WiPFIM: A digital platform for interlinking biocollections of wild plants, fruits, associated insects, and their molecular barcodes.

The current knowledge on insects feeding on fruits is limited, and some of the scarce existing data on the fruit-associated insects are secluded within the host institutions. Consequently, their value is not fully realized. Moreover, in countries like Kenya, the integration of biocollections data within a digital framework has not been fully exploited. To address these gaps, this article presents a description of the development of a web-based platform for data sharing and integrating biodiversity historical data of wild plants, fruits, associated insects, and their molecular barcodes (WiPFIM) while leveraging data science technologies. The barcodes corresponding to the biocollections data were retrieved from BOLD database. The platform is an online resource about fruit-insect interactions that can be of interest to a worldwide community of users and can be useful in building innovative tools. The platform is accessible online at https://test-dmmg.icipe.org/wpfhi.

Clinical outcome assessments of disease burden and progression in late-onset GM2 gangliosidoses.

The late-onset GM2 gangliosidoses, comprising late-onset Tay-Sachs and Sandhoff diseases, are rare, slowly progressive, neurogenetic disorders primarily characterized by neurogenic weakness, ataxia, and dysarthria. The aim of this longitudinal study was to characterize the natural history of late-onset GM2 gangliosidoses using a number of clinical outcome assessments to measure different aspects of disease burden and progression over time, including neurological, functional, and quality of life, to inform the design of future clinical interventional trials. Patients attending the United States National Tay-Sachs & Allied Diseases Family Conference between 2015 and 2019 underwent annual clinical outcome assessments. Currently, there are no clinical outcome assessments validated to assess late-onset GM2 gangliosidoses; therefore, instruments used or designed for diseases with similar features, or to address various aspects of the clinical presentations, were used. Clinical outcome assessments included the Friedreich's Ataxia Rating Scale, the 9-Hole Peg Test, and the Assessment of Intelligibility of Dysarthric Speech. Twenty-three patients participated in at least one meeting visit (late-onset Tay-Sachs, n = 19; late-onset Sandhoff, n = 4). Patients had high disease burden at baseline, and scores for the different clinical outcome assessments were generally lower than would be expected for the general population. Longitudinal analyses showed slow, but statistically significant, neurological progression as evidenced by worsening scores on the 9-Hole Peg Test (2.68%/year, 95% CI: 0.13-5.29; p = 0.04) and the Friedreich's Ataxia Rating Scale neurological examination (1.31 points/year, 95% CI: 0.26-2.35; p = 0.02). Time since diagnosis to study entry correlated with worsening scores on the 9-Hole Peg Test (r = 0.728; p < 0.001), Friedreich's Ataxia Rating Scale neurological examination (r = 0.727; p < 0.001), and Assessment of Intelligibility of Dysarthric Speech intelligibility (r = -0.654; p = 0.001). In summary, patients with late-onset GM2 gangliosidoses had high disease burden and slow disease progression. Several clinical outcome assessments suitable for clinical trials showed only small changes and standardized effect sizes (change/standard deviation of change) over 4 years. These longitudinal natural history study results illustrate the challenge of identifying responsive endpoints for clinical trials in rare, slowly progressive, neurogenerative disorders where arguably the treatment goal is to halt or decrease the rate of decline rather than improve clinical status. Furthermore, powering such a study would require a large sample size and/or a long study duration, neither of which is an attractive option for an ultra-rare disease with no available treatment. These findings support the development of potentially more sensitive late-onset GM2 gangliosidoses-specific rating instruments and/or surrogate endpoints for use in future clinical trials.

The natural evolution of untreated deep endometriosis and the effect of hormonal suppression: A systematic literature review and meta-analysis.

INTRODUCTION: Peritoneal infiltrating and fibrotic endometriosis, also known as deep endometriosis, is the most severe manifestation of the disease that can cause severe complications including bowel and ureteral stenosis. The natural history of these lesions and the possible effect of hormonal treatments on their progression are undefined. Therefore, we conducted a systematic review and meta-analysis to investigate whether and how frequently deep endometriosis progresses over time without or with ovarian suppression. This could inform management decisions in asymptomatic and mildly symptomatic patients. MATERIAL AND METHODS: For this pre-registered systematic review (CRD42023463518), the PubMed and Embase databases were screened, and studies published between 2000 and 2023 that serially evaluated the size of deep endometriotic lesions without or with hormonal treatment were selected. Data on the progression, stability, or regression of deep endometriotic lesions were recorded as absolute frequencies or mean volume variations. Estimates of the overall percentage of progression and corresponding 95% confidence intervals were calculated using a random-effect model. When studies reported lesion progression as pre- and post-treatment volume means, the delta of the two-volume means was calculated and analyzed using the inverse variance method. RESULTS: A total of 29 studies were identified, of which 19 studies with 285 untreated and 730 treated patients were ultimately selected for meta-analysis. The overall estimate of the percentage of lesion progression in untreated individuals was 21.4% (95% CI, 6.8-40.8%; I2 = 90.5%), whereas it was 12.4% during various hormonal treatments (95% CI, 9.0-16.1%; I2 = 0%). Based on the overall meta-analysis estimates, the odds ratio of progression in treated versus untreated patients was 0.52 (95% CI, 0.41-0.66). During hormonal suppression, the mean volume of deep endometriotic lesions decreased significantly by 0.87 cm3 (95% CI, 0.19-1.56 cm3; I2 = 0%), representing -28.5% of the baseline volume. CONCLUSIONS: Untreated deep endometriotic lesions progressed in about one in five patients. Medical therapy reduced but did not eliminate this risk. Given the organ function failure potentially caused by these lesions, the decision whether to use hormonal treatments in asymptomatic or mildly symptomatic women should always be shared, carefully weighing the potential benefits and harms of the two alternatives after extensive counseling.

Natural history of acid sphingomyelinase deficiency among European patients during childhood and adolescence: A retrospective observational study.

Acid sphingomyelinase deficiency (ASMD) is a rare, lysosomal storage disease with limited evidence on its natural history. This retrospective, medical record abstraction study aimed to characterize the natural history of ASMD (types B and A/B) during childhood and adolescence. Recruiting sites were European centers (i.e., France, Germany, Italy, and the United Kingdom) from the ASCEND-Peds trial (NCT02292654); these sites were targeted because of the rarity of ASMD and specialized care provided at these centers. The study population comprised ASMD trial patients (before exposure to treatment) and ASMD non-trial participants who were managed at the same trial sites. Overall, 18 patients were included (11 trials; 7 non-trials; median [Q1; Q3] age at ASMD diagnosis: 2.5 [1.0; 4.0] years). Median follow-up duration was 10.0 years. Frequently reported medical conditions were hepatobiliary (17 [94.4%]) and blood and lymphatic system disorders (16 [88.9%]). Adenoidectomy (3 [16.7%]) was the most commonly reported surgical procedures; gastroenteritis (5 [27.8%]) was the most frequently reported infections, and epistaxis (6 [33.3%]) was the most commonly reported bleeding events. Abnormal spleen (16 [88.9%]) and liver (15 [83.3%]) size and respiratory function (8 [44.4%]) were commonly reported during physical examination. Overall, 11 (61.1%) patients were hospitalized; 6 (33.3%) patients had emergency room visits. Findings were consistent with published literature and support the current understanding of natural history of ASMD.

Prediction of the stage shift growth of early-stage lung adenocarcinomas by volume-doubling time.

Background: Prediction of subsolid nodule (SSN) interval growth is crucial for clinical management and decision making in lung cancer screening program. To the best of our knowledge, no study has investigated whether volume doubling time (VDT) is an independent factor for predicting SSN interval growth, or whether its predictive power is better than that of traditional semantic methods, such as nodular diameter or type. This study aimed to investigate whether VDT could provide added value in predicting the long-term natural course of SSNs (<3 cm) regarding stage shift. Methods: This retrospective study enrolled 132 patients with spectrum lesions of lung adenocarcinoma who underwent two consecutive computed tomography (CT) examinations before surgical tissue proofing between 2012 and 2021 in Kaohsiung Veterans General Hospital. The VDTs were manually calculated from the volumetric segmentation using Schwartz's approximation formula. We utilized logistic regression to identify predictors associated with stage shift progression based on the VDT parameter. Results: The average duration of follow-up period was 3.629 years. A VDT-based nomogram model (model 2) based on CT semantic features, clinical characteristics, and the VDT parameter yielded an area under the curve (AUC) of 0.877 [95% confidence interval (CI): 0.807-0.928]. Compared with model 1 (CT semantic features and clinical characteristics), model 2 exhibited the better predictive performance for stage shift (AUC model 1: 0.833 versus AUC model 2: 0.877, P=0.047). In model 2, significant predictors of stage shift growth included initial nodule size [odds ratio (OR) =4.074, 95% CI: 1.368-12.135; P=0.012], SSN classification (OR =0.042; 95% CI: 0.006-0.288; P=0.001), follow-up period (OR =1.692, 95% CI: 1.337-2.140; P<0.001), and VDT classification (OR =2.327, 95% CI: 1.368-3.958; P=0.002). For the stage shift, the mean progression time for the VDT (>400 d) group was 7.595 years, and median progression time was 7.430 years. Additionally, a VDT ≤400 d is an important prognostic factor associated with aggressive growth behavior with a stage shift. Conclusions: VDT is crucial for predicting SSN stage shift growth irrespective of clinical and CT semantic features. This highlights its significance in informing follow-up protocols and surgical planning, emphasizing its prognostic value in predicting SSN growth.

SARA captures disparate progression and responsiveness in spinocerebellar ataxias.

BACKGROUND: The Scale for Assessment and Rating of Ataxia (SARA) is a widely used clinical scale to assess cerebellar ataxia but faces some criticisms about the relevancy of all its items. OBJECTIVES: To prepare for future clinical trials, we analyzed the progression of SARA and its items in several polyQ spinocerebellar ataxias (SCA) from various cohorts. METHODS: We included data from patients with SCA1, SCA2, SCA3, and SCA6 from four cohorts (EUROSCA, RISCA, CRC-SCA, and SPATAX) for a total of 850 carriers and 3431 observations. Longitudinal progression of the SARA and its items was measured. Cohort, stage and genetic effects were tested. We looked at the respective contribution of each item to the total scale. Sensitivity to change of the scale and the impact of item removal was evaluated by calculating sample sizes needed in various scenarios. RESULTS: Longitudinal progression was significantly different between cohorts in SCA1, SCA2 and SCA3, the EUROSCA cohort having the fastest progression. Advanced-stage patients were progressing slower in SCA2 and SCA6. Items were not contributing equally to the full scale through ataxia severity: gait, stance, hand movement, and heel-shin contributed the most in the early stage, and finger-chase, nose-finger, and sitting in later stages. Few items drove the sensitivity to the change of SARA, but changes in the scale structure could not improve its sensitivity in all populations. CONCLUSION: SARA and its item's progression pace showed high heterogeneity across cohorts and SCAs. However, no combinations of items improved the responsiveness in all SCAs or populations taken separately.

How long does tendinopathy last if left untreated? Natural history of the main tendinopathies affecting the upper and lower limb: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Natural history of disease refers to the progression of a disease process in an individual over time, in the absence of treatment. Understanding natural history of tendinopathies is key for clinicians to make accurate prognostic predictions and design effective intervention studies. OBJECTIVE: To quantify the natural history of the main tendinopathies regarding pain and function and to compare outcomes between untreated individuals and those receiving treatment. METHODS: A systematic literature search was conducted until February 2023, across PubMed, Cochrane, Embase and Scopus databases. Selection criteria included randomized controlled trials (RCTs) with a "wait-and-see" group and cohort studies with ≥3 months of follow-up reporting on pain and function-related outcomes. Standardized mean differences (SMDs) of "wait-and-see" groups were pooled using a random-effects inverse-variance model. Risk of bias was assessed using Cochrane Risk-of-Bias (RoB2), and quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: Six RCTs were included, encompassing 518 subjects with tendinopathy. Pooled results demonstrated significant pain (SMD = 0.30, 95%CI: 0.19-0.41) and physical function improvement (SMD = 0.38, 95%CI: 0.28-0.48). These estimates remained consistent regardless of age or follow-up duration. In rotator cuff tendinopathy, untreated individuals improved but did not fully recover at one year, with similar outcomes to other interventions (e.g., surgery). Subjects with lateral elbow, patellar and achilles tendinopathies when untreated, did not fully resolve symptoms within 12-16 weeks. CONCLUSIONS: This review provides limited conclusions about natural history of tendinopathies. Future studies should incorporate true no-intervention groups to accurately reflect tendinopathy's natural progression.

Transition of cluster headache: Depicting side-changing attacks as a chronic trait in an interview-based follow-up study.

BACKGROUND: Cluster headache presents in an episodic and chronic form, between which patients can convert during the course of disease. We aimed to quantify the rate of cluster headache patients changing phenotype within one and five years and investigate the earlier proposed association between chronification and having side-shifting attacks. METHODS: In total, 430 cluster headache patients well-characterized according to current International Classification of Headache Disorders criteria, who were all participants in a prior transition-study, were re-interviewed in an observational, retrospective, cross-sectional follow-up study design at the Danish Headache Center. RESULTS: The transition rate for the whole cohort was 6.5% within one year and 19.8% within five years. The risk of becoming chronic if episodic was 4.0% within one year and 12.3% within five years. For conversion from chronic to episodic, the corresponding risk was 11.1% and 25.0%, respectively. Alterations in attack-side were reported in 32% of all chronic patients, generating an odds ratio of 2.24 of being chronic as opposed to episodic if experiencing side-shifting attacks. CONCLUSIONS: A higher transition rate since the original cross-sectional study demonstrates cluster headache as a non-static condition. Identifying a risk of transition within one and five years, based on current phenotype along with high odds of being chronic when experiencing a shift of attack-side, offers a valuable clinical compass in the dialogue with the patient.

Unraveling GRIA1 neurodevelopmental disorders: Lessons learned from the p.(Ala636Thr) variant.

Ionotropic glutamate receptors (iGluRs), specifically α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), play a crucial role in orchestrating excitatory neurotransmission in the brain. AMPARs are intricate assemblies of subunits encoded by four paralogous genes: GRIA1-4. Functional studies have established that rare GRIA variants can alter AMPAR currents leading to a loss- or gain-of-function. Patients affected by rare heterozygous GRIA variants tend to have family specific variants and only few recurrent variants have been reported. We deep-phenotyped a cohort comprising eight unrelated children and adults, harboring a recurrent and well-established disease-causing GRIA1 variant (NM_001114183.1: c.1906G>A, p.(Ala636Thr)). Recurrent symptoms included motor and/or language delay, mild-severe intellectual disability, behavioral and psychiatric comorbidities, hypotonia and epilepsy. We also report challenges in social skills, autonomy, living and work situation, and occupational levels. Furthermore, we compared their clinical manifestations in relation to those documented in patients presenting with rare heterozygous variants at analogous positions within paralogous genes. This study provides unprecedented details on the neurodevelopmental outcomes, cognitive abilities, seizure profiles, and behavioral abnormalities associated with p.(Ala636Thr) refining and broadening the clinical phenotype.

Twelve-month Natural History Study of Centrosomal Protein 290 (CEP290)-associated Inherited Retinal Degeneration.

Purpose: To define the clinical characteristics of centrosomal protein 290 (CEP290)-associated inherited retinal degeneration (IRD) and determine which assessments may provide reliable endpoints in future interventional trials. Design: Participants in this natural history study were enrolled into 2 best-corrected visual acuity (BCVA) cohorts: light perception to > 1.0 logarithm of the minimum angle of resolution (logMAR) and 1.0 logMAR to 0.4 logMAR. Each comprised 4 age cohorts (3-5, 6-11, 12-17, and ≥ 18 years). Participants: Patients with CEP290-associated IRD caused by the intron 26 c.2991+1655A>G mutation and BCVA ranging from light perception to 0.4 logMAR. Methods: Best-corrected visual acuity, full-field stimulus threshold (FST) sensitivity, Ora-Visual Navigation Challenge (Ora-VNC) composite score, and OCT-outer nuclear layer (OCT-ONL) average thickness were assessed at screening, baseline, 3 months, 6 months, and 12 months. Main Outcome Measures: Best-corrected visual acuity, FST sensitivity, Ora-VNC composite score, and OCT-ONL average thickness. Results: Twenty-six participants were included in this analysis. Nineteen were female. All participants were White and 4 reported Hispanic ethnicity. At screening, 13 of 16 adult and 9 of 10 pediatric participants had BCVA > 1.0 logMAR. Baseline BCVA was variable (median [range] = 2.0 [0.5, 3.9] logMAR) and was uncorrelated with age, as were VNC composite score, FST sensitivity, and OCT-ONL average thickness. Mean (95% confidence interval [CI]) test-retest variability was -0.04 (-0.09, 0.01) logMAR for BCVA (n = 25); 0.6 (-0.1, 1.3) for VNC composite score (n = 18); and 0.10 (-0.07, 0.27) log cd.s/m2 for red FST (n = 14). A greater than expected test-retest variability (5 [0, 10] µm, n = 14) was observed for OCT-ONL average thickness as nystagmus impacted ability to repeat measures at the same retinal location. Functional assessments were stable over 12 months. Mean (95% CI) change from baseline was 0.06 (-0.17, 0.29) logMAR for BCVA (n = 23); -0.1 (-1.2, 1.0) for VNC composite score (n = 21); and -0.15 (-0.43, 0.14) log cd.s/m2 for red FST (n = 16). Conclusions: Vision was stable over 12 months. Best-corrected visual acuity, FST, and VNC composite score are potentially viable endpoints for future studies in CEP290-associated IRD. Repeatability of OCT measures poses challenges for quantifying anatomical changes in this population. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A case of alpha-gal syndrome: Recall urticaria and 10 years of measurements of IgE to galactose-α-1,3-galactose.

Alpha-gal IgE level can change rapidly. Reassessment of a patient's alpha-gal IgE level may be helpful in the patient's clinical follow-up. Pruritus related to the site of a previous tick bite strengthens the diagnosis of alpha-gal syndrome.

Natural History and Management of Ultrasound-detected Small Renal Angiomyolipoma.

Background: Recent advances in imaging methods increased the incidental detection of small renal angiomyolipoma (AML). However, guidelines for managing small AML are lacking, and decisions about imaging frequency and timing of intervention are made on an individual basis. This study aims to investigate the clinical behavior of small sporadic AML and propose an optimal follow-up strategy. Methods: The study is a retrospective analysis of 168 individuals who had hyperechoic lesions, suggestive of AML detected during abdominal ultrasound as a part of their health checkup. The clinical information of the individuals, including tumor characteristics and renal function, was reviewed. Statistical analysis was performed to identify factors associated with tumor growth and renal function. Results: Most AMLs were small (≤20 mm) and did not exhibit malignant characteristics. The tumors showed a slow growth rate, with a mean growth rate of 0.24 mm/year. Only a small proportion of cases (1.2%) required intervention due to significant enlargement. Factors such as tumor size and gender were not significantly associated with tumor growth rate or renal function. However, younger patients showed a higher tumor growth rate and a more pronounced decline in renal function. Conclusion: Small sporadic AMLs have a slow growth rate and little risk of malignancy. Neither tumor size nor gender was predictive factors for tumor growth or renal function. Nevertheless, close monitoring of tumor growth and renal function is advised, particularly in younger patients. This study highlights the need for further research and guidelines to establish an optimal surveillance protocol for small AMLs.

Natural History of Untreated Idiopathic Sudden Sensorineural Hearing Loss.

OBJECTIVE: Although corticosteroids and other treatments for idiopathic sudden sensorineural hearing loss (ISSNHL) have been described, understanding its prognosis without intervention provides valuable information for patient management. The objective of this study is to provide a comprehensive, quantitative statistical analysis of the natural history of untreated idiopathic sudden sensorineural hearing loss (ISSNHL). STUDY TYPE AND DESIGN: A systematic review and meta-analyses. METHODS: Two independent searches of PubMed, Scopus, Web of Science, and Cochrane Library databases up to June 30, 2022, were performed. Adults with idiopathic sudden sensorineural hearing loss who received placebo or were untreated and had audiometric outcome measures in all study types were reviewed. These data indicative of the natural history of ISSNHL were analyzed, as were study characteristics related to risk of bias. Heterogeneity as assessed via I2 and random effects analyses were performed. RESULTS: Six studies meeting the inclusion criteria yielded 319 untreated patients whose natural history could be assessed. Heterogeneity among studies was moderate, with a variety of reported outcomes. A hearing improvement of at least 30 dB HL was observed in 36% (95% CI 0.28-0.44) of untreated patients, and of at least 10 dB HL was observed in 70% (95% CI 0.57-0.82) of untreated patients at 3 months. The mean hearing gain among untreated patients was 24.0 dB HL (95% CI 2.65-45.37) at 2-3 months. CONCLUSIONS: The observed natural history of ISSNHL suggests that patients can regain some hearing without active treatment. In the absence of future studies collecting prospective natural history data from untreated or placebo-treated ISSNHL patients, the data presented here provide the best available historical control data for reconsideration of results in past ISSNHL studies, as well as a roadmap for design and interpretation of future ISSNHL treatment clinical trials. Furthermore, knowing there is a statistically significant mean hearing gain of 24.0 dB HL in the untreated/placebo group provides an ethical basis for future placebo study of ISSNHL. The current status on ISSNHL management calls for a multi-institutional, randomized, double-blind placebo-controlled trial with validated outcome measures to provide science-based treatment guidance. Laryngoscope, 2024.

Natural History and Prognostic Model of Untreated Papillary Thyroid Cancer: A SEER Database Analysis.

PURPOSE: This investigation leveraged the SEER database to delve into the progression patterns of PTC when left untreated. Furthermore, it aimed to devise and authenticate a nomogram for prognosis prediction for such patients. METHODS: We extracted data from the SEER database, focusing on PTC-diagnosed individuals from 2004-2020. To discern disease progression intervals, median survival times across stages were gauged, and the disease progression time was estimated by subtracting the median survival time of a more severe stage from its preceding stage. Prognostic determinants in the training set were pinpointed using both univariate and multivariate Cox regression. Using these determinants, a prognostic nomogram was crafted. RESULTS: In untreated PTC patients, those in stages I and II had a favorable prognosis, with 10-year overall survival rates of 86.34% and 66.03%, respectively. Patients in stages III and IV had a relatively poorer prognosis. The median survival time of stage III, stage IVA, stage IVB and stage IVC patients was 108months, 43 months, 20 months and 8 months, respectively. The deduced progression intervals from stages III-IVC were 65, 23, and 12 months. In the training set, age, tumor stage, gender, and marital status were identified as independent risk factors influencing the prognosis of untreated PTC, and a nomogram was constructed using these variables. CONCLUSION: In the absence of treatment intervention, early-stage PTC progressed slowly with an overall favorable prognosis. However, in mid to advanced-stage PTC, as tumor stage increased, disease progression accelerated, and prognosis gradually worsened. Age, tumor stage, marital status, and gender were independent risk factors influencing the prognosis of untreated PTC, and the nomogram based on these factors demonstrated good prognostic capability.

PurposeThis investigation leveraged the SEER database to delve into the progression patterns of PTC when left untreated. Furthermore, it aimed to devise and authenticate a nomogram for prognosis prediction for such patients.MethodsWe extracted data from the SEER database, focusing on PTC-diagnosed individuals from 2004-2020. To discern disease progression intervals, median survival times across stages were gauged, and the disease progression time was estimated by subtracting the median survival time of a more severe stage from its preceding stage. Prognostic determinants in the training set were pinpointed using both univariate and multivariate Cox regression. Using these determinants, a prognostic nomogram was crafted.ResultsIn untreated PTC patients, those in stages I and II had a favorable prognosis, with ten-year overall survival rates of 86.34% and 66.03%, respectively. Patients in stages III and IV had a relatively poorer prognosis. The median survival time of stage III, stage IVA, stage IVB and stage IVC patients was 108months, 43 months, 20 months and 8 months, respectively. The deduced progression intervals from stages III-IVC were 65, 23, and 12 months. In the training set, age, tumor stage, gender, and marital status were identified as independent risk factors influencing the prognosis of untreated PTC, and a nomogram was constructed using these variables.ConclusionIn the absence of treatment intervention, early-stage PTC progressed slowly with an overall favorable prognosis. However, in mid to advanced-stage PTC, as tumor stage increased, disease progression accelerated, and prognosis gradually worsened. Age, tumor stage, marital status, and gender were independent risk factors influencing the prognosis of untreated PTC, and the nomogram based on these factors demonstrated good prognostic capability.

Dysregulation of the Immune System in a Natural History Study of 1299 Individuals with Down Syndrome.

Dysregulation of the immune system in individuals with Down syndrome is thought to play a major role in the pathophysiology of many clinical presentations. This natural history of disease study took a comprehensive evaluation of the prevalence of different immune related diagnoses in a cohort of 1299 patients with Down syndrome compared to a 2605 patient control cohort at the Mount Sinai Health System in New York, NY over the past 18 years. We conducted a stepwise analysis of the odds of receiving a diagnosis at the Chapter, Sub-chapter and Diagnosis level of the ICD-CM-10 code system. Individuals in our Down syndrome cohort had higher odds of a diagnosis with inflammatory and autoimmune presentations such as Alopecia areata (OR 6.06, p = 0.01), Other sepsis (OR 4.79, p < 0.001, Purpura and other hemorrhagic conditions (OR 2.31, p < 0.001), and Rosacea (OR 3.11, p < 0.001). They also presented with lower odds of a diagnosis of Herpesviral infection (OR 0.42, p = 0.01), and Viral warts (OR 0.51, p = 0.04). We posit that dysregulation of the immune system in individuals with Down syndrome has impact on infectious diseases, including lowering the incidence of viral disease and increasing its severity. Our data also suggests inflammation and autoimmune mediated diseases, in particular of the skin, are exacerbated in individuals with Down syndrome. Finally, there may be a need for greater clinical attention to non-emergent conditions within the Down syndrome patient population as those can also greatly affect quality of life.

The Impact of Model Assumptions on Personalized Lung Cancer Screening Recommendations.

BACKGROUND: Recommendations regarding personalized lung cancer screening are being informed by natural-history modeling. Therefore, understanding how differences in model assumptions affect model-based personalized screening recommendations is essential. DESIGN: Five Cancer Intervention and Surveillance Modeling Network (CISNET) models were evaluated. Lung cancer incidence, mortality, and stage distributions were compared across 4 theoretical scenarios to assess model assumptions regarding 1) sojourn times, 2) stage-specific sensitivities, and 3) screening-induced lung cancer mortality reductions. Analyses were stratified by sex and smoking behavior. RESULTS: Most cancers had sojourn times <5 y (model range [MR]; lowest to highest value across models: 83.5%-98.7% of cancers). However, cancer aggressiveness still varied across models, as demonstrated by differences in proportions of cancers with sojourn times <2 y (MR: 42.5%-64.6%) and 2 to 4 y (MR: 28.8%-43.6%). Stage-specific sensitivity varied, particularly for stage I (MR: 31.3%-91.5%). Screening reduced stage IV incidence in most models for 1 y postscreening; increased sensitivity prolonged this period to 2 to 5 y. Screening-induced lung cancer mortality reductions among lung cancers detected at screening ranged widely (MR: 14.6%-48.9%), demonstrating variations in modeled treatment effectiveness of screen-detected cases. All models assumed longer sojourn times and greater screening-induced lung cancer mortality reductions for women. Models assuming differences in cancer epidemiology by smoking behaviors assumed shorter sojourn times and lower screening-induced lung cancer mortality reductions for heavy smokers. CONCLUSIONS: Model-based personalized screening recommendations are primarily driven by assumptions regarding sojourn times (favoring longer intervals for groups more likely to develop less aggressive cancers), sensitivity (higher sensitivities favoring longer intervals), and screening-induced mortality reductions (greater reductions favoring shorter intervals). IMPLICATIONS: Models suggest longer screening intervals may be feasible and benefits may be greater for women and light smokers. HIGHLIGHTS: Natural-history models are increasingly used to inform lung cancer screening, but causes for variations between models are difficult to assess.This is the first evaluation of these causes and their impact on personalized screening recommendations through easily interpretable metrics.Models vary regarding sojourn times, stage-specific sensitivities, and screening-induced lung cancer mortality reductions.Model outcomes were similar in predicting greater screening benefits for women and potentially light smokers. Longer screening intervals may be feasible for women and light smokers.

Genetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant.

The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 year longer disease duration (P = 0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behaviour disorder (RBD) and hyposmia (all P-values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease.

Treatment of Brain Arteriovenous Malformations.

Brain arteriovenous malformations (AVMs) are a rare entity of vascular anomalies, characteristic of anatomical shunting where arterial blood directly flows into the venous circulation. The main aim of the active treatment policy of brain AVMs is the prevention of haemorrhage. There are well-established treatment strategies that continually improve in their safety and efficacy, primarily due to the advances in imaging modalities, targeted and novel techniques, the development of alternative treatment approaches, and even better experience with the disease itself. There are interesting imaging novelties that may be prospectively applicable in the decision-making and planning of the most effective treatment approach for individual patients with intracranial AVM. Surgery is often considered the first-line treatment; however, each patient should be evaluated individually, and the risks of the active treatment policy should not overcome the benefits of the spontaneous natural history of the disease. All treatment modalities, i.e., surgery, radiosurgery, endovascular embolization, and observation, are justified but need to be meticulously selected for each individual patient in order to deliver the best treatment outcome. This chapter deals with historical and currently applied dogmas, followed by introductions of advances in each available treatment modality of AVM management.

Linking Angelman and dup15q data for expanded research (LADDER) database: a model for advancing research, clinical guidance, and therapeutic development for rare conditions.

Angelman syndrome (AS) and duplication 15q (dup15q) syndrome are rare neurogenetic conditions arising from a common locus on the long arm of chromosome 15. Individuals with both conditions share some clinical features (e.g. intellectual disability, epilepsy) and often require lifelong care. Disease-modifying therapies for both conditions are emerging, resulting in a significant need for a better understanding of the natural history of both AS and dup15q. Patient advocacy groups for both conditions recognized a need for a data repository that would link data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments, resulting in the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database. This paper describes the development and functionality of the LADDER Database - including challenges, lessons learned, and preliminary feasibility - and how it can be used as a model for other rare conditions.

The LADDER database: a model for advancing research, clinical guidance, and therapeutic development for rare conditions This paper describes the development and functionality of the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database, which is a data repository for two rare neurogenetic conditions: Angelman syndrome (AS) and duplication 15q (dup15q) syndrome. AS and dup15q syndrome arise from genetic abnormalities on chromosome 15 and share some clinical features (e.g. intellectual disability, epilepsy). LADDER was developed by patient advocacy organizations representing each condition in partnership with RTI International. LADDER links data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments for both AS and dup15q syndrome. The LADDER Database can be used as a model for expanding research and enhancing clinical trial readiness in other rare conditions.

A new approach to geostatistical synthesis of historical records reveals capuchin spatial responses to climate and demographic change.

Recent proliferation of GPS technology has transformed animal movement research. Yet, time-series data from this recent technology rarely span beyond a decade, constraining longitudinal research. Long-term field sites hold valuable historic animal location records, including hand-drawn maps and semantic descriptions. Here, we introduce a generalised workflow for converting such records into reliable location data to estimate home ranges, using 30 years of sleep-site data from 11 white-faced capuchin (Cebus imitator) groups in Costa Rica. Our findings illustrate that historic sleep locations can reliably recover home range size and geometry. We showcase the opportunity our approach presents to resolve open questions that can only be addressed with very long-term data, examining how home ranges are affected by climate cycles and demographic change. We urge researchers to translate historical records into usable movement data before this knowledge is lost; it is essential to understanding how animals are responding to our changing world.