Delayed grip relaxation is a common symptom of myotonic dystrophy type 1 (DM1), differing from other muscle diseases. Preclinical studies suggest myotonia may reverse quickly with targeted treatment and video hand opening time (vHOT) could be a straightforward method for assessing myotonia in multicenter trials, but few studies have evaluated vHOT in large DM1 cohorts. This study aimed to evaluate how vHOT performs and relates to other disease aspects in a large, well-characterized DM1 population. The vHOT was conducted in the END-DM1 natural history study across 22 international sites, including adult DM1 patients with a genetic or research criteria diagnosis. The primary outcome involved video-recorded hand opening after a maximum 3-second grip, performed twice at each study visit with 5-minute rest between trials, and blinded scoring at a central site. Muscle strength and function were assessed by myometry, timed functional tests, and patient-reported outcomes. Procedures were repeated after 1 year for a subset of participants. Wilcoxon signed-rank was used to evaluate differences and Spearman correlation for associations. A total of 591 patients with DM1 (mean age 43.7 ± 12.9 years, 57% female) were included, showing a broad spectrum of vHOT severity (median 3.9 seconds, interquartile range 1.8-7.9 seconds). At a single study visit, there were no systematic difference and good agreement between trials (mean difference 0.1 ± 3.7 seconds [p = 0.05], intraclass correlation coefficient 0.84 [95% CI 0.81-0.86]). vHOT correlated relatively weak with self-reported myotonia (ρ = 0.39), and even lower for other measures of muscle impairments such as grip strength (ρ = -0.21) or 9-hole pegboard (ρ = 0.12). 270 patients completed the 1-year follow-up, with vHOT showing no progression (mean difference 0.4 ± 4.7 seconds, p = 0.34). The vHOT procedure was performed successfully in a large international study, with grip relaxation delay varying from minimal to highly prolonged in an unselected cohort. The weak correlation with grip weakness supports the notion that myotonia and weakness are mechanistically distinct. Study limitations include underrepresentation of congenital DM1 and lack of other myotonia measures (e.g., handgrip relaxation myometry). It seems that vHOT is not suitable to assess disease progression, but stability over 1 year may support its use to assess improvement. The END-DM1 observational study is registered with number NCT03981575.

Incidental splenic artery aneurysms: systematic literature review and single-centre study.

Impact of atypical extra-villous trophoblast foci on the natural history and management of post-molar gestational trophoblastic neoplasia.

Corneal staining: Beyond the grade.

The cardiovascular evaluation of candidates for living kidney donation.

IgG4 related coronary artery involvement: A scoping review of the literature.

Diagnosis and management of primary fetal pleural effusion: A narrative review.

Incidental prostate cancer is frequently identified in men undergoing radical cystoprostatectomy for urothelial carcinoma of the bladder. While usually clinically insignificant, its long natural history raises questions about long-term impact as systemic therapies prolong bladder cancer survival. The aim of this study is to describe the natural history, recurrence patterns, and survival outcomes of prostate cancer detected incidentally following radical cystoprostatectomy in a prospective cohort, and to provide a follow-up protocol for these patients. A retrospective cohort study with prospective follow-up of consecutive men undergoing radical cystoprostatectomy with urinary diversion for urothelial carcinoma at a tertiary referral center (1999-2020) was conducted. Follow-up included serial prostate-specific antigen (PSA) testing, imaging, and cause-specific survival. Associations with recurrence and survival were assessed using Cox regression. Incidental prostate cancer was diagnosed in 384 of 940 men (41%). Prostate cancer recurrence was reported in 23 men (6%) at a median of 25mo, most often in bone and lymph nodes. Seven patients died of prostate cancer at a median of 72mo after surgery. Risk factors for recurrence included higher International Society of Urological Pathology grade (hazard ratio [HR] 2.9, 95% confidence interval [CI] 2.2-3.9; p<0.001), locally advanced stage (HR 6.8, 95% CI 4.1-11.2; p<0.001), preoperative PSA (HR 2.3, 95% CI 1.4-3.8; p=0.002), and nodal metastasis (HR 29.3, 95% CI 10.8-79.3; p<0.001), although HR effect estimates were exploratory and based on a limited number of events. Overall survival was determined by bladder cancer stage, comorbidity, and age; prostate cancer features were prognostic only beyond 3yr. Incidental prostate cancer after radical cystoprostatectomy is usually organ confined and of low grade, with a low short-term risk. In long-term survivors with adverse pathological features, incidental prostate cancer represents a clinically non-negligible contributor to cause-specific mortality, despite a low absolute risk at the population level. Selective risk-adapted PSA surveillance should be considered in patients with higher-risk pathology and favorable bladder cancer outcomes following a protocol. We studied men with prostate cancer diagnosed incidentally during bladder cancer surgery. While most cases of prostate cancer were at a low risk and rarely caused early problems, some patients with higher-risk prostate cancer developed metastases or died from the disease later. Careful follow-up for prostate cancer may benefit selected long-term bladder cancer survivors.

Consideration of the natural history of BCL2-positive follicular lymphoma: based on tumor site, histological grade, and histological transformation rate.

Does living in the Andes make cerebral arteriovenous malformations more dangerous? high altitude fails to predict hemorrhage in a large Ecuadorian cohort.

Hepatoid tumors are rare neoplasms that arise outside the liver but exhibit morphological and immunophenotypic features resembling hepatocellular carcinoma. Although hepatoid differentiation sometimes occurs in pancreatic ductal adenocarcinoma, its occurrence in solid pseudopapillary neoplasm (SPN) is exceedingly rare. Consequently, the clinicopathological characteristics and natural history of this variant remain poorly understood. We report a case of a 37-year-old asymptomatic male with a 6mm solid pancreatic body lesion that was incidentally detected during routine abdominal ultrasonography. Multimodal imaging showed a well-circumscribed solid mass showing early-phase hyperenhancement relative to the surrounding pancreatic parenchyma. Tissue samples obtained via endoscopic ultrasonography contained polygonal epithelioid cells with abundant eosinophilic cytoplasm and a hepatoid appearance. In immunohistochemistry, HepPar-1 and CD10 were diffusely positive, chromogranin A and synaptophysin were absent, and β-catenin accumulated within the nucleus, all supporting a diagnosis of SPN with hepatoid differentiation. Although surgical resection was recommended, the patient declined and was subsequently managed with active surveillance. After 5 years of follow-up, the lesion remained morphologically stable without clinical progression. To our knowledge, this case report is the first to describe the long-term natural course of a pancreatic hepatoid SPN managed nonoperatively. The patient's maintained stability supports the indolent biological behavior of this rare variant. Thus, conservative management with close surveillance may be feasible for carefully selected patients with small, asymptomatic tumors. However, additional cases are needed to clarify optimal management strategies.

Vocal fold movement impairment and aspiration risk in children undergoing aerodigestive surgery.

Although current guidelines classify the natural history of chronic hepatitis B (CHB) into several immune phases, a substantial proportion of patients with CHB do not meet criteria for any of the defined immune phases and are considered to be in an indeterminate phase. We aim to perform a meta-analysis to systematically evaluate the prevalence, clinical presentation and outcome of indeterminate CHB patients classified according to American Association for the Study of Liver Diseases (AASLD) 2018 guidelines or European Association for the Study of the Liver (EASL) 2017 guidelines. We searched four databases from inception to Aug 21, 2024, for studies reporting the prevalence, characteristics and/or clinical outcomes of patients with indeterminate CHB classified according to AASLD 2018 guidelines or EASL 2017 guidelines. Of the 4553 studies initially identified, 50 studies met study inclusion criteria and were analysed. The prevalence of indeterminate patients was 38.90% (95% CI: 33.51-44.57) and 38.81% (95% CI: 31.22-46.99) by AASLD 2018 and EASL 2017 guidelines, respectively. Among indeterminate CHB patients, the pooled incidence rate per 1000 person-years for hepatocellular carcinoma and liver-related events was 5.36 (95% CI: 1.38-9.35) and 7.27 (95% CI: 0.00-22.21) per AASLD 2018 guidelines and 5.20 (95% CI: 1.41-8.99) and 9.79 (95% CI: 0.00-25.35) per EASL 2017 guidelines, respectively. Indeterminate phase affects nearly 40% of CHB patients who are at risk for hepatocellular carcinoma and liver-related adverse outcomes. Further research is needed to inform treatment strategies specifically tailored for the indeterminate CHB patients.

This review explores Alzheimer's disease (AD) in individuals with Down syndrome (DS), a genetically defined population with near-universal development of AD neuropathology by age 40. We examine the genetic basis of DS-AD, epidemiology, biomarker trajectories, and clinical trial innovations, highlighting how insights from DS research inform broader AD pathogenesis, early detection, and therapeutic strategies. Advances in biomarker research, including longitudinal studies such as ABC-DS, have mapped predictable trajectories of amyloid, tau, and neurodegeneration in DS-AD, aligning closely with clinical staging. Plasma and CSF biomarkers (Aβ42, p-tau, NfL, GFAP) and neuroimaging modalities (amyloid/tau PET, MRI) demonstrate early and sequential changes decades before dementia onset. Revised AD diagnostic criteria now classify DS individuals as Stage 0 from birth, acknowledging genetic determinism and enabling earlier intervention. Comparative analyses between DS-AD, autosomal-dominant AD, and sporadic AD reveal shared pathological features but distinct timing and distribution of amyloid and tau. Clinical trials targeting amyloid and APP pathways in DS are underway, leveraging predictable disease progression to accelerate therapeutic development. Studying AD in DS provides a unique lens into the natural history of Alzheimer's disease, offering critical insights into genetic drivers, biomarker evolution, and therapeutic opportunities. The genetically defined and biologically concordant nature of DS-AD enables precise staging and early intervention strategies that can be translated to sporadic and familial AD. Continued investment in DS research will advance biomarker validation, refine clinical trial design, and inform personalized treatment approaches for the broader AD population.

Reassessing the prevalence of monophasic, polyphasic and persistent disease courses in still's disease.

Spinal muscular atrophy among US Hutterites: Phenotype variability in the setting of conserved ancestral haplotype and 4 SMN2 copies.

Background: Antisense oligonucleotide tofersen targets SOD1 mRNA and reduces production of misfolded SOD1 protein, with demonstrated biomarker and functional signals in clinical trials and open-label extensions. Real-world reports from genetically heterogeneous SOD1 ALS cohorts describe variable functional trajectories. Data from genetically homogeneous founder populations remain limited. We investigated clinical trajectories in a cohort carrying the same pathogenic SOD1 variant to better characterize mutation-specific patterns in a real-world setting. Methods: We conducted a single-center observational study at the National Referral Center for Neuromuscular Diseases and Clinical Electromyoneurography (UHC Zagreb, Croatia). Eight adults with genetically confirmed SOD1 p.Leu145Phe ALS received intrathecal tofersen according to the approved regimen. ALS Functional Rating Scale–Revised (ALSFRS-R) scores were recorded at each dosing visit, and longitudinal slopes were calculated using linear regression. Safety and tolerability were evaluated descriptively. Biomarker and formal respiratory measurements were not routinely available. Results: All patients exhibited lower limb–onset, predominantly lower motor neuron phenotypes consistent with a slow-progressing founder variant. Median age at symptom onset was 60 years, and median therapeutic delay was 48 months. Median on-treatment ALSFRS-R slope was −0.28 points/month (range +0.04 to −0.57). Two patients demonstrated stable trajectories, while the remainder showed gradual decline. These patterns fall within the slower range reported in heterogeneous real-world SOD1 cohorts and are consistent with the known natural history of this mutation. Tofersen was well tolerated, with no serious treatment-related adverse events. Conclusions: In this genetically homogeneous SOD1 p.Leu145Phe cohort, functional trajectories during tofersen therapy reflected the mutation’s slow-progressing phenotype. These findings provide real-world clinical context but do not permit conclusions regarding treatment efficacy. Further mutation-specific studies incorporating prospective baseline assessment and biomarker monitoring are needed to clarify therapeutic impact.

Adult SMA REACH is a Research and Clinical Hub in the UK that established a collaborative clinical network for Spinal Muscular Atrophy (SMA) in 2020 across 19 clinical sites, patient advocacy groups, regulators, and industry. In recent years, the treatment landscape in the SMA setting has rapidly evolved with Nusinersen and Risdiplam receiving conditional approval via a Managed Access Agreement (MAA) in the UK. Here we describe the structure of a Real-World Data (RWD) collection study implemented to collect standardised outcome measures to inform on the natural history of the disease and the impact of novel treatments. The study also reports data to The National Institute for Health and Care Excellence (NICE) and NHS England (NHSE) for the purpose of the MAA's. The Adult SMA REACH database currently contains data from 466 patients and 2255 visits, with more than 8000 functional outcome measure assessments. Adult SMA REACH provides insights into how real-world data can be used to evaluate treatment outcomes in rare diseases, where conducting randomised controlled trials may be difficult. The registry also offers an infrastructure that supports collaborative research and reduces data silos. In this paper we describe the complexity of establishing such a study and clinical network including considerations for adapting this model to other disease areas. Further information on the Adult SMA REACH data collection study and clinical network can be found on the website (https://adultsmareach.co.uk/) and ClinicalTrials.gov (NCT06978985, https://clinicaltrials.gov/study/NCT06978985).

How does the frequency and location of endometriosis lesions observed at laparoscopy vary with patient age? We find that older patients have more deep lesions and ovarian endometriomas at laparoscopy, although this plateaus around 30 years of age. The natural history and aetiology of endometriosis remain uncertain, with evidence of progression, spontaneous regression, and stable disease in various studies. Cross-sectional analysis of a prospectively collected surgical registry, including data from 104 accredited endometriosis centres across 7 countries, with 14670 cases in total. We analysed data from the British Society for Gynaecological Endoscopy (BSGE) endometriosis centres database, a multicentre international prospective cohort of patients undergoing surgery for deep endometriosis. We included all patients aged 10-55 years from 2009 to 2021. The change in lesion prevalence with age was modelled using three different logistic regression models-non-quadratic, quadratic, and segmented, adjusted for whether they had undergone endometriosis excision in the past. We identified 14670 cases from 104 centres across 7 countries. The mean age at the time of surgery was 35.9 years (SD 7.4). The odds of superficial endometriosis decreased linearly with age by 3% per year (adjusted odds ratio (aOR) 0.97, 95% CI 0.96-0.97, P < 0.001). The following increased before plateauing: bowel endometriosis increased by 7% per year (aOR 1.07, 95% CI 1.05-1.09, P < 0.001) until 32.9 years of age (95% CI 30.5-35.3); deep sidewall disease increased by 7% per year (aOR 1.07, 95% CI 1.05-1.09, P < 0.001) until 31.3 years (95% CI 29.2-33.5); and uterosacral disease increased by 4% per year (aOR 1.04, 95% CI 1.02-1.06, P < 0.001) until 33 years (95% CI 29.3-36.6). Deep bladder disease increased by 12% per year (aOR 1.12, 95% CI 1.04-1.22, P = 0.005) until 28.2 (95% CI 25.8-30.6) years, after which the odds decreased by 2% per year (aOR 0.98, 95% CI 0.97-1.00, P = 0.007). Ovarian endometrioma was best described by a quadratic model, with a starting increase in odds of endometrioma of 20% per year at 10 years (aOR 1.20, 95% CI 1.16-1.23, P < 0.001), and a peak prevalence at 40.9 years of age (95% CI 34.1-47.7, P < 0.001). The total number of sites affected by endometriosis increased by 0.12 sites per year (95% CI 0.10-0.14, P < 0.001) until 32.8 years of age, with no correlation with age after this point. This cross-sectional study only includes patients undergoing excision with pararectal dissection for the treatment of pain, so does not capture patients who do not undergo such surgery, including asymptomatic patients, and cannot provide data on potential disease progression on an individual level. This study supports existing evidence suggesting that older patients with endometriosis have more deep nodules and endometriomas and less superficial disease. No funding was provided for this study. K.V. reports consulting fees from Eli Lilly, Gedeon Richter, Gesynta, and Rickett (all paid to institution); speakers' fees from Gedeon Richter and Reckitt (both paid to institution); membership of the Medical Advisory Panel of Endometriosis UK (unpaid); past presidency of the International Association for the Study of Pain (IASP) Special Interest Group (SIG) on Abdominal and Pelvic Pain (unpaid). N/A.

The natural history of ulcerative colitis is characterized by the occurrence of recurrent flares. Flares in ulcerative colitis may be attributed to the natural history of the disease or other extraneous factors. Two important causes for iatrogenic flares are Clostridioides difficile infection and cytomegalovirus (CMV) colitis. We evaluated the prevalence of Clostridioides difficile infection in patients with moderate to severe ulcerative colitis admitted to a tertiary care hospital. This prospective study carried out at a tertiary care center in India evaluated patients of ulcerative colitis who presented with an acute flare of the disease over a 13-month period from May 2023 to May 2024. An enquiry of antibiotic exposure in the preceding eightweeks prior to the current admission was obtained. Simultaneous testing of glutamate dehydrogenase (GDH) and Clostridioides difficile toxin assay was done in all patients within 24hours of admission by the enzyme-linked immunosorbent assay (ELISA) technique. Of the 140 patients with an acute flare associated with ulcerative colitis who were evaluated for Clostridioides difficile infection, four tested positive for both GDH and toxin A and/or B giving an overall prevalence of 2.9%. Two of these four (50%) patients had prior exposure to antibiotics at the time of admission. Each of the four patients with Clostridioides difficile infection had an uneventful recovery post treatment with oral vancomycin and metronidazole. Our data suggests that C. difficile is not a major causative factor for flares in patients with moderate to severe ulcerative colitis at a tertiary care hospital in northern India.