Variability In Disease Progression Research Articles

Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage

Medulloblastomas with extensive nodularity are cerebellar tumors characterized by two distinct compartments and variable disease progression. The mechanisms governing the balance between proliferation and differentiation in MBEN remain poorly understood. Here, we employ a multi-modal single cell transcriptome analysis to dissect this process. In the internodular compartment, we identify proliferating cerebellar granular neuronal precursor-like malignant cells, along with stromal, vascular, and immune cells. In contrast, the nodular compartment comprises postmitotic, neuronally differentiated malignant cells. Both compartments are connected through an intermediate cell stage resembling actively migrating CGNPs. Notably, we also discover astrocytic-like malignant cells, found in proximity to migrating and differentiated cells at the transition zone between the two compartments. Our study sheds light on the spatial tissue organization and its link to the developmental trajectory, resulting in a more benign tumor phenotype. This integrative approach holds promise to explore intercompartmental interactions in other cancers with varying histology.

The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop.

Objectives: This study combines two innovative mouse models in a major gene discovery project to assess the influence of host genetics on asbestos related disease (ARD). Conventional genetics studies provided evidence that some susceptibility to mesothelioma is genetic. However, the identification of host modifier genes, the roles they may play, and whether they contribute to disease susceptibility remain unknown. Here we report a study designed to rapidly identify genes associated with mesothelioma susceptibility by combining the Collaborative Cross (CC) resource with the well-characterised MexTAg mesothelioma mouse model. Methods: The CC is a powerful mouse resource that harnesses over 90% of common genetic variation in the mouse species, allowing rapid identification of genes mediating complex traits. MexTAg mice rapidly, uniformly, and predictably develop mesothelioma, but only after asbestos exposure. To assess the influence of host genetics on ARD, we crossed 72 genetically distinct CC mouse strains with MexTAg mice and exposed the resulting CC-MexTAg (CCMT) progeny to asbestos and monitored them for traits including overall survival, the time to ARD onset (latency), the time between ARD onset and euthanasia (disease progression) and ascites volume. We identified phenotype-specific modifier genes associated with these traits and we validated the role of human orthologues in asbestos-induced carcinogenesis using human mesothelioma datasets. Results: We generated 72 genetically distinct CCMT strains and exposed their progeny (2,562 in total) to asbestos. Reflecting the genetic diversity of the CC, there was considerable variation in overall survival and disease latency. Surprisingly, however, there was no variation in disease progression, demonstrating that host genetic factors do have a significant influence during disease latency but have a limited role once disease is established. Quantitative trait loci (QTL) affecting ARD survival/latency were identified on chromosomes 6, 12 and X. Of the 97-protein coding candidate modifier genes that spanned these QTL, eight genes (CPED1, ORS1, NDUFA1, HS1BP3, IL13RA1, LSM8, TES and TSPAN12) were found to significantly affect outcome in both CCMT and human mesothelioma datasets. Conclusion: Host genetic factors affect susceptibility to development of asbestos associated disease. However, following mesothelioma establishment, genetic variation in molecular or immunological mechanisms did not affect disease progression. Identification of multiple candidate modifier genes and their human homologues with known associations in other advanced stage or metastatic cancers highlights the complexity of ARD and may provide a pathway to identify novel therapeutic targets.

Prevalence Of Different Stages Of Oral Submucous Fibrosis In India: A Cross Sectional Study

Background: Oral Submucous Fibrosis (OSMF) is a persistent and gradually developing disorder that impacts the mouth and occasionally the throat. It is marked by an inflammatory response just beneath the epithelium and alterations in the fibroelastic components of the lamina propria. These changes result in stiffness of the oral mucosa, limited mouth opening (trismus), and challenges with eating. OSMF is distinguished by its significantly elevated potential to progress into malignancy, compared to other oral lesions with a risk of malignancy, predominantly affecting those of Indian and Southeast Asian descent. The global prevalence rate stands at 2.28% - 8.62%, with a notable gender disparity in occurrence and a malignant transformation rate of 4.2%. Aim: The objective of this research is to evaluate the prevalence and distribution by gender of OSMF stages within a private dental institution, with a particular emphasis on examining the relationship between the frequency of the disease and the occurrence of its stages. Materials and Methods: Over a period of 32 months, a cross-sectional analysis was carried out in the outpatient section of the Department of Oral Medicine and Radiology. After receiving approval from the ethics committee, 337 individuals diagnosed with OSMF were selected for inclusion in the study, with information categorized according to gender and age. Results: The study found a significant male predominance (94%) among the patients, with a mean age of 31-50 years. Stage 2 OSMF was more prevalent among both genders, followed by stage 3 and 1, indicating a specific pattern of disease progression. Discussion: Consistent with previous studies, our research confirmed a male predominance in OSMF occurrence. The age and stage distribution aligns partially with existing literature, suggesting a predominant affliction of individuals in their mid-life. Contrary to Anuna Liala Mathew et al.'s findings, our study observed a higher prevalence of stage 2 OSMF, underscoring potential variations in disease progression or detection practices. Conclusion: OSMF presents a significant public health challenge due to its high malignant transformation potential and association with arecanut and tobacco use. This study highlights the urgent need for public education on the adverse effects of these substances and calls for enhanced awareness and management strategies for OSMF, particularly considering its prevalence and severity among males in the studied population.

Molecular evolution, virology and spatial distribution of HCV genotypes in Pakistan: A meta-analysis

BackgroundHepatitis C, caused by the Hepatitis C Virus (HCV), is the second most common form of viral hepatitis. The geographical distribution of HCV genotypes can be quite complex, making it challenging to ascertain the most prevalent genotype in a specific area. MethodsTo address this, a review was conducted to determine the prevalence of HCV genotypes across various provinces and as a whole in Pakistan. The scientific literature regarding the prevalence, distribution, genotyping, and epidemiology of HCV was gathered from published articles spanning the years 1996–2020. ResultsGenotype 1 accounted for 5.1% of the patients, with its predominant subtype being 1a at 4.38%. The frequencies of its other subtypes, 1b and 1c, were observed to be 1.0% and 0.31% respectively. Genotype 2 had a frequency of 2.66%, with the most widely distributed subtype being 2a at 2.11% of the patients. Its other subtypes, 2b and 2c, had frequencies of 0.17% and 0.36% respectively. The most prevalent genotype among all isolates was 3 (65.35%), with the most frequent subtype being 3a (55.15%), followed by 3b (7.18%). The prevalence of genotypes 4, 5, and 6 were scarce in Pakistan, with frequencies of 0.97%, 0.08%, and 0.32% respectively. The prevalence of untypeable and mixed genotypes was 21.34% and 3.53% respectively. Estimating genotypes proves to be a productive method in assisting with the duration and selection of antiviral treatment. Different HCV genotypes can exhibit variations in their response to specific antiviral treatments. Different genotypes may have distinct natural histories, including variations in disease progression and severity. Some genotypes may lead to more rapid liver damage, while others progress more slowly. ConclusionsThis information can guide screening and testing strategies, helping to identify individuals at higher risk of developing severe complications. Studying the distribution of HCV genotypes in a population can provide valuable insights into the transmission dynamics of the virus.

Incompletely Penetrant Variants Underlie the Familial Variability in Disease Progression in Adults with ADPKD

Incompletely Penetrant Variants Underlie the Familial Variability in Disease Progression in Adults with ADPKD

Muscle fibrosis as a prognostic biomarker in facioscapulohumeral muscular dystrophy: a retrospective cohort study

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant epigenetic disorder with highly variable muscle involvement and disease progression. Ongoing clinical trials, aimed at counteracting muscle degeneration and disease progression in FSHD patients, increase the need for reliable biomarkers. Muscle magnetic resonance imaging (MRI) studies showed that the appearance of STIR-positive (STIR+) lesions in FSHD muscles represents an initial stage of muscle damage, preceding irreversible adipose changes. Our study aimed to investigate fibrosis, a parameter of muscle degeneration undetectable by MRI, in relation to disease activity and progression of FSHD muscles. We histologically evaluated collagen in FSHD1 patients’ (STIR+ n = 27, STIR− n = 28) and healthy volunteers’ (n = 12) muscles by picrosirius red staining. All patients (n = 55) performed muscle MRI before biopsy, 45 patients also after 1 year and 36 patients also after 2 years. Fat content (T1 signal) and oedema/inflammation (STIR signal) were evaluated at baseline and at 1- and 2-year MRI follow-up. STIR+ muscles showed significantly higher collagen compared to both STIR− (p = 0.001) and healthy muscles (p < 0.0001). STIR− muscles showed a higher collagen content compared to healthy muscles (p = 0.0194). FSHD muscles with a worsening in fatty infiltration during 1- (P = 0.007) and 2-year (P < 0.0001) MRI follow-up showed a collagen content of 3.6- and 3.7-fold higher compared to FSHD muscles with no sign of progression. Moreover, the fibrosis was significantly higher in STIR+ muscles who showed a worsening in fatty infiltration in a timeframe of 2 years compared to both STIR− (P = 0.0006) and STIR+ muscles with no sign of progression (P = 0.02). Fibrosis is a sign of muscle degeneration undetectable at MRI never deeply investigated in FSHD patients. Our data show that 23/27 of STIR+ and 12/28 STIR− muscles have a higher amount of collagen deposition compared to healthy muscles. Fibrosis is higher in FSHD muscles with a worsening in fatty infiltration thus suggesting that its evaluation with innovative non-invasive techniques could be a candidate prognostic biomarker for FSHD, to be used to stratify patients and to evaluate the efficacy of therapeutic treatments.

Describing and characterising variability in ALS disease progression

Background, Objectives Decrease in the revised ALS Functional Rating Scale (ALSFRS-R) score is currently the most widely used measure of disease progression. However, it does not sufficiently encompass the heterogeneity of ALS. We describe a measure of variability in ALSFRS-R scores and demonstrate its utility in disease characterization. Methods We used 5030 ALS clinical trial patients from the Pooled Resource Open-Access ALS Clinical Trials database to calculate variability in disease progression employing a novel measure and correlated variability with disease span. We characterized the more and less variable populations and designed a machine learning model that used clinical, laboratory and demographic data to predict class of variability. The model was validated with a holdout clinical trial dataset of 84 ALS patients (NCT00818389). Results Greater variability in disease progression was indicative of longer disease span on the patient-level. The machine learning model was able to predict class of variability with accuracy of 60.1–72.7% across different time periods and yielded a set of predictors based on clinical, laboratory and demographic data. A reduced set of 16 predictors and the holdout dataset yielded similar accuracy. Discussion This measure of variability is a significant determinant of disease span for fast-progressing patients. The predictors identified may shed light on pathophysiology of variability, with greater variability in fast-progressing patients possibly indicative of greater compensatory reinnervation and longer disease span. Increasing variability alongside decreasing rate of disease progression could be a future aim of trials for faster-progressing patients.

Going Off-Script: Dilemmas in the Evaluation and Treatment of Syphilis in Four Patients

Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum. Currently, rates of infection are increasing across all populations worldwide, with disproportionate impact on men who have sex with men, adolescents, and young adults. Syphilis is well-known for its variability in disease progression and clinical presentation, which complicates prompt and accurate diagnosis. Acute care settings have become the frontline in the battle against this syphilis surge, and providers must be prepared to recognize syphilis presentation, initiate appropriate testing, and establish contact tracing for individuals who may have been exposed. The purpose of this manuscript is to serve as a teaching tool for syphilis diagnosis and treatment, and we present four cases that showcase the risks and variable clinical presentation, discussing the challenges involved in managing each case. The authors then summarize key learning points related to diagnosis, treatment, and follow-up.

Oral bemnifosbuvir (AT-527) vs placebo in patients with mild-to-moderate COVID-19 in an outpatient setting (MORNINGSKY).

Aim: This phase III study assessed the efficacy/safety/antiviral activity/pharmacokinetics of bemnifosbuvir, a novel, oral nucleotide analog to treat COVID-19. Patients & methods: Outpatient adults/adolescents with mild-to-moderate COVID-19 were randomized 2:1 to bemnifosbuvir/placebo. Time to symptom alleviation/improvement (primary outcome), risk of hospitalization/death, viral loadand safety were evaluated. Results: Although the study was discontinued prematurely and did not meet its primary end point, bemnifosbuvir treatment resulted in fewer hospitalizations (71% relative risk reduction), COVID-19-related medically attended hospital visits, and COVID-19-related complications compared with placebo. No reduction in viral load was observed. The proportion of patients with adverse events was similar; no deaths occurred. Conclusion: Bemnifosbuvir showed hospitalization reduction in patients with variable disease progression risk and was well tolerated. Clinical Trial Registration: NCT04889040 (ClinicalTrials.gov).

Regulation of MicroRNA Expression in Scleroderma and Idiopathic Pulmonary Fibrosis: A Research Study

Introduction: Scleroderma (SSc) is an autoimmune disorder with the hallmark of fibrosis of the skin, vasculature and internal organs. Patients with SSc and undifferentiated connective tissue disease (UCTD) are susceptible to interstitial lung disease (ILD), leading to decreased lung function and death. Idiopathic pulmonary fibrosis (IPF) is a form of ILD that is not associated with extrapulmonary manifestations. In this study, lung involvement of SSc was studied by observing how disease progression and pathogenesis differ among patients with SSc, UCTD, and ILD compared to healthy controls and patients with IPF. Our group has previously identified disease targets through microRNA sequencing, including the DICER enzyme, which works closely with the protein DGCR8 and the enzyme DROSHA in the RNA interference pathway. The canonical pathway stipulates that DICER processes microRNAs in the cytosol while DGCR8 and DROSHA process microRNAs in the nucleus. DICER, DROSHA, and DGCR8 are hypothesized to contribute to ILD progression. Methods: Human peripheral blood mononuclear cells (PBMCs) were isolated from voluntary participants, including healthy controls. PBMCs were subsequently lysed with subcellular fractionation buffer. Western blotting was done on the resulting cytosolic and nucleic fractions for DICER, DROSHA, and DGCR8 protein expression. The cytosolic fractions were normalized to GAPDH, while the nucleic fractions were normalized to B2M. Nonparametric Kruskal‐Wallis tests were used for statistical analysis. Results: The medians were significantly higher for healthy controls for DICER in the nucleus with a p-value of 0.0302, and DROSHA in the cytosol with a p-value of 0.0406 compared to patients with SSc, UCTD, and IPF. Discussion: Differences in expression were found for DROSHA in the cytosol and DICER in the nucleus, suggesting dysregulation of the non-canonical RNA interference pathways in SSc, UCTD, and IPF patients. Variability of disease progression within the groups could lead to variable enzyme and protein levels within the same disease status. With larger sample sizes, statistically insignificant differences would become significant. Lipid nanoparticle technology could be used to deliver deficient microRNAs to silence mRNA in patients. Conclusion: Due to dysregulation of the RNA interference pathway, microRNAs may be inadequately processed in the patient groups.

The application of metabolomics toward idiopathic pulmonary fibrosis and potential metabolomic value of diverse samples in interstitial lung diseases

AbstractInterstitial lung diseases (ILDs), also known as diffuse lung diseases, pose a significant challenge to the respiratory health of individuals worldwide. Among these conditions, idiopathic pulmonary fibrosis (IPF) is one of the most prevalent, contributing substantially to morbidity and mortality. However, IPF is characterized by high heterogeneity, presenting a substantial obstacle to clinical program development and scientific research due to significant variations in disease progression, treatment response, and prognosis. Recent advances in metabolomics have enabled the identification of specific biochemical pathways and disease biomarkers, offering a beacon of hope for patients afflicted with various diseases. Remarkably, metabolomics has made significant strides in ILDs, particularly in IPF. Metabonomics, a branch of life science, provides an in‐depth analysis of metabolic pathways and the specific biological molecular composition of omics, obtained primarily from biological samples such as serum, plasma, pleural effusion, bronchoalveolar lavage fluid, lung surgical biopsy samples, urine, feces, sputum, and cerebrospinal fluid. In this review, we aim to provide a comprehensive overview of the application of metabolomics in ILDs, with a particular focus on IPF. By summarizing the current state of research in this field, we hope to shed light on the latest advances, challenges, and opportunities that metabolomics can provide in managing ILDs.

Evaluation of advanced imaging biomarkers at kidney failure in patients with ADPKD: a pilot study.

Autosomal dominant polycystic kidney disease (ADPKD) presents with variable disease severity and progression. Advanced imaging biomarkers may provide insights into cystic and non-cystic processes leading to kidney failure in different age groups. This pilot study included 39 ADPKD patients with kidney failure, stratified into three age groups (<46, 46-56, >56 years old). Advanced imaging biomarkers were assessed using an automated instance cyst segmentation tool. The biomarkers were compared with an age- and sex-matched ADPKD cohort in early chronic kidney disease (CKD). Ht-total parenchymal volume correlated negatively with age at kidney failure. The median Ht-total parenchymal volume was significantly lower in patients older than 56 years. Cystic burden was significantly higher at time of kidney failure, especially in patients who reached it before age 46 years. The cyst index at kidney failure was comparable across age groups and Mayo Imaging Classes. Advanced imaging biomarkers showed higher correlation with Ht-total kidney volume in early CKD than at kidney failure. Cyst index and parenchymal index were relatively stable over 5 years prior to kidney failure, whereas Ht-total cyst volume and cyst parenchymal surface area increased significantly. Age-related differences in advanced imaging biomarkers suggest variable pathophysiological mechanisms in ADPKD patients with kidney failure. Further studies are needed to validate the utility of these biomarkers in predicting disease progression and guiding treatment strategies.

Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals

FINCA syndrome [MIM: 618278] is an autosomal recessive multisystem disorder characterized by fibrosis, neurodegeneration and cerebral angiomatosis. To date, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected on at least one allele. Common manifestations included lung or muscle fibrosis, respiratory distress, developmental delay, neuromuscular symptoms and seizures often followed by early death due to rapid disease progression.Here, we present 15 individuals from 12 families with an overlapping phenotype associated with nine novel NHLRC2 variants identified by exome analysis. All patients described here presented with moderate to severe global developmental delay and variable disease progression. Seizures, truncal hypotonia and movement disorders were frequently observed. Notably, we also present the first eight cases in which the recurrent p.(Asp148Tyr) variant was not detected in either homozygous or compound heterozygous state.We cloned and expressed all novel and most previously published non-truncating variants in HEK293-cells. From the results of these functional studies, we propose a potential genotype-phenotype correlation, with a greater reduction in protein expression being associated with a more severe phenotype.Taken together, our findings broaden the known phenotypic and molecular spectrum and emphasize that NHLRC2-related disease should be considered in patients presenting with intellectual disability, movement disorders, neuroregression and epilepsy with or without pulmonary involvement.

MiRNA Signature in CSF From Patients With Primary Progressive Multiple Sclerosis.

Primary progressive multiple sclerosis (PPMS) displays a highly variable disease progression with a characteristic accumulation of disability, what makes difficult its diagnosis and efficient treatment. The identification of microRNAs (miRNAs)-based signature for the early detection in biological fluids could reveal promising biomarkers to provide new insights into defining MS clinical subtypes and potential therapeutic strategies. The objective of this cross-sectional study was to describe PPMS miRNA profiles in CSF and serum samples compared with other neurologic disease individuals (OND) and relapsing-remitting MS (RRMS). First, a screening stage analyzing multiple miRNAs in few samples using OpenArray plates was performed. Second, individual quantitative polymerase chain reactions (qPCRs) were used to validate specific miRNAs in a greater number of samples. A specific profile of dysregulated circulating miRNAs (let-7b-5p and miR-143-3p) was found downregulated in PPMS CSF samples compared with OND. In addition, in serum samples, miR-20a-5p and miR-320b were dysregulated in PPMS against RRMS and OND, miR-26a-5p and miR-485-3p were downregulated in PPMS vs RRMS, and miR-142-5p was upregulated in RRMS compared with OND. We described a 2-miRNA signature in CSF of PPMS individuals and several dysregulated miRNAs in serum from patients with MS, which could be considered valuable candidates to be further studied to unravel their actual role in MS. This study provides Class II evidence that specific miRNA profiles accurately distinguish PPMS from RRMS and other neurologic disorders.

Longitudinal Assessment of Creatine Kinase, Creatine/Creatinineratio, and Myostatin as Monitoring Biomarkers in Becker Muscular Dystrophy.

The slow and variable disease progression of Becker muscular dystrophy (BMD) urges the development of biomarkers to facilitate clinical trials. We explored changes in 3 muscle-enriched biomarkers in serum of patients with BMD over 4-year time and studied associations with disease severity, disease progression, and dystrophin levels in BMD. We quantitatively measured creatine kinase (CK) using the International Federation of Clinical Chemistry reference method, creatine/creatinineratio (Cr/Crn) using liquid chromatography-tandem mass spectrometry, and myostatin with ELISA in serum and assessed functional performance using the North Star Ambulatory Assessment (NSAA), 10-meter run velocity (TMRv), 6-Minute Walking Test (6MWT), and forced vital capacity in a 4-year prospective natural history study. Dystrophin levels were quantified in the tibialis anterior muscle using capillary Western immunoassay. The correlation between biomarkers, age, functional performance, mean annual change, and prediction of concurrent functional performance was analyzed using linear mixed models. Thirty-four patients with 106 visits were included. Eight patients were nonambulant at baseline. Cr/Crn and myostatin were highly patient specific (intraclass correlation coefficient for both = 0.960). Cr/Crn was strongly negatively correlated, whereas myostatin was strongly positively correlated with the NSAA, TMRv, and 6MWT (Cr/Crn rho = -0.869 to -0.801 and myostatin rho = 0.792 to 0.842, all p < 0.001). CK showed a negative association with age (p = 0.0002) but was not associated with patients' performance. Cr/Crn and myostatin correlated moderately with the average annual change of the 6MWT (rho = -0.532 and 0.555, p = 0.02). Dystrophin levels did not correlate with the selected biomarkers nor with performance. Cr/Crn, myostatin, and age could explain up to 75% of the variance of concurrent functional performance of the NSAA, TMRv, and 6MWT. Both Cr/Crn and myostatin could potentially serve as monitoring biomarkers in BMD, as higher Cr/Crn and lower myostatin were associated with lower motor performance and predictive of concurrent functional performance when combined with age. Future studies are needed to more precisely determine the context of use of these biomarkers.

Hepatic fat as a novel marker for high-risk coronary atherosclerotic plaque features in familial hypercholesterolaemia

Background & aimsHepatic steatosis has been associated with increased risk of coronary artery disease. Individuals with familial hypercholesterolaemia have accelerated but variable progression of coronary artery disease. We investigated whether hepatic steatosis is associated with novel coronary atherosclerosis biomarkers in adults with heterozygous familial hypercholesterolaemia, using comprehensive coronary computed tomographic angiography. MethodsWe conducted a cross-sectional study of 213 asymptomatic patients with familial hypercholesterolaemia (median age 54.0 years, 59 % female) who underwent coronary computed tomographic angiography for cardiovascular risk assessment in an outpatient clinic. High-risk plaque features, plaque volume and pericoronary adipose tissue attenuation were assessed. From concurrently captured upper abdominal images, severity of hepatic steatosis was computed, as liver minus spleen computed tomography attenuation and stratified into quartiles. ResultsOf 213 familial hypercholesterolaemia patients, 59 % had coronary artery calcium, 36 % obstructive coronary artery disease (≥50 % stenosis) and 77 % high-risk plaque features. Increasing hepatic steatosis was associated with higher calcium scores, more high-risk plaque features and presence of obstructive coronary artery disease. Hepatic steatosis was associated with the presence of high-risk plaque features (OR: 1.48; 95 % CI: 1.09–2.00; p = 0.01), particularly in the proximal coronary segments (OR: 1.52; 95 % CI: 1.18–1.96; p = 0.001). Associations persisted on multivariable logistic regression analysis adjusting for cardiometabolic factors, obstructive coronary artery disease and calcium score. Hepatic steatosis was associated with higher plaque volumes (Q4: 499 mm3 vs Q1: 414 mm3, p = 0.02), involving mainly low attenuation and noncalcified plaques (both p = 0.03). No differences in pericoronary adipose tissue attenuation were observed. ConclusionsHepatic steatosis is associated with multiple indices of advanced coronary atherosclerosis in familial hypercholesterolaemia patients, particularly high-risk plaque features, independent of conventional cardiovascular risk factors and markers. This may involve specific mechanisms related to hepatic steatosis.Clinical trial number: N/A.

FP.04 Three-year natural history study in Becker muscular dystrophy in The Netherlands

The slow and highly variable disease progression observed in BMD stresses the need to develop outcome measures for clinical trials. We evaluated the responsiveness of different assessments in a cohort of adult BMD patients followed for 3 years. We included 36 genetically confirmed BMD patients (median age at baseline 42.3 years, range 18.6-67.3) of whom 28 were ambulant at baseline (78%). We conducted ambulatory assessments (6WMT, NSAA, 10-meter walk velocity (TMWv), time to rise from floor velocity (TRFv)), PUL1.2 and bilateral maximal voluntary isometric contraction (grip, knee/hip/elbow flexion and extension). The median change and the standard response mean (SRM) at 1- and 3-year follow-up were calculated. Sample sizes (SS) were calculated assuming 50% reduction in disease progression over a 3 year clinical trial with 1:1 randomization. We observed a large variability across all measures, for example the median at baseline for the 6MWT was 439.10m (range 84.30 to 650.00), median change at 1 year follow-up -8.15 (-151.90 to 182.22) and at 3-years -14.50(-151.90 to 158.72). After 1-year follow-up, the SRM was below 0.8 for all considered outcomes. At 3-year follow-up, TMWv and TRFv showed a responsiveness with SRM above 0.8 (1.91, SS 17 and -0.90, SS 79 respectively). Three strength measurements showed SRM >0.8: right elbow flexion (SRM = -1.01, SS 62), left elbow flexion (SRM = -0.85, SS 88) and left hip flexion (SRM = -0.81, SS 96). Of the 29 patients who completed the PUL1.2 at 3rd year follow-up visit, 20 (69%) obtained the maximum score of 74 points. Only one patient lost ambulation during the study. BMD is hallmarked by large inter-individual variability at baseline and follow-up. A relatively stable disease course is common even with 3 years. The ceiling effect of the PUL1.2 illustrates the need for adequate outcome measures in non-ambulant patients.

Two decades of tuberculosis surveillance reveal disease spread, high levels of exposure and mortality and marked variation in disease progression in wild meerkats.

Infections with tuberculosis (TB)-causing agents of the Mycobacterium tuberculosis complex threaten human, livestock and wildlife health globally due to the high capacity to cross trans-species boundaries. Tuberculosis is a cryptic disease characterized by prolonged, sometimes lifelong subclinical infections, complicating disease monitoring. Consequently, our understanding of infection risk, disease progression, and mortality across species affected by TB remains limited. The TB agent Mycobacterium suricattae was first recorded in the late 1990s in a wild population of meerkats inhabiting the Kalahari in South Africa and has since spread considerably, becoming a common cause of meerkat mortality. This offers an opportunity to document the epidemiology of naturally spreading TB in a wild population. Here, we synthesize more than 25 years' worth of TB reporting and social interaction data across 3420 individuals to track disease spread, and quantify rates of TB social exposure, progression, and mortality. We found that most meerkats had been exposed to the pathogen within eight years of first detection in the study area, with exposure reaching up to 95% of the population. Approximately one quarter of exposed individuals progressed to clinical TB stages, followed by physical deterioration and death within a few months. Since emergence, 11.6% of deaths were attributed to TB, although the true toll of TB-related mortality is likely higher. Lastly, we observed marked variation in disease progression among individuals, suggesting inter-individual differences in both TB susceptibility and resistance. Our results highlight that TB prevalence and mortality could be higher than previously reported, particularly in species or populations with complex social group dynamics. Long-term studies, such as the present one, allow us to assess temporal variation in disease prevalence and progression and quantify exposure, which is rarely measured in wildlife. Long-term studies are highly valuable tools to explore disease emergence and ecology and study host-pathogen co-evolutionary dynamics in general, and its impact on social mammals.

The SWC4 subunit of the SWR1 chromatin remodeling complex is involved in varying virulence of Metarhizium brunneum isolates offering role of epigenetic regulation of pathogenicity

ABSTRACT The host – pathogen interaction is a multifactorial process subject to a co-evolutionary arms race consisting of rapid changes in both host and pathogen, controlled at the genetic and epigenetic levels. Previously, we showed intra-species variation in disease progression and pathogenicity in aphids for Metarhizium brunneum isolates MbK and Mb7. Herein, we compared genomic, epigenetic, and metabolomic variations between these isolates and their effects on pathogenicity. Genomic variation could not completely explain the observed differences between the isolates. However, differential N6-adenine methylation (6 mA) and its correlation to reduced expression of the essential SWC4 subunit of SWR1 chromatin-remodelling complex (SWR1-C) led us to hypothesize a role for swc4 in the varying pathogenicity. Mutagenesis of the essential swc4 gene in MbKisolate resulted in reduction of secondary-metabolite (SM) secretion and impaired virulence in Galleria mellonella. Our results suggest the role of SWC4 in the regulation of SMs and the role of both SWC4 and SWR1-C in virulence of M. brunneum isolates. A better understanding of epigenetic regulation of SM production and secretion in entomopathogenic fungi may enable theirmanipulation for better biocontrol performance, and expand possibilities for environmentally friendly pest control.

Clinical Evidence for Variegated Silencing in Patients With Friedreich Ataxia.

Background and ObjectivesFriedreich ataxia (FRDA) is a neurodegenerative disease caused by a GAA triplet repeat (GAA-TR) expansion in intron 1 of the FXN gene. Patients have 100–1,300 GAA triplets compared with less than 30 in healthy controls. The GAA-TR expansion leads to FXN silencing, and consequent frataxin protein deficiency results in progressive ataxia, scoliosis, cardiomyopathy, and diabetes. The overt heterogeneity in age at onset and disease severity is explained partly by the length of the GAA-TR, in which shorter repeats correlate with milder disease. Evidence of variegated silencing in FRDA suggests that patients with shorter repeats retain a significant proportion of cells with FXN genes that have escaped GAA-TR expansion–induced silencing, explaining the less severe frataxin deficiency in this subpopulation. In ex vivo experiments, the proportion of spared cells negatively correlates with GAA-TR length until it plateaus at 500 triplets, an indication that the maximal number of silenced cells has been reached. In this study, we assessed whether an analogous ceiling effect occurs in severity of clinical features of FRDA by analyzing clinical outcome data.MethodsThe FRDA Clinical Outcome Measures Study database was used for a cross-sectional analysis of 1,000 patients with FRDA. Frataxin levels were determined by lateral flow immunoassays.ResultsThe length of the GAA-TR in our cohort predicted frataxin level (R2 = 0.38, p < 0.0001) and age at onset (R2 = 0.46, p < 0.0001) but only with GAA-TRs with ≤700 triplets. Age and disease duration predicted performance on clinical outcome measures, and such predictions in linear regression models statistically improved in the subcohort of patients with >700 GAA triplets. The prevalence of cardiomyopathy and scoliosis increased as GAA-TR length increased up to 700 GAA triplets where prevalence plateaued.DiscussionOur data suggest that there is a ceiling effect on the clinical consequences of GAA-TR length in FRDA, as would be predicted by variegated silencing. Patients with GAA-TRs of >700 triplets represent a subgroup in which the severity of clinical manifestations based on GAA-TR length have reached maximal levels and therefore display limited clinical variability in disease progression.