Variability In Disease Progression Research Articles

Use of Artificial Intelligence to Predict Outcomes in Mild Aortic Valve Stenosis

Abstract Background and Aims Aortic stenosis (AS) is a common and progressive disease which, if left untreated, results in increased morbidity and mortality. Monitoring and follow-up care can be challenging due to significant variability in disease progression. This study aimed to develop machine learning models to predict the risks of disease progression and mortality in patients with mild aortic stenosis. Methods A comprehensive database including 9611 patients with serial transthoracic echocardiograms was collected from a single institution across 3 clinical sites. The dataset included parameters from echocardiograms, electrocardiograms, laboratory values, and diagnosis codes. Data from a single clinical site was preserved as an independent test group. Machine learning models were trained to identify progression to severe stenosis and all-cause mortality and tested in their performance for endpoints at 2 and 5 years. Results In the independent test group, the AS progression model differentiated those with progression to severe AS within 2 and 5 years with an area under the curve (AUC) of 0.86 for both. The feature of greatest importance was aortic valve mean gradient, followed by other valve hemodynamic measurements including valve area and dimensionless index. The mortality model identified those with mortality within 2 years and 5 years with an AUC of 0.84 and 0.87, respectively. Smaller reduced-input validation models had similarly robust findings. Conclusions Machine learning models can be used in patients with mild AS to identify those at high risk for disease progression and mortality. Implementation of such models may facilitate real-time, patient-specific follow-up recommendations.

EZH2 inhibition or genetic ablation suppresses cyst growth in autosomal dominant polycystic kidney disease

BackgroundAutosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent genetic disorder characterized by the formation of renal cysts leading to kidney failure. Despite known genetic underpinnings, the variability in disease progression suggests additional regulatory layers, including epigenetic modifications.MethodsWe utilized various ADPKD models, including Pkd1 and Ezh2 conditional knockout (Pkd1delta/delta:Ezh2delta/delta) mice, to explore the role of Enhancer of Zeste Homolog 2 (EZH2) in cystogenesis. Pharmacological inhibition of EZH2 was performed using GSK126 or EPZ-6438 across multiple models.ResultsEZH2 expression was significantly upregulated in Pkd1−/− cells, Pkd1delta/delta mice, and human ADPKD kidneys. EZH2 inhibition attenuates cyst development in MDCK cells and a mouse embryonic kidney cyst model. Both Ezh2 conditional knockout and GSK126 treatment suppressed renal cyst growth and protected renal function in Pkd1delta/delta mice. Mechanistically, cAMP/PKA/CREB pathway increased EZH2 expression. EZH2 mediated cystogenesis by enhancing methylation and activation of STAT3, promoting cell cycle through p21 suppression, and stimulating non-phosphorylated β-catenin in Wnt signaling pathway. Additionally, EZH2 enhanced ferroptosis by inhibiting SLC7A11 and GPX4 in ADPKD.ConclusionOur findings elucidate the pivotal role of EZH2 in promoting renal cyst growth through epigenetic mechanisms and suggest that EZH2 inhibition or ablation may serve as a novel therapeutic approach for managing ADPKD.

Comparative pathogenesis of Ethiopia/Habru/2014 Lineage-IV peste des petits ruminants virus in goats and cattle

BackgroundPeste des Petits Ruminants (PPR) is a highly contagious viral disease primarily affecting goats and sheep, with clinical manifestations ranging from peracute disease to subclinical infection, particularly in atypical hosts such as cattle. The role of atypical hosts such as cattle to the spread of PPR remains controversial, with conflicting reports in the literature. Despite its worldwide significance, considerable knowledge gaps exist regarding the pathogenesis and clinical progression in both primary and atypical hosts. This study aimed to elucidate the tissue tropism, pathogenesis, virus shedding, clinical progression, and pathology associated with experimental PPR virus infection in indigenous goats and cattle. To this end, 32 animals—16 goats and 16 cattle—were intranasally inoculated with the Ethiopia/Habru/2014 Lineage-IV strain of the PPR virus followed by detailed clinical evaluations and systematic sampling at pre-established intervals to assess serological conversion, viral shedding, and the pathogenesis of the infection across both species.ResultsThe results show that goats exhibited typical clinical signs 4 days post-inoculation, with seroconversion by day 6 and early detection of viral RNA in swabs and tissues by day 3 and virus isolation starting day 4. In contrast, cattle exhibited minimal clinical signs, with seroconversion occurring at day 8 with viral RNA detected in tissue samples at day 4 and virus isolation starting day 6 in tissues and in a single nasal swab at day 8. Clinical scores and tissue positivity rates significantly differed between goats and cattle (P = 0.007 and P < 0.001, respectively). While goats exhibited expected gross and histopathological lesions, cattle showed only nonspecific lesions.ConclusionsTogether, our findings highlight the importance of comparative pathology studies for better understanding virus dynamics and transmission pathways that may help inform more effective PPR control programs. Future research should explore the pathogenesis of different PPRV lineages in cattle, assessing variations in disease progression and potential for epidemiological impact.

Impact of Disease Burden of Patients with Psoriasis on Biologic Therapy Switching: Real-World Evidence from the CorEvitas Psoriasis Registry.

Due to variable psoriasis symptoms, disease progression, and individual responses to therapy, patients may start, stop, or switch biologic therapies. Real-world data on the associated disease burden of patients with psoriasis who do and do not switch biologics are incomplete. This study compared disease burden among patients from the CorEvitas Psoriasis Registry (July 2017-December 2021) who switched biologics and those who did not within 4-12months following initiation. Disease-related patient-reported outcomes (PROs) were recorded, including skin pain, itching, activity impairment, and effects on health-related quality of life (HRQoL). Disease severity was measured by body surface area (BSA) and Psoriasis Area and Severity Index (PASI). Unadjusted and adjusted regression models were used to compare study outcome measures between the two groups. This study included 2145 patients, with 159 classified as switchers and 1986 as non-switchers. The most common reason for switching therapy was failure to maintain initial response (51.7%; n = 78). Moderate-to-severe disease (BSA ≥ 3) was found among 83.0% (n = 132) of switchers versus 26.1% (n = 516) of non-switchers. PASI > 5 was reported among 49.7% (n = 79) of switchers versus 8.6% (n = 171) of non-switchers. Differences in skin pain, itching, and effects on HRQoL between switchers and non-switchers were larger in magnitude for bio-experienced patients. Patients who switched biologic therapy experienced a greater disease burden of psoriasis across PROs than non-switchers. Patient-centered factors may be important drivers of biologic switching. Our findings suggest the association between switching and disease burden may be stronger among patients with prior biologic therapy experience.

Comprehensive four-year disease progression assessment of myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is a heterogeneous neuromuscular disorder characterized by progressive muscle weakness and myotonia. This study investigates the progression of muscular strength and function over a four-year period. Patients with DM1 were examined at baseline and four years later. The following metrics were assessed over time: muscle strength (Medical Research Council-sumscore), hand-grip strength (Martin-Vigorimeter), hand-grip relaxation time (myotonia), and limitations in activities of daily living and (DM1ActivC questionnaire). A total of 648 patients entered the registry. Recruitment and follow-up is ongoing. In our manuscript, we focus on, 187 patients who were followed for 4 years. A significant decline in MRC sum score was observed, with distal muscles showing more deterioration. Hand-grip strength decreased significantly, with notable differences between sex and phenotype classified by disease onset. Surprisingly, an improvement of myotonia was observed. Follow-up analysis revealed a significant interaction between myotonia and grip-strength over time. Thus, the improvement in myotonia is likely explained by decreased in grip strength. Finally, there was a significant reduction in DM1ActivC score, indicating decreased activity and social participation. This study demonstrated variability in disease progression depending on sex, phenotype and disease status. This research demonstrates a nuanced pattern of disease progression, highlighting the need to combine different outcome measures to fully understand the complexity of DM1.

Temporal Pattern Analysis of Ultrasound Surveillance Data in Vascular Connective Tissue Disorders.

Ehlers-Danlos syndrome (EDS), Marfan syndrome (MFS), and Loeys-Dietz syndrome (LDS) are connective tissue disorders frequently associated with vascular aneurysm formation, dissections, and subsequent major complications. Regular imaging surveillance is recommended for these conditions. However, no guidelines currently exist regarding imaging modality or surveillance intervals. This retrospective single-center observational study analyzed clinical and imaging data of patients attending an outpatient clinic for vascular connective tissue disorders between August 2008 and January 2024. Imaging (1424 data points in total) and clinical data were extracted from electronic health records. Analysis primarily included a comparison of vessel diameter progression across imaging modalities, with an additional review of the clinical history of vascular events. In total, 19 patients with vascular connective tissue disorders (vCTDs) underwent consultations at our outpatient clinic. Nine (47.4%) patients experienced vascular events, while two (10.5%) passed away during the study period. Multimodal imaging surveillance revealed a tendency towards arterial diameter increase. Consistent ultrasound monitoring provided more reliable diameter progression data for the same arterial segment than a combination of imaging modalities. Temporal analysis indicated a tendency for the continuous growth of the abdominal aorta, the common and internal carotid artery, and the common femoral and popliteal artery. The study highlights the importance of standardized, modality-specific imaging protocols in monitoring patients with vCTDs. The variability in disease progression among these patients further complicates surveillance strategies, contemplating the need for individualized approaches. Further research and prospective multicenter studies are required to refine and improve monitoring protocols.

Retinal vascular reactivity in carriers of X-linked inherited retinal disease - a study using optical coherence tomography angiography.

Female carriers of X-linked inherited retinal diseases (IRDs) can show highly variable phenotypes and disease progression. Vascular reactivity, a potential disease biomarker, has not been investigated in female IRD carriers. In this study, functional optical coherence tomography angiography (OCT-A) was used to dynamically assess the retinal microvasculature of X-linked IRD carriers. Genetically confirmed female carriers of IRDs (choroideremia or X-linked retinitis pigmentosa), and healthy women were recruited. Macular angiograms (3x3mm, Zeiss Plex Elite 9000) were obtained in 36 eyes of 15 X-linked IRD female carriers and 21 age-matched control women. Two tests were applied to test vascular reactivity: (i) mild hypoxia and (ii) handgrip test, to induce a vasodilatory or vasoconstrictive response, respectively. Changes to vessel density (VD) and vessel length density (VLD) were independently evaluated during each of the tests for both the superficial and deep capillary plexuses. In the control group, the superficial and deep VD decreased during the handgrip test (p<0.001 and p=0.037, respectively). Mean superficial VLD also decreased during the handgrip test (p=0.025), while the deep plexus did not change significantly (p=0.108). During hypoxia, VD and VLD increased in the deep plexus (p=0.027 and p=0.052, respectively) but not in the superficial plexus. In carriers, the physiologic vascular responses seen in controls were not observed in either plexus during either test, with no difference in VD or VLD noted (all p>0.05). Functional OCT-A is a useful tool to assess dynamic retinal microvascular changes. Subclinical impairment of the physiological vascular responses seen in carriers of X-linked IRDs may serve as a valuable clinical biomarker.

Demographic factors associated with within-individual variability of lung function for adults with cystic fibrosis: A UK registry study

Background: Lung function is a key outcome used in the evaluation of disease progression in cystic fibrosis. The variability of individual lung function measurements over time (within-individual variability) has been shown to predict subsequent lung function changes. Nevertheless, the association between within-individual lung function variability and demographic and genetic covariates has not been quantified.Methods: We performed a longitudinal analysis of data from a cohort of 7099 adults with cystic fibrosis (between 18 and 49 years old) from the UK cystic fibrosis registry, containing annual review data between 1996 and 2020. A mixed-effects location-scale model is used to quantify mean FEV1 (forced expiratory volume in 1 s) trajectories and FEV1 within-individual variability as a function of sex, age at annual review, diagnosis after first year of life, homozygous F508 genotype and birth cohort.Results: Mean FEV1 decreased with age and lung function variability showed a near-quadratic trend by age. Males showed higher FEV1 mean and variability than females across the whole age range. Earlier diagnosis and homozygous F508 genotype were also associated with higher FEV1 mean and variability. Individuals who died during follow-up showed on average higher lung function variability than those who survived.Conclusions: Key variables known to be linked with mean lung function in cystic fibrosis are also associated with an individual’s lung function variability. This work opens new avenues to understand the role played by lung function variability in disease progression and its utility in predicting key outcomes such as mortality.

Artificial intelligence and personalized diagnostics in periodontology: A narrative review.

Periodontal diseases pose a significant global health burden, requiring early detection and personalized treatment approaches. Traditional diagnostic approaches in periodontology often rely on a "one size fits all" approach, which may overlook the unique variations in disease progression and response to treatment among individuals. This narrative review explores the role of artificial intelligence (AI) and personalized diagnostics in periodontology, emphasizing the potential for tailored diagnostic strategies to enhance precision medicine in periodontal care. The review begins by elucidating the limitations of conventional diagnostic techniques. Subsequently, it delves into the application of AI models in analyzing diverse data sets, such as clinical records, imaging, and molecular information, and its role in periodontal training. Furthermore, the review also discusses the role of research community and policymakers in integrating personalized diagnostics in periodontal care. Challenges and ethical considerations associated with adopting AI-based personalized diagnostic tools are also explored, emphasizing the need for transparent algorithms, data safety and privacy, ongoing multidisciplinary collaboration, and patient involvement. In conclusion, this narrative review underscores the transformative potential of AI in advancing periodontal diagnostics toward a personalized paradigm, and their integration into clinical practice holds the promise of ushering in a new era of precision medicine for periodontal care.

The natural history of progressive myoclonus ataxia

Progressive myoclonus ataxia (PMA) is a rare clinical syndrome characterized by the presence of progressive myoclonus and ataxia, and can be accompanied by mild cognitive impairment and infrequent epileptic seizures. This is the first study to describe the natural history of PMA and identify clinical, electrophysiological, and genetic features explaining the variability in disease progression.A Dutch cohort of consecutive patients meeting the criteria of the refined definition of PMA was included. The current phenotype was assessed during in-person consultation by movement disorders experts, and retrospective data was collected to describe disease presentation and progression, including brain imaging and therapy efficacy. Extensive genetic and electrophysiological tests were performed. The presence of cortical hyperexcitability was determined, by either the identification of a cortical correlate of myoclonic jerks with simultaneous electromyography-electroencephalography or a giant somatosensory evoked potential.We included 34 patients with PMA with a median disease duration of 15 years and a clear progressive course in most patients (76%). A molecular etiology was identified in 82% patients: ATM, CAMTA1, DHDDS, EBF3, GOSR2, ITPR1, KCNC3, NUS1, POLR1A, PRKCG, SEMA6B, SPTBN2, TPP1, ZMYND11, and a 12p13.32 deletion. The natural history is a rather homogenous onset of ataxia in the first two years of life followed by myoclonus in the first 5 years of life. Main accompanying neurological dysfunctions included cognitive impairment (62%), epilepsy (38%), autism spectrum disorder (27%), and behavioral problems (18%). Disease progression showed large variability ranging from an epilepsy free PMA phenotype (62%) to evolution towards a progressive myoclonus epilepsy (PME) phenotype (18%): the existence of a PMA-PME spectrum. Cortical hyperexcitability could be tested in 17 patients, and was present in 11 patients and supported cortical myoclonus. Interestingly, post-hoc analysis showed that an absence of cortical hyperexcitability, suggesting non-cortical myoclonus, was associated with the PMA-end of the spectrum with no epilepsy and milder myoclonus, independent of disease duration. An association between the underlying genetic defects and progression on the PMA-PME spectrum was observed.By describing the natural history of the largest cohort of published patients with PMA so far, we see a homogeneous onset with variable disease progression, in which phenotypic evolution to PME occurs in the minority. Genetic and electrophysiological features may be of prognostic value, especially the determination of cortical hyperexcitability. Furthermore, the identification of cortical and non-cortical myoclonus in PMA helps us gain insight in the underlying pathophysiology of myoclonus.

Ultrasonographic Insights into Peripheral Psoriatic Arthritis: Updates in Diagnosis and Monitoring.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis, characterized by heterogeneous clinical manifestations and variable disease progression. Ultrasonography has emerged as a valuable tool in the diagnosis and monitoring of PsA, providing real-time visualization of joint and soft tissue abnormalities. This review highlights recent advancements in ultrasonographic techniques for the assessment of PsA, including the identification of typical features, the role of power Doppler imaging in detecting active inflammation, and the potential of ultrasound for guiding treatment decisions. Additionally, we discuss the utility of ultrasound in assessing treatment response and monitoring disease progression in patients with PsA, with a focus on novel imaging modalities. By elucidating the evolving role of ultrasonography in PsA management, this article aims to enhance clinicians' understanding of its utility in facilitating early diagnosis, optimizing treatment strategies, and improving patient outcomes.

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).