Clinical Disease Progression Research Articles

Fibroblast activation protein inhibitor PET/CT as an emerging diagnostic modality in interstitial lung disease and other fibrotic conditions.

Interstitial lung diseases (ILD) encompass a wide range of disorders characterized by alveolar inflammation and fibrotic tissue remodeling, marked by significant morbidity and mortality. Systemic sclerosis (SSc), among other connective tissue diseases, is a frequent cause of ILD. Assessment of pulmonary fibrosis is frequently constrained by the delayed manifestations of profibrotic activation of fibroblasts, which results in late macroscopic alterations detectable by standard imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) scans. 68Ga-labeled fibroblast activation protein inhibitors (68Ga-FAPI [fibroblast activation protein inhibitor]) are novel radionuclides used in the selective positron emission tomography/computed tomography (PET/CT) detection of profibrotic fibroblasts, a key player in fibrotic tissue remodeling. Application of 68Ga-FAPI in different target organs undergoing fibrosis, such as lung and heart, highlights its efficacy in detecting ongoing fibrotic processes, since FAPI tracer uptake has been correlated with clinical disease progression markers in SSc-ILD. This feature could enable physicians to detect subclinical fibrotic activity and tailor an individualised therapy plan on a case by case basis. The use of 68Ga-FAPI in ILD and other fibrotic conditions may emerge as a novel tool in future clinical practice for both activity monitoring and treatment optimisation. Other tracers tested in ILD of different etiologies have shown promising results and may in future also be considered for potential application in SSc-ILD.

Hospital Mortality in Acute Decompensation of Alcoholic Liver Cirrhosis: Can Novel Survival Markers Outperform Traditional Ones?

Background: There is a strong correlation between systemic inflammation intensity and clinical presentation, disease progression, and survival during liver cirrhosis decompensation. This study aimed to evaluate the prognostic performance of blood-based biomarkers as meta-inflammation markers, including NLR, PLR, LMR, INPR, MPR, ALBI, FIB4, and APRI, in predicting hospital mortality in patients with acute decompensation of alcohol-related liver cirrhosis. Methods: Data from 411 patients with their first onset of acute decompensation were analyzed, forming two groups: deceased and survived during hospitalization. Generalized partial least squares regression analysis was applied to explore the effects of surrogate indicators on mortality rates, using mortality rate as the dependent variable. Root Mean Square Error, Akaike's, and Bayesian information criteria determined that four components accounted for most of the variance. Results: Variables with significant negative contributions to the outcome prediction (ranked by standardized regression coefficients) were encephalopathy grade, total bilirubin, Child-Turcotte-Pugh score, MELD, NLR, MPV, FIB4, INR, PLR, and ALT. Coefficient sizes ranged from -0.63 to -0.09, with p-values from 0 to 0.018. Conclusions: NLR, PLR, and FIB4 significantly contribute to hospital mortality prediction in patients with acute decompensation of alcohol-related liver cirrhosis. Conversely, some variables used to predict liver disease severity, including INPR, APRI, LMR, and ALBI score, did not significantly contribute to hospital mortality prediction in this patient population.

In situ assessment of neuroinflammatory cytokines in different stages of ovine natural prion disease.

According to the neuroinflammatory hypothesis, a cytokine-mediated host innate immune response may be involved in the mechanisms that contribute to the process of neurodegeneration. Specifically, regarding prion diseases, some experimental murine models have evidenced an altered profile of inflammatory intermediaries. However, the local inflammatory response has rarely been assessed, and never in tissues from different natural models throughout the progression of neurodegeneration. The aim of this study was to use immunohistochemistry (IHC) to in situ assess the temporal protein expression of several cytokines in the cerebellum of sheep suffering from various clinical stages of scrapie. Clear changes in the expression of most of the assessed markers were observed in the affected sheep compared to the healthy control sheep, and from different stages. In summary, this preliminary IHC study focusing in the Purkinje cell layer changes demonstrate that all cytokines or respective receptors studied (IL-1, IL-1R, IL-2R, IL-6, IL-10R, and TNFαR) except for IFNγR are disease-associated signaling proteins showing an increase or decrease in relation to the progression of clinical disease. In the future, this study will be extended to other inflammatory mediators and brain regions, focusing in particular on the release of these inflammatory mediators by astroglial and microglial populations.

Tertiary lymphoid structures and B-cell infiltration are IPF features with functional consequences.

Recent literature has shown the presence of B cells and autoantibodies in idiopathic pulmonary fibrosis (IPF) which would imply the presence of tertiary lymphoid structures (TLS, sites where the immune response is triggered), yet TLS are not considered features of the histological characteristics of IPF. This study aims to quantify the presence, size, and degree of activation of TLS in biopsied and explanted lungs from patients with early- and late-IPF, never treated with antifibrotics, and relate their presence and activity to the clinical course, disease progression, and lung inflammation. Immunohistochestry for B cells and CD4, CD8, and CD45 cells was performed in lung tissue from IPF patients: 18 at diagnosis (early), 39 explanted (end-stage), and 12 smoking controls. TLS activation was assessed by CD40 expression. Spirometry along 31 (12-72) months of follow-up was used to characterize end-stage IPF as slow progressors or rapid progressors. B cells, along with other inflammatory cells, were higher in early- and end-stage IPF than in controls (p < 0.001). In rapid progressors, all inflammatory cells were higher than in slow progressors (p < 0.05). TLS were present in 100% of early- and end-stage IPF and in 50% of controls. In end-stage IPF, the TLS area and activation score were higher than in early IPF (p < 0.0001; p = 0.005) and controls (p < 0.04; p < 0.002). TLS activation score correlated with FVC decline during follow-up in rapid progressors (r = 0.73; p = 0.007) but not in slow progressors. A prominent B-cell infiltration, along with the presence of TLS, the activity of which correlates with FVC decline, is an important component of IPF from the beginning of the disease, likely playing an important role on its mechanism and progression.

Acute Retinal Necrosis: A Review of Diagnosis and Management

Acute retinal necrosis (ARN) is a profound infection of the retina, marked by acute panuveitis, retinal periarteritis, and widespread necrotizing retinitis. The etiology of ARN involves human herpesviruses, such as herpes simplex virus (HSV) and varicella-zoster virus (VZV), which can lead to severe visual impairment or even blindness. A diagnosis of ARN is based on clinical characteristics and disease progression according to the standard diagnostic criteria established by the American Uveitis Society (AUS) in 1994. The polymerase chain reaction(PCR) of aqueous specimens can enable identification of the type of virus. Early initiation of antiviral medication is essential for treatment efficacy to stop lesion progression, accelerate the healing process, and prevent contralateral eye involvement. Ocular complications of ARN include atrophic retina, multiple retinal breaks, rhegmatogenous retinal detachment (RRD), tractional retinal detachment (TRD), optic atrophy, macular edema, epiretinal membrane (ERM), and retinal and optic disc neovascularization. This review summarizes the clinical features, diagnostic criteria, and recently recommended ARN management.

Living systematic review and comprehensive network meta-analysis of ALS clinical trials: study protocol.

Amyotrophic lateral sclerosis (ALS) is a fatal neurogenerative disease with no effective treatment to date. Despite numerous clinical trials, the majority of studies have been futile in their effort to significantly alter the course of the disease. However, these studies may still provide valuable information for identifying patient subgroups and generating new hypotheses for future research. Additionally, synthesising evidence from these studies may help overcome the limitations of individual studies. Network meta-analysis may refine the assessment of efficacy in specific patient subgroups, evaluate intervention characteristics such as mode of administration or biological mechanisms of action, and rank order promising therapeutic areas of interest. Therefore, we aim to synthesise the available evidence from ALS clinical trials. We will conduct a systematic review to identify all clinical trials that assessed disease-modifying pharmaceutical therapies, cell therapies, or supplements in patients with ALS. Outcomes of interest are clinical disease progression outcomes and survival. We will conduct this search in the period Q4 2024 in three databases: PubMed, Embase and ClinicalTrials.gov for studies from 1999 to 2023. Individual patient data and aggregate data will be collected and subsequentially synthesised in meta-analytical models. The final model will be presented as an open-source web application with biannual updates of the underlying data, thereby providing a 'living' overview of the ALS clinical trial landscape. No ethics approvals are required. Findings will be presented at relevant conferences and submitted to peer-reviewed journals. Data will be stored anonymously in secure repositories.

Comparison of Chikungunya Virus-Induced Disease Progression and Pathogenesis in Type-I Interferon Receptor-Deficient Mice (A129) and Two Wild-Type (129Sv/Ev and C57BL/6) Mouse Strains.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus causing a debilitating febrile illness with rheumatic disease symptoms of arthralgia and arthritis. Since its spread outside of Africa in 2005, it continues to cause outbreaks and disseminates into new territories. Intervention strategies are urgently required, including vaccination and antiviral approaches. To test efficacy, the use of small animal models is required. Two mouse strains, A129, with a deficiency in their type-I interferon (IFN) receptor, and C57BL/6 are widely used. A direct comparison of these strains alongside the wild-type parental strain of the A129 mice, 129Sv/Ev, was undertaken to assess clinical disease progression, viral loads in key tissues, histological changes and levels of sera biomarkers. Our results confirm the severe disease course in A129 mice which was not observed in the parental 129Sv/Ev strain. Of the two wild-type strains, viral loads were higher in 129Sv/Ev mice compared to C57BL/6 counterparts. Our results have established these models and parameters for the future testing of vaccines and antiviral approaches.

Longitudinal objective assessment of speech in Multiple Sclerosis

BackgroundRemote objective tests may supplement in-clinic examination to better inform treatment decisions. Previous cross-sectional studies presented objective speech metrics as potential markers of Multiple Sclerosis (MS) disease progression. ObjectiveTo examine the short-term stability and long-term sensitivity of speech metrics to MS progression. MethodsWe prospectively recorded speech from people with MS at baseline, six, twelve weeks, and at ten months or longer after baseline (1y+). Only people with a definite diagnosis of MS and without other potential causes of dysarthria were included. Speech tasks comprehended 1) a sustained vowel /a/, 2) saying the days of the week, 3) repeating the non-word pa-ta-ka multiple times as fast as possible, 4) reading the Grandfather Passage, and 5) telling a personal story. We selected speech metrics of interest according to their association with MS presence, correlation with general disability, and short-term metric stability in the absence of disease progression. Selected speech metrics were analysed for short- versus long-term changes in the whole MS cohort and in the clinically stable versus progression subgroups at 1y+. ResultsSixty-nine people with MS participated (76.8 % female, age mean 47.5 ± 11.1 SD, EDSS median 3.5, interquartile range 3.5). Twenty-six unique speech metrics satisfied the suitability criteria. On average, reading rate improved 3.5 % for all people with MS and 6.5 % for slow readers with MS from baseline to the six-week, driven by a reduction in pauses. At 1y+, participants showed a 3.1 % average reduction in vocalization time during the reading task, which was similar in the progression (n = 29) and non-progression (n = 40) groups and thus unrelated to disease progression. Both findings are in the opposite direction of what would be generally expected for deterioration in speech performance and might be attributable to familiarity and training effects. Other speech metrics showed either negligible change or a similar variability between short-term and long-term differences. ConclusionMost individual long-term changes were small and within short-term variability intervals, irrespective of clinical disease progression. Familiarity and practice effects might have blunted the measurement of change. The present lack of longitudinal sensitivity of speech in MS contradicts previous cross-sectional findings and requires further investigation.

The Protective Effect of Astragalus Polysaccharide on Experimental Autoimmune Encephalomyelitis in Mice by Activating the AMPK/JAK/STAT3/Arginase-1 Signaling Pathway.

This study aimed to investigate the protective effect and mechanism of Astragalus polysaccharide (APS) on autoimmune encephalomyelitis. C57BL/6 mice were randomly divided into the blank control group, EAE group, and APS intervention group (n=15/group). The Experimental Autoimmune Encephalomyelitis (EAE) mouse model was established by active immunization. The pathological changes in the spinal cord were evaluated by Hematoxylin-eosin (HE) and Luxol Fast Blue (LFB) staining. The number of CD11b+ Gr-1+ myeloid-derived suppressor cells (MDSCs) in the spleen tissues of mice in each group was determined by immunofluorescence staining. The expression of Arginase-1 in the spinal cord and spleen of each group was detected by immunofluorescence double staining. The TNF-α, IL-6, and Arginase-1 levels in the spleen were detected by ELISA assay. A western blot was used to detect the protein expression of the AMPK/JAK/STAT3/Arginase-1 signaling pathway. After the intervention of APS, the incidence of autoimmune encephalomyelitis in mice of the APS group was significantly lower than that in the EAE group, and the intervention of APS could significantly delay the onset time in the EAE mice, and the score of neurological function deficit in mice was significantly lower than that in EAE group (P < 0.05). APS intervention could reduce myelin loss and improve the inflammatory response of EAE mice. Moreover, it could induce the expression of CD11b+ GR-1 + bone MDSCs in the spleen and increase the expression of Arginase-1 in the spinal cord and spleen. This study further demonstrated that APS can protect EAE mice by activating the AMPK/JAK/STAT3/Arginase-1 signaling pathway. After the intervention of APS, myelin loss and inflammatory response of EAE mice were effectively controlled. APS promoted the secretion of Arginase-1 by activating MDSCs and inhibited CD4+T cells by activating AMPK/JAK/STAT3/Arginase-1 signaling pathway, thus improving the clinical symptoms and disease progression of EAE mice.

Deep-learning generated B-line score mirrors clinical progression of disease for patients with heart failure

BackgroundUltrasound can detect fluid in the alveolar and interstitial spaces of the lung using the presence of artifacts known as B-lines. The aim of this study was to determine whether a deep learning algorithm generated B-line severity score correlated with pulmonary congestion and disease severity based on clinical assessment (as identified by composite congestion score and Rothman index) and to evaluate changes in the score with treatment. Patients suspected of congestive heart failure underwent daily ultrasonography. Eight lung zones (right and left anterior/lateral and superior/inferior) were scanned using a tablet ultrasound system with a phased-array probe. Mixed effects modeling explored the association between average B-line score and the composite congestion score, and average B-line score and Rothman index, respectively. Covariates tested included patient and exam level data (sex, age, presence of selected comorbidities, baseline sodium and hemoglobin, creatinine, vital signs, oxygen delivery amount and delivery method, diuretic dose).ResultsAnalysis included 110 unique subjects (3379 clips). B-line severity score was significantly associated with the composite congestion score, with a coefficient of 0.7 (95% CI 0.1–1.2 p = 0.02), but was not significantly associated with the Rothman index.ConclusionsUse of this technology may allow clinicians with limited ultrasound experience to determine an objective measure of B-line burden.

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.

B - 32 Neurological Problems in Boxers during the 20th Century: a Review and Synthesis

Abstract Objective There are no validated clinical diagnostic criteria for chronic traumatic encephalopathy or traumatic encephalopathy syndrome (TES). To understand the historical clinical condition, its applicability to modern day athletes, and the pathogenesis of clinical problems, we examined the literature in boxers from the 20th century, with specific attention to neurological findings and characteristics of clinical disease progression. Data Selection Data were extracted for 243 boxers included in 45 articles published between 1928 and 1999, including cases from articles originally published in German. The presence or absence of 22 neurological signs and features were extracted. Data Synthesis The most common neurological problems were slurring dysarthria (49%), gait disturbances (44%), and memory loss (36%), with several other problems that were less frequent, including hyperreflexia (25%), ataxia (22%), increased tone (19%), and extensor Babinski sign (16%). Frank dementia appeared in some cases (17%). There were significantly fewer neurological deficits reported in boxers who fought in the latter part of the 20th century compared to boxers who fought earlier in the century. For most cases, there were no comments about whether the neurological problems were progressive (145, 60%). A progressive condition was described in 71 cases (29%) and a stationary or improving condition was described in 27 cases (11%). Canonical neurodegenerative disease-like progression was described in 15 cases (6%). Conclusions Neurological problems associated with boxing-related neurotrauma during the 20th century are the foundation for present day TES. However, the clinical signs and features in the 20th century differ in most ways from the modern criteria for TES.

Asuhan Keperawatan Jiwa pada Ny. R Dengan Masalah Utama Risiko Perilaku Kekerasan Akibat Skizofrenia Tak Terinci di Ruang Arimbi RSJD dr. Amino Gondohutomo Provinsi Jawa Tengah

Schizophrenia is a syndrome with a variety of causes, where each patient exhibits different clinical manifestations, therapeutic responses, and disease progression. Clinical manifestations of schizophrenia include disorganized speech, restlessness, pacing, and aggression, often exhibited through violent behavior. According to WHO data, in 2019, approximately 24 million people worldwide suffered from schizophrenia (WHO, 2019). The purpose of this paper is to understand the nursing care process for Mrs. R, with the main issue being the risk of violent behavior due to unspecified schizophrenia. The writing method used is a descriptive case study through a nursing process approach, where the assessment is conducted using interview techniques, observation, documentation review, and literature study. The nursing diagnoses identified include the risk of violent behavior, self-concept disturbance: low self-esteem, and self-care deficit. The interventions developed involve implementing strategies for both the patient and the family. The evaluation of the nursing care for Mrs. R showed that the diagnosis of risk of violent behavior was partially resolved, and the self-care deficit was resolved.

BEST1 associated bestrophinopathies with angle closure and post-surgical malignant glaucoma

ABSTRACT Introduction Mutations in BEST1 gene have been linked to the development of refractory angle closure glaucoma (ACG). This study aims to delineate the clinical characteristics, genetic mutations, and disease progression in patients with autosomal recessive bestrophinopathy (ARB) and autosomal dominant Best vitelliform macular dystrophy (BVMD) who are presented with treatment-resistant ACG. Methods This retrospective analysis encompasses a comprehensive ophthalmic assessment, retinal imaging, and mutational profiling of six patients diagnosed with bestrophinopathy and concurrent ACG, with a particular emphasis on the risk of post-glaucoma filtration surgery malignant glaucoma (MG). Exome sequencing was conducted utilizing a next-generation sequencing (NGS) based gene panel. Results The cohort included five patients with ARB and one with BVMD, with a mean (±SD) age at ACG diagnosis of 35.1 ± 6.9 years. NGS analysis revealed homozygous BEST1 variants in four patients (ARB; cases 1–4) and a heterozygous BEST1 variant in one patient (BVMD; case 5). One patient (ARB; case 6), despite a recessive pedigree, showed a single heterozygous variant, suggesting the presence of an undetected heterozygous variant indicative of compound heterozygous autosomal recessive inheritance. A novel non-frameshift deletion (c.841_843delTTC; p.Phe281del) was identified in case 2. Surgical intervention was required due to uncontrolled glaucoma in all cases except case 4. All five cases that underwent glaucoma filtration surgery developed MG, which was effectively managed with combined iridozonulo-hyaloido-vitrectomy (IZHV) and pars plana vitrectomy (PPV). Cases 5 and 6, harboring a heterozygous pathogenic variant (c.241 G>A; p.Val81Met), experienced refractory MG and corneal decompensation necessitating multiple interventions. Conclusion Genomic analysis plays a pivotal role in the management of bestrophinopathies with ACG. Characterization of mutational types facilitates prognostication and enables timely interventions. IZHV with PPV emerges as a promising standalone or adjunctive procedure for the management of glaucoma among patients with BEST1 mutations and ACG.

Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Genetic variants of Nuclear Factor-Kappa B were associated with different outcomes of Hepatitis C virus infection among Egyptian patients.

Hepatitis C virus (HCV) is a major risk factor for chronic hepatitis and hepatocellular carcinoma (HCC). Nuclear factor kappa B (NF-κB) is a transcription factor that functions in health and disease. Genetic variants of the NF-κB gene can affect its function and are associated with chronic inflammatory changes and malignant transformation. This case-control study is aimed to determine the possible association between NF-κB genetic variants and different outcomes of HCV infection among Egyptian patients. 295 subjects were recruited with allocation of participants in the representative group according to results of serological and molecular tests. Patients in the case group (group A) were further divided into three subgroups; subgroup I, mild chronic HCV, subgroup II, cirrhosis, and subgroup III, HCC subgroups (59 for each subgroup), group B included participants who experienced spontaneous viral clearance (n=59). All were compared to matched healthy control subjects, Group C (n=59). All participants were genotyped for NF-κB polymorphisms, rs11820062 by TaqMan assay and rs28362491 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Risk analysis indicated that subjects carrying the rs11820062 A genotype are more susceptible to HCV infection (OR: 3.1; 95%, CI= 1.4-6.9). Subjects carrying the rs28362491 insertion genotype are at more risk of progression to cirrhosis when compared to healthy-controls and patients with mild chronic HCV (OR:7.7; 95% CI=2.4-24.3 and OR:5.1, 95% CI= 1.7-15.7, respectively) and also are at more risk of developing HCC when compared to healthy controls (OR:2.6; 95% CI= 0.94-7.3). Polymorphisms affecting NF-κB different genes would modulate HCV infection susceptibility and clinical disease progression among Egyptian patients.

Clustering Methods in Rheumatic and Musculoskeletal Disease Research: An Educational Guide to Best Research Practices.

Clinical manifestations and disease progression often exhibit significant variability among patients with rheumatic diseases, complicating diagnosis and treatment strategies. A better understanding of disease heterogeneity may allow for personalized treatment strategies. Cluster analysis is a class of statistical methods that aims to identify subgroups or patterns within a dataset. Cluster analysis is a type of unsupervised learning, meaning there are no outcomes or labels to guide the analysis (ie, there is no ground truth). This makes it difficult to assess the accuracy or validity of the identified clusters, and these methods therefore require thoughtful planning and careful interpretation. Here, we provide a high-level overview of clustering, including different types of clustering methods and important considerations when undertaking clustering, and review some examples from the rheumatology literature.

Simulating the clinical manifestations and disease progression of human sepsis: A monobacterial injection approach for animal modeling

ABSTRACT Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, with great clinical heterogeneity, high morbidity, and high mortality. At the same time, there are many kinds of infection sources, the pathophysiology is very complex, and the pathogenesis has not been fully elucidated. An ideal animal model of sepsis can accurately simulate clinical sepsis and promote the development of sepsis-related pathogenesis, treatment methods, and prognosis. The existing sepsis model still uses the previous Sepsis 2.0 modelling standard, which has some problems, such as many kinds of infection sources, poor repeatability, inability to take into account single-factor studies, and large differences from clinical sepsis patients. To solve these problems, this study established a new animal model of sepsis. The model uses intravenous tail injection of a single bacterial strain, simplifying the complexity of multibacterial infection, and effectively solving the above problems.

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.

Active and non-active secondary progressive multiple sclerosis patients exhibit similar disability progression: results of an Italian MS registry study (ASPERA)

‘Active’ and ‘non-active’ secondary progressive MS (SPMS) have distinct pathophysiological mechanisms and clinical characteristics, but there is still no consensus regarding the frequency of these MS forms in the real-world setting. We aimed to evaluate the frequency of ‘active’ and ‘non-active’ SPMS in a large cohort of Italian MS patients and the differences in terms of clinical and MRI characteristics and disease progression. This multicenter study collected data about MS patients who have transitioned to the SP form in the period between 1st January 2014 and 31st December 2019 and followed by the MS centers contributing to the Italian MS Registry. Patients were divided into ‘active SPMS’ and ‘non-active SPMS’, based on both reported MRI data and relapse activity in the year before conversion to SPMS. Out of 68,621, 8,316 (12.1%) patients were diagnosed with SPMS. Out of them, 872 (10.5%) were classified into patients with either ‘active’ or ‘non-active’ SPMS. A total of 237 were classified into patients with ‘active SPMS’ (27.2%) and 635 as ‘non-active SPMS’ (72.8%). ‘Non-active SPMS’ patients were older, with a longer disease duration compared to those with ‘active SPMS’. The percentages of patients showing progression independent of relapse activity (PIRA) at 24 months were similar between ‘active’ and ‘non-active’ SPMS patients (67 [27.4%] vs 188 [29.6%]; p = 0.60). In the ‘active’ group, 36 (15.2%) patients showed relapse-associated worsening (RAW). Comparison of the survival curves to EDSS 6 and 7 according to disease activity did not show significant differences (p = 0.68 and p = 0.71). ‘Active’ and ‘non-active’ SPMS patients had a similar risk of achieving disability milestones, suggesting that progression is primarily attributed to PIRA and only to a small extent to disease activity.