Natural History Research Articles

Treatments Used Among Patients with Psoriasis: A First Look at a New Patient-Centered Psoriasis Registry

Introduction: Psoriasis management in the US has changed substantially, with increasing treatment options including new topical, oral, and biologic medications. The objective of this study was to examine the demographics, disease characteristics, and treatment usage in the first patients enrolled in the new patient-centered psoriasis registry, the FORWARD Psoriasis Registry. Methods: Adult patients with psoriasis were recruited from dermatology offices as part of a national practice group, through a patient support program for deucravacitinib, and online from the FORWARD registry website between August and December 2023. Patients were not required to be on therapy for psoriasis. We descriptively report demographics, disease characteristics, and current treatments at enrollment. Results: A total of 702 patients met inclusion criteria and completed the full enrollment questionnaire. Mean age was 53 years and 66% were female; mean BMI was 30 (SD 7); 88% self-reported as White and 6% as Hispanic. A diagnosis of psoriatic arthritis was reported by 28%. Most (75%) had private insurance. Median psoriasis duration was 10 (IQR 3–23) years. 85% had plaque psoriasis, 19% guttate, 14% inverse, 6% generalized pustular, and 3% erythrodermic. Body surface area as assessed by the PREPI questionnaire was minimal (<1% BSA) in 21%, mild (1%–2%) in 39%, moderate (3%–10%) in 34%, and severe (>10%) in 6%. The most commonly used therapies included IL-23 inhibitors (11%), IL-17 inhibitors (8%), apremilast (7%), and TNF inhibitors (5%). Additionally, 14% of the cohort were using deucravacitinib; 62% reported using topicals, and 48% reported use of any systemic agent.Conclusion: The FORWARD psoriasis registry represents a new patient-centered approach and proof of concept for studies seeking to understand the natural history of the disease, treatment outcomes, and treatment needs relevant for individuals with psoriasis, and long-term outcomes related to comorbidities.

Feeding ecology of two wild sympatric canids in protected areas of northeastern Argentina

AbstractThe role of mesocarnivores in wildlife communities tends to be overlooked, which has led to a large gap in natural history knowledge. In northeastern Argentina, two mesocarnivore foxes, Cerdocyon thous and Lycalopex gymnocercus, live in sympatry in noncompetitive coexistence. Their feeding habits have been studied in many occasions; however, the studies related to trophic variability in a wider spatial scale remain scarce. In this study, we aimed to analyze how the diet of these foxes varies in three protected areas in Argentina: the Mburucuyá National Park (MNP), the “San Nicolás Portal” (SN), and the Natural Reserve Rincón de Santa María (RSM). We collected fecal samples in each area, identified them using thin layer chromatography at species level, and classified the found feeding items to obtained two parameters: occurrence and relative frequency. Furthermore, we compared the diet of the two species in each site and between sites using chi‐square and estimated trophic niche breadth and overlap between the species. We found that both species consumed different food categories, with variable frequencies across study sites. We observed that in each area, the foxes differed in diet composition. However, we found no differences between the diet compositions of C. thous and L. gymnocercus, showing high niche overlap in each site. Here, we show the plasticity of both fox species in changing their diets even with small geographical variation. Both species can coexist even with a high diet overlap, possibly explained by their noncompetitive coexistence which may occur due to the current changes in the ecosystem interactions, or partitioning may exist but on a smaller niche level.

Dorsal Column Spinal Cord Stimulation Attenuates Brain-Spine Connectivity through Locomotion and Visuospatial-Specific Area Activation in Progressive Freezing of Gait

Introduction: Freezing of gait (FOG) is a clinical phenomenon with major life impairments and significant reduction in quality of life for affected patients. FOG is a feature of Parkinson’s Disease and a hallmark of primary progressive freezing of gait (PPGF), currently reclassified as Progressive Supranuclear Palsy-progressive gait freezing (PSP-PGF). The pathophysiology of FOG and particularly PGF, which is a rare degenerative disorder with a progressive natural history of gait decline, are poorly understood. Mechanistically, changes in oscillatory activity and synchronization in frontal cortical regions, the basal ganglia, and the midbrain locomotor region have been reported, indicating that dysrhythmic oscillations and coherence could play a causal role in the pathophysiology of FOG. DBS and SCS have been tested as therapeutic neuromodulation avenues for FOG with mixed outcomes. Methods: We analyzed gait and balance in three patients with PSP-PGF who received percutaneous thoracic spinal cord stimulation (SCS) and utilized magnetoencephalography (MEG), electroencephalography (EEG), and electromyography (EMG) to evaluate functional connectivity between the brain and spine. Results: Gait and balance did not worsen over a 13-month period. This observation was accompanied by decreased beta-band spectral power in the whole brain and particularly in the basal ganglia. This was accompanied by increased functional connectivity in and between the sensorimotor cortices, basal ganglia, temporal cortex, and cerebellum, and a surge in corticomuscular coherence when SCS was paired with visual cues Conclusion: Our results suggest synergistic activity between brain and spinal circuits upon SCS for FOG in PGF, which may have implications for future brain-spine interfaces and closed-loop neuromodulation for patients with FOG.

A hairy giant among dwarves: Trichopelma grande, a distinct new species of tarantula from Cuba (Araneae: Theraphosidae)

ABSTRACT Large size, tropical climate, topographic complexity, and millions of years of isolation have turned the Greater Antillean islands into natural laboratories of evolution. Several groups have experienced explosive diversification across these islands, leading to highly diverse and endemic biotas and species experiencing unique adaptations. Here we describe a new tarantula species from the Viñales area, a biodiversity hotspot in western Cuba. Despite being a middle-sized species with large projected setae on the legs, reminiscent of those in arboreal tarantulas, phylogenomic analysis, diagnostic morphological features, and trap-door retreat building behaviour identifies it as the largest known representative of Trichopelma, and the only one with such hirsute legs. We provide mitochondrial barcoding data and a database of ultraconserved elements loci of the holotype of this species, which will help to include it in future phylogenetic studies of Theraphosidae. Given its limited distribution range, and its apparent absence in natural history collections despite its distinct appearance, this species might be scarce, positioning it as a potential conservation concern. http://www.zoobank.org/urn:lsid:zoobank.org:pub:2F9ED7A1-1345-4295-A876-6B617ABF7C75

Cervical intraepithelial neoplasia and cervical cytology in pregnancy

Cervical cancer screening during pregnancy presents unique challenges for cytologic interpretation. This review focuses on pregnancy-associated cytomorphological changes and their impact on diagnosis of cervical intraepithelial neoplasia (CIN) and cervical cancer. Pregnancy-induced alterations include navicular cells, hyperplastic endocervical cells, immature metaplastic cells, and occasional decidual cells or trophoblasts. These changes can mimic abnormalities such as koilocytosis, adenocarcinoma in situ, and high-grade squamous intraepithelial lesions, potentially leading to misdiagnosis. Careful attention to nuclear features and awareness of pregnancy-related changes are crucial for correct interpretation. The natural history of CIN during pregnancy shows higher regression rates, particularly for CIN 2, with minimal risk of progression. Management of abnormal cytology follows modified risk-based guidelines to avoid invasive procedures, with treatment typically deferred until postpartum. The findings reported in this review emphasize the importance of considering pregnancy status in cytological interpretation, highlight potential problems, and provide guidance on differentiating benign pregnancy-related changes from true abnormalities. Understanding these nuances is essential for accurate diagnosis and proper management of cervical abnormalities in pregnant women.

The natural history of Amblyomma maculatum sensu lato, a vector of Rickettsia parkeri rickettsiosis, in southern Arizona.

Amblyomma maculatum sensu lato (s.l.) is an ixodid tick found in the semi-arid southwestern United States and northern Mexico where it is a parasite of medical and veterinary significance, including as a vector for Rickettsia parkeri, a cause of spotted fever rickettsiosis in the Americas. To describe the comprehensive natural history of this tick, monthly small mammal trapping and avian mist netting sessions were conducted at sites in Cochise County Arizona, within the Madrean Archipelago region where human cases of R. parkeri rickettsiosis and adult stages of A. maculatum s.l. were previously documented. A total of 1949 larvae and nymphs were removed from nine taxonomic groups of rodents and ten species of birds and were used in combination with records for adult stages collected both from vegetation and hunter-harvested animals to model seasonal activity patterns. A univoltine phenology was observed, initiated by the onset of the annual North American monsoon and ceasing during the hot, dry conditions preceding the following monsoon season. Cotton rats (Sigmodon spp.) were significantly more likely to be infested than other rodent taxa and carried the highest tick loads, reflecting a mutual affinity of host and ectoparasite for microhabitats dominated by grass.

Macrophage Activation Syndrome in MIS-C.

Multisystem inflammatory syndrome (MIS-C) represents a diagnostic challenge because of its overlap with Kawasaki disease, Kawasaki disease shock syndrome, and toxic shock syndrome. Macrophage activation syndrome (MAS) is a frequently fatal complication of various pediatric inflammatory disorders and has been reported in MIS-C. Early diagnosis and prompt initiation by immune modulating therapies are essential for effectively managing MAS. We conducted a retrospective study to determine the frequency, natural history, diagnostic metrics, treatment, and outcome of MAS in MIS-C within a large cohort of patients across 84 Latin American centers in 16 countries. We compared the clinical and laboratory characteristics between patients with and without MAS. Among 1238 patients with MIS-C, 212 (17.1%) fulfilled MAS criteria. Gastrointestinal and neurologic manifestations were more frequent in cases where MIS-C was complicated by MAS. Patients presenting with MIS-C complicated by MAS had a mortality rate of 12%, which was higher than those without it. Mortality was associated with MAS, seizures, arthritis, and shock. A ferritin or erythrocyte sedimentation rate ratio of >18.7 exhibited a sensitivity of 88.2% and a specificity of 75% in diagnosing MAS in MIS-C. MAS in MIS-C patients is associated with increased morbidity and mortality rates in the largest MIS-C Latin American cohort. Early recognition and appropriate management are crucial in improving patient outcomes and reducing mortality rates.

Patient-Reported Outcomes in RLBP1 Retinal Dystrophy: Longitudinal Assessment in a Prospective Natural History Study.

To evaluate the performance of two non-disease-specific patient-reported outcome (PRO) instruments, the National Eye Institute Visual Function Questionnaire-25 (VFQ-25) and the Low Luminance Questionnaire (LLQ), in patients with retinaldehyde-binding protein 1 retinal dystrophy (RLBP1 RD). PROs were assessed using the VFQ-25 and LLQ. Rasch analysis was conducted to estimate person and item measures of the VFQ-25 and LLQ questionnaires to determine the association between the two PROs. In addition, the association between these two instruments and their correlations to weighted measures of visual function and disease progression were analyzed in this three-year PRO-focused sub-study of a five-year prospective natural history study. Forty-two patients participated, with most of them having completed at least two PRO follow-up visits at least one year apart. The mean VFQ-25 scores were lowest for distance activities (39.2-49.0) and peripheral vision (37.5-52.4), with mean LLQ subscale scores generally low (<41), except for the emotional distress subscale. Using Rasch analysis, calibrated item and person measures along with their standard errors were estimated for both ePROs. This indicated that the distribution of the VFQ-25 and LLQ item measures well covered the distribution of person function in this group. This suggests that the item difficulties well cover the person-level performance in this population. As well, the two PROs showed a strong and significant correlation at all assessed time points as assessed with Pearson correlation coefficient (0.81, 0.91, 0.81 and 0.87 at baseline, 1/1.5, 2/2.5 (P < 0.001) and 3/3.5 years (P = 0.002)). The composite scores of both PRO questionnaires strongly correlated with clinical measures of visual function. At 2 to 2.5 years of follow-up, meaningful statistically significant declines in peripheral vision (both VFQ-25 and LLQ), distance vision (VFQ-25), and extreme lighting in dark and bright light (LLQ) subscales were noted. This study demonstrated a strong association between VFQ-25 and LLQ scores and their association with clinical measures of visual function. PRO instruments can provide insights into the specific disabilities of this unique patient population and help to guide appropriate outcome measures for future clinical trials.

Clinicopathologic, Proteomic and Outcome Characteristics of Renal Apolipoprotein C-II Amyloidosis: A Case Series.

Amyloidosis derived from apolipoprotein C-II (AApoCII) is a recently discovered, rare form of amyloidosis. Data on clinical presentations and natural history are very limited. This study defines the clinicopathologic, proteomic and outcome characteristics of renal AApoCII. Case series. Twenty-five renal AApoCII cases were identified from the Mayo Clinic Tissue Proteomics Laboratory archives from January 2008 through January 2024. All patients were White, 19 were ≥65 years old at diagnosis, and 18 were female. Seven had a family history of CKD. Patients presented with proteinuria (median 3.3 g/day) and reduced kidney function (n=16, median creatinine 1.6 mg/dl). No patient had clinical evidence of other organ involvement by amyloidosis or features of monogenic hypertriglyceridemia. Histologically, amyloid deposits were often weakly positive for Congo red and involved glomeruli in all cases (with a nodular pattern in 22), whereas extraglomerular involvement was less common and generally mild. Proteomic analysis revealed abundant spectra for Apo C-II and for all 3 amyloid signature proteins (Apo E, Apo A-IV and SAP) in all cases, and detected an Apo C-II variant in 14 (K19T [p.Lys41Thr] in 12 and E47V [p.Glu69Val] in 2). Among 22 patients with follow-up available, there were 12 ESKD events and 2 deaths without ESKD during an average (SE) follow up of 75.5 (12.5) months. Retrospective design, small sample size, APOC2 gene sequencing performed in a smaller subset. AApoCII mostly affects the kidney, and manifests in the elderly with proteinuria and CKD. A minority of these patients had a family history of kidney disease. Kidney failure occurred in about half, whereas overall survival was more favorable.

Retinopathy in Mucopolysaccharidoses.

To determine the pattern(s) of onset, variation, and progression of retinopathy in patients with Mucopolysaccharidosis (MPS). Prospective, longitudinal, observational study. Between November 2015 and March 2023, individuals with MPS were recruited from Ophthalmology clinics at the Manchester Royal Eye Hospital, United Kingdom. Participants underwent assessment of visual acuity, corneal clouding, intraocular pressure, along with fundoscopy, ultra-widefield (UWF) colour fundus photography, fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT), and electroretinography (ERG), where feasible. Evaluation of findings from clinical examination, retinal imaging, and electroretinogram studies, to ascertain the presence and patterns of retinopathy. Data was collected for 75 patients, including 45 MPS I, 9 MPS II, 13 MPS IVA, and 8 MPS VI, aged 3-58 years. Fundus photography was conducted in 65 patients, FAF in 61, OCT in 58, and electrodiagnostic studies in 36 participants. Retinopathy was defined as signs of retinal disease evident through retinal examination or fundus photography such as depigmentation, bone-spicule pigmentation, vascular tortuosity, retinal pigment epithelium (RPE) mottling/other changes, macular atrophy/puckering/epiretinal membranes, FAF findings such as a central hyperautofluorescent dot, hyperautofluorescent parafoveal ring, hypoautofluorescent lesions around fovea (double bull's eye), areas of hyper/hypoautofluorescence, and extrafoveal changes, OCT imaging features such as central external limiting membrane (ELM) thickening, RPE disturbance, photoreceptor layer loss, parafoveal retinal atrophy, and outer retinal/intrachoroidal cavities, or electroretinogram studies revealing rod-mediated retinopathy or rod-cone dystrophy. Retinopathy was confirmed in 32 patients, including 25 MPS I, 4 MPS II, 1 MPS IVA, and 2 MPS VI. Five participants were first diagnosed with retinopathy with clinical examination, while 31 participants were identified on UWF colour fundus photography supported by FAF and OCT. 21 patients exhibited ERG abnormalities consistent with retinopathy. Fifteen of the total 32 participants described symptoms of nyctalopia. The onset of retinopathy varied substantially, with initial detection between 2 and 53 years of age. MPS patients as young as 2 may develop retinopathy, diagnosed through fundus examination, ophthalmic imaging, or ERG. Emerging treatments, including gene therapy, may prevent or stabilise retinopathy. Phenotypic data and natural history of MPS-related retinopathy are thus of paramount importance.

Two new Gastroptychia Kobelt &amp; Möllendorff, 1900 from Darjeeling and West Khasi Hills, northeastern India (Gastropoda: Cyclophoroidea: Diplommatinidae)

Two new species, namely Gastroptychia geoffreyi sp. nov. and Gastroptychia collicola sp. nov., are described respectively from Darjeeling and West Khasi Hills, northeastern India based on historical collections at the Natural History Museum, London. Gastroptychia collicola sp. nov. is distinguished from sympatric species by the presence of a unique palatal swelling and a palatal lamella, while Gastroptychia geoffreyi sp. nov. is distinguished from sympatric species by its dense ribs. The type specimens of all sympatric sinistral species, namely Gastroptychia insignis (Godwin-Austen, 1870), Gastroptychia gibbosa (W. T. Blanford, 1868), Gastroptychia gibberosa (Godwin-Austen, 1892), and Gastroptychia jaintiaca (Godwin-Austen, 1870), are illustrated for comparison.

Abstract B024: Personalized tumor-informed circulating tumor (ct) DNA for advanced thyroid carcinoma

Abstract Background: Clinical adoption of personalized tumor-informed ctDNA testing is increasing with clinical validation in monitoring for recurrence for colorectal, breast, bladder, &amp; ovarian tumors, as well as treatment response for immune-checkpoint inhibitors regardless of tumor type. However, few studies have evaluated tumor-informed ctDNA testing in patients (pts) with advanced thyroid carcinoma (TC). Methods: This retrospective cohort study identified pts with advanced TC, with any histology, treated at an academic institution with ctDNA testing (Signatera™, Natera Inc.) performed during routine clinical care at any point during the disease natural history after requiring referral to medical oncology. The goal was to investigate the feasibility of personalized, tumor-informed ctDNA testing in advanced TC, and characteristics associated with ctDNA detectability &amp; values. Results: Between 1/1/24 &amp; 8/20/24, ctDNA testing was obtained in 45 pts with advanced TC (median age: 63y, 58% male). Testing could not be performed in 4 (9%) pts due to inadequate tumor tissue. Initial tests were in progress for 7 (16%) pts at data cutoff. Thirty-four pts had available results for at least 1 blood draw, including 19 (56%) with radioiodine refractory (RAIR) differentiated TC (DTC), 10 (29%) with anaplastic TC (ATC), &amp; 5 (15%) with medullary TC (MTC). ctDNA was detected in 16/34 (47%) pts with advanced TC. These included 8/19 (42%) pts with RAIR DTC (range: 0.05–346.26 mean tumor molecules, MTM/mL), including 4/4 (100%) about to initiate new systemic Rx, 1/4 (25%) on ongoing systemic Rx, &amp; 3/11 (27.3%) on active surveillance not requiring systemic Rx. 4/10 (40%) with ATC had detectable ctDNA (range: 3.57–80.55 MTM/mL), including 4/4 (100%) about to initiate new systemic Rx, &amp; 0/6 in those with disease control on ongoing Rx or on active surveillance after completion of Rx. 4/5 (80%) with MTC (range: 0.04–94.72 MTM/mL), including 4/4 (100%) on ongoing systemic Rx &amp; 0/1 on active surveillance. Radiographic evidence of disease was observed in 28/34 (82%) pts, with ctDNA detection in 16/28 (57%). For all cases, there was a significant association between anatomic tumor burden represented by the no. of organ sites involved by advanced TC (median:2.5, range:0-6) &amp; ctDNA detectability (Mann-Whitney, p=0.003). In pts with a ctDNA-positive result (n=16), there was a modest correlation between ctDNA quantitative values &amp; no. of involved organ sites (Spearman’s rho=0.48), but was not statistically significant (p=0.06). Similarly, modest correlation with serum biomarkers was observed but not statistically significant in RAIR DTC (with serum thyroglobulin, n=8, rho=0.52, p=0.18), &amp; MTC (with serum calcitonin, n=4, rho=0.8, p=0.2). Conclusions: Personalized ctDNA testing is feasible and often detectable in pts with advanced TC. Further research is warranted to ascertain factors associated with ctDNA test performance, and understand whether ctDNA monitoring can guide optimal timing for initiation of systemic Rx in advanced TC, as well as the dynamics of ctDNA on systemic Rx. Citation Format: Kartik Sehgal, Theodora Pappa, Michael J. Dennis, Nicole J. Scarfo, Michelle S. Mullin, Tura Coombs, Roy B. Tishler, Danielle N. Margalit, Ravindra Uppaluri, Rosh K. Sethi, Jonathan D. Schoenfeld, Justine A. Barletta, Gerard M. Doherty, Erik K. Alexander, Laura A. Goguen, Eleni M. Rettig, Robert I. Haddad, Glenn J. Hanna. Personalized tumor-informed circulating tumor (ct) DNA for advanced thyroid carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B024.

The natural history of paediatric trigger thumbs. A prospective cohort study.

The aim of this study was to report the natural history of paediatric trigger thumbs, determining the rate and factors predictive of spontaneous resolution. A total of 62 patients presenting with 79 thumbs locked in flexion were observed for a mean of 4.2 years. The median age at presentation was 20.5 months. The spontaneous resolution rate was 37% at 5 years and 50% at 8 years of follow-up. Of the thumbs, 27% had undergone surgery at 5 years and 48% at 8 years. Thumbs that spontaneously resolved did so at a mean of 3.4 years. Thumbs presenting with an interphalangeal joint angle of less than 30° were likely to resolve spontaneously, with a sensitivity of 0.50 and specificity of 0.82. It is reasonable to offer observation alone for 4 to 5 years as the first line of management for paediatric trigger thumb.Level of evidence: III.

Susceptible-Infectious-Susceptible Epidemic Model with Symmetrical Fluctuations: Equilibrium States and Stability Analyses for Finite Systems.

Accurate prediction of epidemic evolution faces challenges such as understanding disease dynamics and inadequate epidemiological data. A recent approach faced these issues by modeling susceptible-infectious-susceptible (SIS) dynamics based on the first two statistical moments. Here, we improve this approach by including finite-size populations and analyzing the stability of the resulting model. Results underscore the influence of uncertainties and population size in the natural history of the epidemic.

Odd New Spring: Towards Evolving Landscapes and a Reorientation in Design Practice (2024)

"Odd New Spring: Towards Evolving Landscapes and a Reorientation in Design Practice" is an artistic research PhD project that explores methods for designers to engage with local environments, interdisciplinary communities, and professional fields in new ways. The project repositions unwanted plants, specifically Invasive Alien Plant Species, as a foundation for knowledge creation and new local activities. This approach challenges the perception of these plants as strictly agonistic and reframes them in the context of sustainability, production, and resource management. Through the artistic practice, the plants are connected to stories from the past and visions for the future, encouraging reflection on current classifications and relations. The work culminated in the exhibition "Odd New Spring" at the University Museum in Bergen's Natural History Collections. Here, experimental artefacts, storytelling objects, interdisciplinary dialogues, and reflections point towards a new design position. The project envisions the designer as a bridge-builder across disciplines, fostering sustainable practices and coexistence within local landscapes. Supervised by Mette L'orange (architect MNAL and visual artist) and Tim Parry-Williams (Professor of Art: Textiles, KMD). Photo: Odd New Spring 2024, Siren Elise Wilhelmsen

Abstract 4117032: Investigating the natural history and risk factors underlying deterioration in early-stage hypertrophic cardiomyopathy: findings from SOLENOID

Background: Understanding the natural history and factors contributing to heterogeneous outcomes in patients with early-stage hypertrophic cardiomyopathy (HCM) is crucial to improving patient management. Aim: Utilizing a real-world data cohort spanning multiple centers, we described the natural history of early-stage HCM patients and identified risk factors for disease progression. Methods: SOLENOID is an observational study conducted in five academic centers (two in France, UK, Spain and the US). Inclusion criteria were patients with confirmed HCM seen between 2010 and 2022 in NYHA class I, or in “early stage” NYHA class II (defined by an NT-pro BNP&lt;300 pg/ml, resting or provoked LVOT&lt;50 mmHg, LAVi&lt;35 ml/m2, E/e’&lt;14, without a history of atrial fibrillation (AF), and not on HCM-specific therapy). The endpoint was a composite of NYHA class worsening, new onset of AF and cardiovascular hospitalization. To identify risk factors, univariate analyses were conducted in each center, and then aggregated through a meta-analysis. Results: A total of 1044 patients were included with a median follow-up of 3.9 years (IQR 1.5-7.0). The mean age was 53±16 years, with 30% females and 42% of NYHA I were treated with beta-blockers. Genetic tests in 57% of patients revealed mutations, primarily in MYBPC3 (29%) and MYH7 (12%). During follow-up, the composite endpoint has an incidence of 27% and 41% at 3 and 5 years. The main contributor was NYHA class worsening with an incidence of 24% and 35% at 3 and 5 years. AF at inclusion (log-HR=1.56, p&lt;0.001), baseline level of NT-proBNP (log-HR=0.75, p&lt;0.001) and age at inclusion (log-HR=0.24, p=0.005) were the main predictors of the composite endpoint. Conclusion: Nearly 30% of the early-stage HCM patients experienced disease progression within a 3 year follow-up period, highlighting a medical unmet need. Further studies are needed to assess whether the population characterized by elevated NT-proBNP, or pre-existing AF at inclusion, may benefit from more intensive surveillance and, in future HCM-specific therapy.

Natural History from Appendiceal Mucocele to Jelly Belly

Mucocele of the appendix and pseudomyxoma peritonei are rare diseases. The clinical findings are nonspecific in the early stages of the disease. The sequelae of appendiceal mucocele, its perforation, and extensive peritoneal involvement via pseudomyxoma peritonei (jelly belly) are repeatedly described in the literature. We present the typical findings in the natural history of the disease.

Abstract 4122035: The Distinct Natural History, Phenotype Spectrum, Familial Penetrance and Clinical Outcomes in Desmin ( DES )-Associated Cardiomyopathy

Background: Pathogenic/likely pathogenic variants (P/LP) in the desmin ( DES ) gene cause heterogeneous cardiomyopathy and skeletal myopathy phenotypes. Research Questions: Limited data suggest that patients with P/LP DES variants have a high incidence of major adverse cardiac events (MACEs), including cardiac conduction disease requiring pacemaker implantation (CCD-PM), sustained ventricular arrhythmias (VA), and heart failure (HF) events (HF hospitalization, heart transplant, HF-related death). However, small cohort sizes have limited full clinical characterization. Aims: We aimed to describe the natural history, phenotype spectrum, familial penetrance and MACE in patients with P/LP DES variants identified via clinical genetic testing. Methods: We conducted a systematic review and individual patient data meta-analysis of cardiac and skeletal myopathy phenotypes and MACE (CCD-PM, VA and HF events) in patients with P/LP DES variants by retrieving publications from Medline (PubMed) and Embase. Diagnosis of cardiomyopathy or MACE were both considered evidence of cardiac involvement. Results: Out of 4,212 screened records, 72 met inclusion criteria. In total, 230 patients were included (52.6% male, 52.2% probands, median age: 31 years at first evaluation [22.0; 42.8]). Eighty-five (37.0%) patients showed isolated cardiac involvement, 89 (38.7%) cardiac and skeletal muscle involvement, 39 (17.0%) only skeletal muscle involvement, and 17 (7.4%) had neither phenotype. Overall, 130 (56.5%) patients were diagnosed with a cardiomyopathy and 134 (57.4%) patients developed MACE (96 [41.7%] had CCD-PM, 36 [15.7%] sustained VA, and 43 [18.7%] HF events). Familial cardiac disease penetrance was 69.1% (76/110) in relatives with P/LP DES variants. Out of 40 patients who presented with isolated CCD-PM phenotype, 18 (45.0%) were diagnosed with a cardiomyopathy after 6 [2.0; 16.0] years of follow-up. In multivariable analysis, male sex and non-missense variants were associated with higher risk of sustained VA (HR 2.71, p=0.008, and HR 4.62, p&lt;0.001, respectively) and HF events (HR 2.63, p=0.005, and HR 2.79, p=0.015). Conclusions: DES cardiomyopathy demonstrates a distinct natural history, characterized by high familial penetrance and a high MACE burden. Male patients and those carrying non-missense variants are at higher risk for sustained VA events and may benefit from primary preventive ICD implantation even in the absence of severe LV systolic dysfunction.

A framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases.

Individualized genetic therapies-medicines that precisely target a genetic variant that may only be found in a small number of individuals, as few as only one-offer promise for addressing unmet needs in genetic disease, but present unique challenges for trial design. By nature these new individualized medicines require testing in individualized N-of-1 trials. Here, we provide a framework for maintaining scientific rigor in N-of-1 trials. Building upon best practices from traditional clinical trial design, recent guidance from the United States Food and Drug Administration, and our own clinical research experience, we suggest key considerations including comprehensive baseline natural history, selection of appropriate clinical outcome assessments (COAs) individualized to the patient genotype-phenotype for safety and efficacy assessment over time, and specific statistical considerations. Standardization of N-of-1 trial designs in this fashion will maximize efficient learning from this next generation of targeted individualized therapeutics.

RADT-48. ANALYSIS OF PROTON RADIATION THERAPY INDUCED CONTRAST ENHANCEMENT: A SINGLE INSTITUTION, RETROSPECTIVE STUDY

Abstract Proton radiotherapy (PRT) has superior physical dose distribution with a lesser integral off target radiation dose exposure compared with standard photon radiotherapy resulting in reduced toxicity of uninvolved normal tissues. However, there may be toxicity in areas targeted for high dose treatment as a result of uncertainty about the relative radiobiologic effect (RBE) of proton radiotherapy compared with photon radiotherapy and the potential for localized high doses at the end of the proton beam range (Bragg peak). This may result in radiation-induced contrast enhancement (RICE) reflecting transient toxicity or permanent injury, particularly when associated with concurrent chemotherapy. We analyzed 150 consecutive adult patients, with a histopathologic diagnosis of CNS malignancy, who underwent only PRT at Johns Hopkins Hospital between 2019 – 2023 with least 1 year of follow-up imaging. RICE was defined as a new post-treatment contrast enhancement on MRI within the radiation field. The determination of disease progression or RICE was confirmed with additional follow-up MRI or pathology. RICE was identified in 14 cases (9.3%). The median age was 48 y (range 19 – 72 years), sex 50% female. Diagnosis was 5 astrocytoma, 3 meningioma, 2 glioblastoma, 1 medulloblastoma, 2 oligodendroglioma, 1 tectal glioma. 4/5 astrocytoma patients were grade 2, 2/3 meningioma was grade 1, 1/3 was grade 2, 2/2 oligodendroglioma was grade 2. The median time since completing PRT to development of RICE was 3.5 months. The median radiation dose was 52.20 Gye (range 23.40 - 60.06). Dexamethasone was used in 11 patients (78 %) and in bevacizumab was used 2. Chemotherapy with temozolomide 7 (50%), PCV 1, and none in 5. 12 (85%) patients were still alive. PRT can also be associated with radiation injury in the target, and more information is needed about the incidence, natural history, and associations with localized dosimetry.