mitochondrial transfer.

Oral epithelial dysplasia includes a range of clinical oral mucosal diseases with potentially malignant traits. Dental pulp stem cells (DPSCs) are potential candidates for cell-based therapies targeting various diseases. However, the effect of DPSCs on the progression of oral mucosal precancerous lesions remains unclear. Animal experiments were conducted to assess the effect of human DPSCs (hDPSCs). We measured the proliferation, motility and mitochondrial respiratory function of the human dysplastic oral keratinocyte (DOK) cells cocultured with hDPSCs. Mitochondrial transfer experiments were performed to determine the role mitochondria from hDPSCs in the malignant transformation of DOK cells. hDPSCs injection accelerated carcinogenesis in 4NQO-induced oral epithelial dysplasia in mice. Coculture with hDPSCs increased the proliferation, migration, invasion and mitochondrial respiratory function of DOK cells. Mitochondria from hDPSCs could be transferred to DOK cells, and activated mTOR signaling pathway in DOK cells. Our study demonstrates that hDPSCs activate the mTOR signaling pathway through mitochondrial transfer, promoting the malignant transformation of oral precancerous epithelial lesions.

Prediction of clinical prognosis and drug sensitivity in hepatocellular carcinoma through the combination of multiple cell death pathways.

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor, highlighting a significant need for reliable predictive models to assess clinical prognosis, disease progression, and drug sensitivity. Recent studies have highlighted the critical role of various programmed cell death pathways, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, entotic cell death, NETotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis, oxeiptosis, and disulfidptosis, in tumor development. Therefore, by investigating these pathways, we aimed to develop a predictive model for HCC prognosis and drug sensitivity. We analyzed transcriptome, single-cell transcriptome, genomic, and clinical information using data from the TCGA-LIHC, GSE14520, GSE45436, and GSE166635 datasets. Machine learning algorithms were used to establish a cell death index (CDI) with seven gene signatures, which was validated across three independent datasets, showing that high CDI correlates with poorer prognosis. Unsupervised clustering revealed three molecular subtypes of HCC with distinct biological processes. Furthermore, a nomogram integrating CDI and clinical information demonstrated good predictive performance. CDI was associated with immune checkpoint genes and tumor microenvironment components using single-cell transcriptome analysis. Drug sensitivity analysis indicated that patients with high CDI may be resistant to oxaliplatin and cisplatin but sensitive to axitinib and sorafenib. In summary, our model offers a precise prediction of clinical outcomes and drug sensitivity for patients with HCC, providing valuable insights for personalized treatment strategies.

Detection and differentiation of fowl adenovirus serotype 4 and duck adenovirus 3 using high resolution melting curve assay

Fowl adenovirus type 4 (FAdV-4) and duck adenovirus type 3 (DAdV-3) are the causative agents of clinical diseases in poultry and have caused considerable economic losses to the waterfowl industry in China. Both FAdV-4 and DAdV-3 are classified into the genus Aviadenovirus under the family Adenoviridae. The high-resolution melting (HRM) assay has become a useful method for virus genotyping, which offers the possibility of rapidly developing a differentiation technique in which the melting profile depends on the GC content of the product in the qPCR platform. The aim of this study was to develop a qPCR-HRM assay for sensitive FAdV-4 and DAdV-3 detection and differentiation. Here, specific primers were designed on the basis of the 100 K genes of FAdV-4 and DAdV-3, and a qPCR-HRM assay was established through optimization of the reaction conditions. A specificity test revealed that this method could detect only FAdV-4 and DAdV-3, with no cross-reaction with other common duck-derived viruses. A sensitivity test revealed that the lowest detection limits of FAdV-4 and DAdV-3 were 2.84 copies/µL and 2.85 copies/µL, respectively. A repeatability test demonstrated that the coefficient of variation was less than 2.5 % in both the intragroup and the intergroup analyses. Field sample distributions of FAdV-4 and DAdV-3 were investigated, and the percentages of DAdV-3-positive, FAdV-4-positive and coinfection-positive in Muscovy ducks were 27.78 %, 16.67 % and 11.11 %, respectively. Further studies are needed to provide more insight into the pathogenesis of FAdV-4 and DAdV-3 coinfection in ducks. In conclusion, the qPCR-HRM assay provides an accurate, sensitive, reliable and cost-effective alternative method for detecting and distinguishing FAdV-4 and DAdV-3.

Efficient management of pulmonary embolism diagnosis using a two-step interconnected machine learning model based on electronic health records data.

Pulmonary Embolism (PE) is a life-threatening clinical disease with no specific clinical symptoms and Computed Tomography Angiography (CTA) is used for diagnosis. Clinical decision support scoring systems like Wells and rGeneva based on PE risk factors have been developed to estimate the pre-test probability but are underused, leading to continuous overuse of CTA imaging. This diagnostic study aimed to propose a novel approach for efficient management of PE diagnosis using a two-step interconnected machine learning framework directly by analyzing patients' Electronic Health Records data. First, we performed feature importance analysis according to the result of LightGBM superiority for PE prediction, then four state-of-the-art machine learning methods were applied for PE prediction based on the feature importance results, enabling swift and accurate pre-test diagnosis. Throughout the study patients' data from different departments were collected from Sina educational hospital, affiliated with the Tehran University of medical sciences in Iran. Generally, the Ridge classification method obtained the best performance with an F1 score of 0.96. Extensive experimental findings showed the effectiveness and simplicity of this diagnostic process of PE in comparison with the existing scoring systems. The main strength of this approach centered on PE disease management procedures, which would reduce avoidable invasive CTA imaging and be applied as a primary prognosis of PE, hence assisting the healthcare system, clinicians, and patients by reducing costs and promoting treatment quality and patient satisfaction.

Associations Between Paramagnetic Rim Lesion Evolution and Clinical and Radiologic Disease Progression in Persons With Multiple Sclerosis.

Recent technological advances have enabled visualizing in vivo a subset of chronic active brain lesions in persons with multiple sclerosis (pwMS), referred to as "paramagnetic rim lesions" (PRLs), with iron-sensitive MRI. PRLs predict future clinical disease progression, making them a promising clinical and translational imaging marker. However, it is unknown how disease progression is modified by PRL evolution (PRL disappearance, new PRL appearance). This is key to understanding MS pathophysiology and may help inform selection of sensitive endpoints for clinical trials targeting chronic active inflammation. To this end, we assessed the longitudinal associations between PRL disappearance and new PRL appearance and clinical disability progression and brain atrophy. PwMS and healthy controls (HCs) were included from a larger prospective, longitudinal cohort study at the University at Buffalo if they had available 3T MRI and clinical visits at baseline and follow-up timepoints. PwMS with sufficient clinical data for confirmed disability progression (CDP) analysis were included in a Disability Progression Cohort, and pwMS and HCs with brain volumetry data at baseline and follow-up were included in MS and HC Brain Atrophy cohorts. PRLs were assessed at baseline and follow-up and assigned as disappearing, newly appearing, or persisting at follow-up. Linear models were fit to compare annualized PRL disappearance rates or new PRL appearance (yes/no) with annualized rates of CDP and progression independent of relapse activity (PIRA) or with annualized rates of brain atrophy, adjusting for covariates including baseline PRL number and follow-up time. Statistical analyses were corrected for false discovery rate (FDR; i.e., q-value). In total, 160 pwMS (73.8% female; mean baseline age 46.6 ± 11.4 years; mean baseline disease duration 13.8 ± 10.6 years; median follow-up time 5.6 [interquartile range 5.2-7.8] years; 26.9% progressive MS) and 27 HCs (74.1% female; mean baseline age 43.9 ± 13.6 years; median follow-up time 5.4 [5.2-5.6] years) were enrolled. Greater PRL disappearance rates were associated with reduced rates of CDP (β mean = -0.262, 95% CI -0.475 to -0.049, q = 0.028) and PIRA (β mean = -0.283, 95% CI -0.492 to -0.073, q = 0.036), and new PRL appearance was associated with increased rates of PIRA (β mean = 0.223, 95% CI 0.049-0.398, q = 0.036). By contrast, no associations between new PRL appearance or PRL disappearance and brain volume changes survived FDR correction (q > 0.05). Our results show that resolution of existing PRLs and lack of new PRLs are associated with improved clinical outcomes. These findings further motivate the need for novel therapies targeting microglia-mediated brain inflammation and adoption of clinical strategies to prevent appearance of new PRL.

Task-Specific Transformer-Based Language Models in Health Care: Scoping Review

Background Transformer-based language models have shown great potential to revolutionize health care by advancing clinical decision support, patient interaction, and disease prediction. However, despite their rapid development, the implementation of transformer-based language models in health care settings remains limited. This is partly due to the lack of a comprehensive review, which hinders a systematic understanding of their applications and limitations. Without clear guidelines and consolidated information, both researchers and physicians face difficulties in using these models effectively, resulting in inefficient research efforts and slow integration into clinical workflows. Objective This scoping review addresses this gap by examining studies on medical transformer-based language models and categorizing them into 6 tasks: dialogue generation, question answering, summarization, text classification, sentiment analysis, and named entity recognition. Methods We conducted a scoping review following the Cochrane scoping review protocol. A comprehensive literature search was performed across databases, including Google Scholar and PubMed, covering publications from January 2017 to September 2024. Studies involving transformer-derived models in medical tasks were included. Data were categorized into 6 key tasks. Results Our key findings revealed both advancements and critical challenges in applying transformer-based models to health care tasks. For example, models like MedPIR involving dialogue generation show promise but face privacy and ethical concerns, while question-answering models like BioBERT improve accuracy but struggle with the complexity of medical terminology. The BioBERTSum summarization model aids clinicians by condensing medical texts but needs better handling of long sequences. Conclusions This review attempted to provide a consolidated understanding of the role of transformer-based language models in health care and to guide future research directions. By addressing current challenges and exploring the potential for real-world applications, we envision significant improvements in health care informatics. Addressing the identified challenges and implementing proposed solutions can enable transformer-based language models to significantly improve health care delivery and patient outcomes. Our review provides valuable insights for future research and practical applications, setting the stage for transformative advancements in medical informatics.

Real-world clinical outcomes and rationale for initiating abatacept as a first-line biologic for patients with anticitrullinated protein antibody- and rheumatoid factor-positive rheumatoid arthritis

Aim: In rheumatoid arthritis (RA), seropositivity for both anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF) is associated with disease severity and therapeutic response. Biologic (b) disease-modifying antirheumatic drugs (DMARDs) such as abatacept are recommended after inadequate response or contraindication to conventional synthetic DMARDs. This retrospective cohort study aimed to describe changes in Clinical Disease Activity Index (CDAI) measures over 12 months among patients with ACPA+ and RF+ RA with an inadequate response to methotrexate treated with abatacept as a first-line bDMARD. Patients & methods: Patient data were abstracted from medical records by treating rheumatologists. Analyses included McNemar tests for paired proportions or paired t -tests to assess longitudinal changes in CDAI scores, and Kaplan–Meier methods for time-to-event outcomes. Serious AEs and rationale for initiating treatment were recorded. Results: Overall, 296 patients were included. Mean CDAI scores improved (decreased) by 34.0, 61.0 and 74.0% (all p < 0.001) from baseline to 3–6 months, 6–12 months and ≥12 months after abatacept initiation, respectively. Of 279 patients not in CDAI low disease activity (LDA) or remission at baseline, 24.7% of patients achieved it within 6 months, 56.3% within 12 months and 71.0% at any point during follow-up after abatacept initiation. Median time to CDAI LDA/remission was 10.2 months. Serious AEs were reported in 2.4% of patients. Common reasons reported by rheumatologists for initiating abatacept were effectiveness/efficacy (52.7%), safety (31.4%) and patient preference (25.3%). Conclusion: In this analysis of patients with ACPA+ and RF+ RA treated with abatacept as a first-line bDMARD in a clinical practice setting, clinical outcomes and remission rates were improved at all time points, providing real-world evidence to further support the use of abatacept in this patient population.

Abstract A010: Development and characterization of novel models of lobular breast cancer metastases

Abstract Invasive lobular carcinoma (ILC) is the most common special histological subtype of breast cancer, after No Special Type (NST, ductal carcinoma/IDC), and affects 10-15% of all breast cancer patients. ILC is characterized by E-cadherin loss, Estrogen Receptor (ER) positivity, and a distinct single file invasive growth pattern associated with a unique pattern of metastasis. ILC metastasizes to common breast cancer sites like bone and lung, but ILC also spreads to gynecologic tissues, the peritoneum, gastrointestinal tract and central nervous system - with enrichment for orbital and leptomeningeal metastases. In vitro and in vivo models of ILC metastasis have not been extensively developed. Models of spontaneous metastasis from ER+ breast cancer overall are critically limited; ER+ ILC metastases models present only micro-metastatic disease with extremely long latency (>9 months). Together these issues limit research on the unique nature of metastatic ILC. We leveraged mammary intraductal (MIND) xenografting with two ER+ ILC cell lines (MM134 and 44PE) and confirmed prior reports that these lines spontaneously metastasize to bone, brain, ovary, uterus, lung, and adrenal glands with up to 100% incidence. Importantly, we find that supplementation with low dose estradiol (E2) in drinking water rapidly advances metastatic progression, but not primary tumor growth. Using ex vivo bioluminescence imaging (BLI), we find BLI+ lesions are detectable as early as 90 days. At 150 days post-challenge, 100% of mice have BLI+ metastases at multiple sites. Beyond 22 weeks, 100% of mice present with symptomatic and ultimately lethal CNS metastases. BLI+ macro-metastatic lesions were isolated and expanded ex vivo as organotrophic cell line variants. Analysis of RNA-seq data is ongoing to evaluate 1) common factors enriched in metastatic ILC, and 2) organotrophic factors and pathways enriched in specific metastatic sites. In patients with ILC, bone metastases are typically the first site of metastatic development, occur at a higher incidence versus NST, and are associated with increased morbidity. Bone metastases from ILC patients are more osteogenic compared to the characteristically osteolytic lesions of NST. To examine how ILC cells may promote osteoblastic responses, we prepared ILC and NST conditioned media (CM) and applied it to differentiating osteoblasts (OB). We observed increased OB differentiation and increased mineral deposition with ILC CM compared to NST CM, supporting that ILC cell lines have a distinct impact on the bone microenvironment which may manifest in vivo yet be defined in vitro. Collectively, our observations support that ER+ ILC cell lines can recapitulate key features of clinical disease progression, including spontaneous metastasis mimicking clinical phenotypes. We are leveraging these models to better understand the ILC metastatic cascade and adaptation to unique metastatic niches, and to identify shared and unique attributes of ILC metastases that can be exploited for advancing therapeutics. Citation Format: Joseph L. Sottnik, Matthew J. Sikora. Development and characterization of novel models of lobular breast cancer metastases [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A010.

Leveraging Real-World Evidence to Define Severe RSV Lower Respiratory Tract Disease in Adults.

As no standard case definitions for respiratory syncytial virus-associated lower respiratory tract disease (RSV-LRTD) in adults are available, this study analyzed definitions for severe RSV-LRTD from previously published data in hospital and community cohorts of adults with RSV-associated symptoms. The frequency, sensitivity, and specificity of acute respiratory disease symptoms among hospitalized and community cohorts of adults with RSV were analyzed. RSV-LRTD signs/symptoms assessed included shortness of breath (dyspnea), cough and/or fever, wheezing/rales/rhonchi (abnormal lung sounds by auscultation), sputum production, tachypnea, hypoxemia, and pleuritic chest pain. Dyspnea and tachypnea provided the best differentiation between hospitalized and community RSV-positive cases. The severe RSV-LRTD case definition yielding one of the highest and best-balanced sensitivity and specificity was dyspnea paired with either abnormal lung sounds by auscultation, hypoxemia, tachypnea, cough and/or fever, sputum, or chest pain. Dyspnea alone, and in combination with certain other lower respiratory tract disease signs/symptoms, was a leading symptomatic indicator for severe RSV outcomes. These results contribute to the harmonization of case definitions for RSV disease.

A Bayesian analysis integrating expert beliefs to better understand how new evidence ought to update what we believe: a use case of chiropractic care and acute lumbar disc herniation with early surgery.

A Bayesian approach may be useful in the study of possible treatment-related rare serious adverse events, particularly when there are strongly held opinions in the absence of good quality previous data. We demonstrate the application of a Bayesian analysis by integrating expert opinions with population-based epidemiologic data to investigate the association between chiropractic care and acute lumbar disc herniation (LDH) with early surgery. Experts' opinions were used to derive probability distributions of the incidence rate ratio (IRR) for acute LDH requiring early surgery associated with chiropractic care. A 'community of priors' (enthusiastic, neutral, and skeptical) was built by dividing the experts into three groups according to their perceived mean prior IRR. The likelihood was formed from the results of a population-based epidemiologic study comparing the relative incidence of acute LDH with early surgery after chiropractic care versus primary medical care, with sensitive and specific outcome case definitions and surgery occurring within 8- and 12-week time windows after acute LDH. The robustness of results to the community of priors and specific versus sensitive case definitions was assessed. The most enthusiastic 25% of experts had a prior IRR of 0.42 (95% credible interval [CrI], 0.03 to 1.27), while the most skeptical 25% of experts had a prior IRR of 1.66 (95% CrI, 0.55 to 4.25). The Bayesian posterior estimates across priors and outcome definitions ranged from an IRR of 0.39 (95% CrI, 0.21 to 0.68) to an IRR of 1.40 (95% CrI, 0.52 to 2.55). With a sensitive definition of the outcome, the analysis produced results that confirmed prior enthusiasts' beliefs and that were precise enough to shift prior beliefs of skeptics. With a specific definition of the outcome, the results were not strong enough to overcome prior skepticism. A Bayesian analysis integrating expert beliefs highlighted the value of eliciting informative priors to better understand how new evidence ought to update prior existing beliefs. Clinical epidemiologists are encouraged to integrate informative and expert opinions representing the end-user community of priors in Bayesian analyses, particularly when there are strongly held opinions in the absence of definitive scientific evidence.

Baseline Characteristics of Participants in STAREE: A Randomized Trial for Primary Prevention of Cardiovascular Disease Events and Prolongation of Disability-Free Survival in Older People.

The risk-benefit balance of statin use in healthy older people is uncertain. We describe the baseline characteristics of the STAREE (Statins in Reducing Events in the Elderly) trial, which is a randomized, double-blind, placebo-controlled trial among community-dwelling older people; the trial evaluated the effect of atorvastatin 40 mg for the prevention of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke), and on disability-free survival (survival free of both dementia and persistent physical disability). STAREE enrolled people aged ≥70 years from 1583 general practices across Australia with no history of clinical cardiovascular disease, diabetes, or dementia. Baseline data collected included demographic, clinical, cognitive (Modified Mini-Mental State Examination), psychological (Center for Epidemiologic Studies Short Depression Scale), lifestyle, medical, physical, blood and urine measures, and quality of life. Demographic and clinical characteristics of study participants were then compared with publicly available landmark statin trials. A total of 9971 participants were recruited (mean±SD age 74.7±4.5 years, 4023 (40%) ≥75 years, 52% women) between July 2015 and March 2023. The mean low-density lipoprotein cholesterol was 3.27 mmol/L (SD=0.72; 126 mg/dL). Hypertension was reported by 43% of participants and the mean blood pressure was 136/80 mm Hg. Compared with previous landmark statin trials that included primary prevention cohorts, STAREE is unique in including such a large number of older (≥75 years) independent-living people. STAREE is the largest primary prevention trial of statins powered to address the important clinical outcomes of major cardiovascular events, disability-free survival, and cognition in older people. https://www.clinicaltrials.gov; Unique identifier: NCT02099123.

Haematogenous seeding in mycosis fungoides and Sézary syndrome: Current evidence and clinical implications.

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of diseases characterised by abnormal neoplastic T-cell growth in the skin. Mycosis fungoides (MF), the most common CTCL, manifests as erythematous skin patches and/or plaques, tumours or erythroderma. The disease may involve blood, lymph nodes and rarely viscera. Sézary syndrome (SS) is a unique leukaemia/lymphoma syndrome related to MF, which presents with blood and skin involvement at diagnosis. The pathogenesis of MF/SS is not fully elucidated. The presence of skin lesions at distant sites underpins a hypothesis that MF/SS lesions may develop through haematogenous seeding. Phenotypic similarities between malignant and normal T-cells led to the notion that disease-initiating mutations occur in specific subtypes of mature T-cells, which are responsible for most CTCLs. However, this mature T-cell precursor model is not always consistent with clinical observations and research on MF/SS pathogenesis. Here, we review evidence supporting an alternative model of pathogenesis for MF/SS involving haematogenous seeding as a key process responsible for the initiation and progression of the disease. According to this hypothesis, malignant transformation occurs at an early stage of T-cell development (probably in bone marrow or thymus), yielding circulating neoplastic T-cells which colonise the skin where the microenvironment is most permissive for proliferation and evolution. These mutated precursor cells seed the skin where they find a suitable niche to develop into clinically perceptible disease. Subsequently, malignant T-cells can re-enter the bloodstream, re-seed pre-existing lesions and seed new areas of the skin, causing synchronous and convergent changes in the transcriptomic profile of lesions and tumours, and clinical disease progression - 'consecutive haematogenous seeding' captures this temporal phenomenon. This model radically changes the current understanding of CTCL pathogenesis, transforming it from a primarily cutaneous disease with secondary involvement of blood, to a systemic disease, where the spread of malignant cells through the blood to the skin is not a phenomenon of advanced disease but is an essential component of pathogenesis. This understanding of MF/SS could have several clinical implications, including standardising our approach to assessing blood tumour burden, potential advances in prognosis and monitoring, and investigating combination treatments to improve patient outcomes.

Symptom profile, case and symptom clustering, clinical and demographic characteristics of a multicentre cohort of 1297 patients evaluated for Long-COVID.

Long-COVID symptoms remain incompletely defined due to a large heterogeneity in the populations studied, case definitions, and settings of care. The aim of this study was to assess, in patients accessing care for Long-COVID, the profile of symptoms reported, the possible clustering of symptoms and cases, the functional status compared to pre-infection, and the impact on working activity. Multicentre cohort study with a collection of both retrospective and prospective data. Demographics, comorbidities, severity and timing of acute COVID, subjective functional status, working activity and presence of 30 different symptoms were collected using a shortened version of the WHO Post COVID-19 Case Report Form. The impact on working activity was assessed in multivariable logistic regression models. Clustering of symptoms was analysed by hierarchical clustering and the clustering of cases by two-step automatic clustering. The study evaluated 1297 individuals (51.5% women) from 30 clinical centres. Men and women had different profiles in terms of comorbidities, vaccination status, severity and timing of acute SARS-CoV-2 infection. Fatigue (55.9%) and dyspnea (47.2%) were the most frequent symptoms. Women reported more symptoms (3.6 vs. 3.1, p < 0.001), with a significantly higher prevalence of memory loss, difficult concentration, cough, palpitation or tachycardia, dermatological abnormalities, brain fog, headache and visual disturbances. Dyspnea was more common in men. In the cluster analysis of the 19 more common symptoms, five aggregations were found: four two-symptom clusters (smell and taste reduction; anxiety and depressed mood; joint pain or swelling and muscle pain; difficult concentration and memory loss) and one six-symptom cluster (brain fog, equilibrium/gait disturbances, headache, paresthesia, thoracic pain, and palpitations/tachycardia). In a multivariable analysis, headache, dyspnea, difficult concentration, disturbances of equilibrium or gait, visual disturbances and muscular pain were associated with reduced or interrupted working activity. Clustering of cases defined two clusters, with distinct characteristics in terms of phase and severity of acute infection, age, sex, number of comorbidities and symptom profile. The findings provide further evidence that Long-COVID is a heterogeneous disease with manifestations that differ by sex, phase of the pandemic and severity of acute disease, and support the possibility that multiple pathways lead to different clinical manifestations.

Pediatric Rash Illness Outbreak with Initial Positive Measles Immunoglobulin M Antibody Test Results - American Samoa, March-July 2023.

On April 24, 2023, the American Samoa Department of Health (ASDoH) declared a public health emergency amid concern about a possible measles outbreak given low 2-dose vaccination coverage at the time. ASDoH had received two positive measles immunoglobulin (Ig) M test results after Flag Day festivities 1 week earlier from vaccinated children. ASDoH performed active case finding, took actions to mitigate transmission, and requested technical assistance from CDC. ASDoH implemented a vaccination campaign to improve suboptimal coverage. Confirmatory molecular testing of specimens from these initial persons under investigation (PUIs) was not possible, but subsequent testing of specimens from additional PUIs by Hawaii State Laboratories Division and CDC ruled out measles. In settings with low measles prevalence, measles antibody testing results have low positive predictive value and can lead to difficulties with interpreting results. Testing for additional pathogens revealed a variety of viruses known to cause common childhood viral exanthems. Both molecular and serologic testing should be performed for all suspected measles cases. To decrease the probability of false-positive IgM results, testing should be reserved for cases that meet the Council of State and Territorial Epidemiologists measles case definition, especially those in persons with no evidence of immunity and with a history of recent international travel. In addition, maintaining high measles vaccination coverage can prevent future outbreaks.

Association of rheumatoid factor, anti-citrullinated protein antibodies and shared epitope with clinical response to initial treatment in patients with early rheumatoid arthritis: data from a randomised controlled trial

ObjectivesTo investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional...

Live-Cell RNA Imaging with a DNA-Functionalized Metal-Organic Framework-Based Fluorescent Probe.

Live-cell fluorescence imaging of tumor-associated miRNAs is significant for understanding the cancer onset and progression and the diagnosis and prognosis of clinical diseases. In this protocol, we describe the construction of a DNA-functionalized metal-organic framework-based fluorescent probe and demonstrate that the probe can be used to detect miRNA in vitro and live-cell imaging. The formed DNA-MOF probe can specifically target miRNA with high sensitivity and specificity. The detection limit of the extracellular assay is as low as the picomolar level. In addition, we found that the probe could permeate cells and can be successfully applied in intracellular miRNA imaging, even achieving the distinction of cancer cells and normal cells, as well as the cancer cell lines with different miRNA expression levels.

Operationalisation of post-COVID condition case definition in a comprehensive research protocol.

Post-COVID-19 condition (PCC) is a prevalent and high-burden sequela of SARS-CoV-2 infection. Because of the complexity of its manifestations, PCC case definition currently lacks standardisation and reproducibility. We aimed to devise a simple screening tool to boost reproducibility and comparability of PCC case definition across PCC studies, and to provide a framework in which to reliably identify suspected PCC cases. We also developed a comprehensive assessment protocol based on the most frequently reported PCC characteristics. Within a European multi-centre study and based on the conclusions of a previous systematic review, we devised a checklist to assess the presence of PCC-associated symptoms and their temporal relationship with COVID-19. The checklist was developed to include three symptom cores (cognitive, psychiatric, and general). For each symptom, onset is assessed within 3 months after COVID-19 resolution and persistence for at least 2 months. Any symptom fulfilling this criterion is sufficient to prompt suspicion of PCC. At least one symptom is required in the cognitive or psychiatric domains to suspect PCC with neuropsychiatric involvement. Our protocol features an extensive neuropsychological evaluation and self-administered scales for mood, anxiety, stress-related symptoms, sleep disorders, quality of life, disability, mental health, and personality traits; scales for quantitative assessment of fatigue and headache are also included. Consistent identification of PCC cases is crucial to correctly include patients in research and clinical studies. We propose a simple, reproducible, and flexible screening tool and a proposal for a comprehensive assessment that could be employed to enhance standardisation and comparability.