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INTRODUCTION: Bilingualism has historically been claimed to be a risk factor for developmental stuttering. The Early Childhood Longitudinal Study, Kindergarten Class of 2010-11 (ECLS-K:2011) ostensibly contains evidence to test that claim. METHODS: We analyze data from monolingual and bilingual children in Kindergarten through fifth grade in the ECLS-K:2011. RESULTS AND DISCUSSION: The prevalence, male/female ratio, and onset and recovery of reported stuttering in the ECLS are inconsistent with widely-accepted clinical reports of stuttering. We argue that the reported figures may be misleading. We discuss some factors that may inflate the reported prevalence, including a lack of awareness of the difference between stuttering vs. normal disfluencies, and the informal usage of the word stuttering on the part of teachers and parents to describe typical disfluencies.

The unfolded state of proteins presents many challenges to elucidate the structural basis for biological function. This state is characterized by a large degree of structural heterogeneity which makes it difficult to generate structural models. However, recent experiments into the initial folding events of the 104-residue ribonuclease homologue onconase (ONC) were able to identify the regions in the protein that participate in the initial folding of this protein. Therefore, to gain additional structural insight into the unfolded state of proteins, this study utilized molecular dynamics simulations using the UNited-RESidue (UNRES) force field to evaluate whether there is a good agreement between the experimentally determined initial structures and the structures identified by computer simulations along a folding pathway. Indeed, these UNRES simulations accurately identified the two regions experimentally observed to form the initial native structure along the folding pathway of ONC. In addition, these regions are determined to be chain folding initiation sites (CFIS) according to methods developed previously. Subsequent self-organization maps (SOM) analysis has revealed key structural states involved in these early folding events.

Last year, I reported on preliminary results of an anatomically-inspired deep learning model of the visual system and its role in explaining the face inversion effect. This year, I will report on new results and some variations on network architectures that we have explored, mainly as a way to generate discussion and get feedback. This is by no means a polished, final presentation! We look forward to the group’s suggestions for these projects.

Item does not contain fulltext, Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Item does not contain fulltext, The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by progressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to unaffected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals.

The aetiology of nodding syndrome remains unclear, and comprehensive genotyping and phenotyping data from patients remain sparse. Our objectives were to characterize the phenotype of patients with nodding syndrome, investigate potential contributors to disease aetiology, and evaluate response to immunotherapy. This cohort study investigated members of a single-family unit from Lamwo District, Uganda. The participants for this study were selected by the Ugandan Ministry of Health as representative for nodding syndrome and with a conducive family structure for genomic analyses. Of the eight family members who participated in the study at the National Institutes of Health (NIH) Clinical Center, three had nodding syndrome. The three affected patients were extensively evaluated with metagenomic sequencing for infectious pathogens, exome sequencing, spinal fluid immune analyses, neurometabolic and toxicology testing, continuous electroencephalography and neuroimaging. Five unaffected family members underwent a subset of testing for comparison. A distinctive interictal pattern of sleep-activated bursts of generalized and multifocal epileptiform discharges and slowing was observed in two patients. Brain imaging showed two patients had mild generalized cerebral atrophy, and both patients and unaffected family members had excessive metal deposition in the basal ganglia. Trace metal biochemical evaluation was normal. CSF was non-inflammatory and one patient had CSF-restricted oligoclonal bands. Onchocerca volvulus-specific antibodies were present in all patients and skin snips were negative for active onchocerciasis. Metagenomic sequencing of serum and CSF revealed hepatitis B virus in the serum of one patient. Vitamin B6 metabolites were borderline low in all family members and CSF pyridoxine metabolites were normal. Mitochondrial DNA testing was normal. Exome sequencing did not identify potentially causal candidate gene variants. Nodding syndrome is characterized by a distin

Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or "primed" by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder.

Contains fulltext : 299952.pdf (Publisher’s version ) (Open Access), BACKGROUND: KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined. METHODS: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature. RESULTS: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones. CONCLUSION: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of ANKRD11 variants in skeletal and brain development.

The Verde River Watershed in Arizona provides crucial habitat for native and introduced fish species, particularly in mid-level perennial streams. However, increasing human and environmental pressures pose a risk to these environments. With an increased likelihood of habitat degradation, it is important to identify and protect habitat features essential for fishes inhabiting these streams. I conducted radio telemetry surveys to assess habitat use and selection by two common fish species in two wilderness tributaries of the Verde River: Wet Beaver Creek and West Clear Creek. I tracked 23 Desert Sucker Catostomus clarkii and 19 Black Bass Micropterus spp. in West Clear Creek, and 38 Desert Sucker and 43 Black Bass in Wet Beaver Creek for one year. I developed habitat selection models by comparing features used by fish to available stream features. My analysis revealed that Desert Sucker generally selected deep moving waters and Black Bass generally selected deep low velocity areas. Both fish often utilized areas with cobble substrate, canopy cover, and instream cover. Our results highlight the importance of stream features such as velocity, depth, and substrate in habitat selection. Furthermore, I demonstrate the effectiveness of radio telemetry tracking in remote wilderness locations. These findings provide valuable insights into habitat selection by Verde River Watershed fishes, which can inform conservation efforts and management strategies.

Introduction: Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Methods: Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. Results: In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. Conclusion: The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5Brelated neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Objective: Fear of recurrence (FoR) affects the quality of life of head and neck cancer survivors. Identification of factors predisposing to FoR may help to recognize and treat patients at risk. Materials and methods: For this exploratory study, 101 disease-free head and neck cancer survivors completed a cross-sectional survey in 2017 that included the FoR questionnaire at a random point in time during their follow-up. Additionally, the patients were asked to choose their favorite among four follow-up schedules with or without systematic imaging and varying frequency of visits. Results: Elevated FoR was present in 36.6% of patients. Females and patients ≤65 years showed significantly higher FoR overall scores than males (score difference 3.40; CI 0.49-6.32; p = 0.022) and patients >65 years (score difference 4.25; CI 1.58-6.92; p = 0.002). A history of cancer recurrence or second primary malignancy increased the relative risk (RR) for elevated FoR (RR 1.7; CI 1.01-2.86; p = 0.046). Tumor stage and treatment modality were not significantly associated with elevated FoR or FoR overall score. Higher FoR overall scores were recorded in patients who favored intensive follow-up plans (mean overall FoR score 18 vs. 15; SD 7.7; p = 0.076) and systematic imaging in follow-up (17 vs. 13, SD 7.1; p = 0.034). Conclusion: Fear of recurrence in head and neck cancer patients is associated with female sex, younger age, and history of a past recurrence or second primary malignancy. Due to its high prevalence, it should be addressed in clinical practice and future research.

Background: KBG syndrome is caused by haploinsufficiency of ANKRD11and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined. Methods: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature. Results: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones. Conclusion: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects ofANKRD11variants in skeletal and brain development.

Last year, I reported on preliminary results of an anatomically-inspired deep learning model of the visual system and its role in explaining the face inversion effect. This year, I will report on new results and some variations on network architectures that we have explored, mainly as a way to generate discussion and get feedback. This is by no means a polished, final presentation! We look forward to the group’s suggestions for these projects.

The face-inversion effect, or the drastic decrease in accuracyseen when a participant is asked to identify inverted faces whencompared to upright faces, is an effect that is not found in objectinversion. Here we suggest a new explanation of this effect usingcomputational models to show that the phenomenon can beexplained by the anatomical mapping from the visual field toprimary visual cortex. We propose that the way inverted faces aremapped onto the cortex is fundamentally different from the wayupright faces are mapped. Our work first shows the advantages ofthis mapping due to its scale and rotation invariance when used asinput to a convolutional neural network. We train the network toperform recognition tasks and show it exhibits scale andrealistically constrained rotation invariance. We then confirm thatthe decline in accuracy seen when a participant is asked to identifyinverted faces is not seen in the network with inverted objectrecognition tasks. With the support of these two findings, we testthe face-inversion effect on our network and are able to show theunique decline in accuracy, suggesting that the way the visual fieldis mapped onto the primary visual cortex is a key facet in themanifestation of this effect.

We report on preliminary results of an anatomically-inspired deep learning model of the visual system and its role in explaining the face inversion effect. Contrary to the generally accepted wisdom, our hypothesis is that the face inversion effect can be accounted for by the representation in V1 combined with the reliance on the configuration of features due to face expertise. We take two features of the primate visual system into account: 1) The foveated retina; and 2) The log-polar mapping from retina to V1. We simulate acquisition of faces, etc., by gradually increasing the number of identities the network learns. We find that the more faces the network knows, the more the network shows the face inversion effect. In contrast, a standard convolutional network’s inversion performance drops to nearly 0 in the same situation.

We report on preliminary results of an anatomically-inspired deep learning model of the visual system and its role in explaining the face inversion effect. Contrary to the generally accepted wisdom, our hypothesis is that the face inversion effect can be accounted for by the representation in V1 combined with the reliance on the configuration of features due to face expertise. We take two features of the primate visual system into account: 1) The foveated retina; and 2) The log-polar mapping from retina to V1. We simulate acquisition of faces, etc., by gradually increasing the number of identities the network learns. We find that the more faces the network knows, the more the network shows the face inversion effect. In contrast, a standard convolutional network’s inversion performance drops to nearly 0 in the same situation.

To what extent do speakers decompose morphologically complex words, such as segmentable, into their morphological constituents? In this article, we argue that spelling errors in English affixes reflect morphological boundary strength and degrees of segmentability. In support of this argument, we present a case study examining the spelling of the suffixes -able/-ible, -ence/-ance, and -ment in an online resource (Tweets), in forms such as , , , and . Based on previous research on morphological productivity and boundary strength (Hay, 2002; Hay & Baayen, 2002, 2005), we hypothesized that morphological segmentability should affect the choice between vs. , vs. , and vs. <-mint>. An analysis of roughly 23,000 non-standard spellings is consistent with that hypothesis, underscoring the usefulness of spelling variation as a source of evidence for morphological segmentability and for the role of morphological representations in language production and comprehension.

Research on age-related changes in speech has primarily focused on comparing “young” vs. “elderly” adults. Yet, listeners are able to guess talker age more accurately than a binary distinction would imply, suggesting that acoustic characteristics of speech change continually and gradually throughout adulthood. We describe acoustic properties of vowels produced by eleven talkers based on naturalistic speech samples spanning a period of 28 years, from ages 21 to 49. We find that the position of vowels in F1/F2 space shifts towards the periphery with increasing talker age. Based on Generalized Additive Mixed Effects models, we show that this shift is not fully attributable to changes in vowel duration or to segmental context. We discuss the implications of our results for research on aging and speech, and for research in which durational shortening and spectral characteristics of vowels are assumed to reflect a unitary process of phonetic reduction.

To what extent do speakers decompose morphologically complex words, such as segmentable, into their morphological constituents? In this article, we argue that spelling errors in English affixes reflect morphological boundary strength and degrees of segmentability. In support of this argument, we present a case study examining the spelling of the suffixes -able/-ible, -ence/-ance, and -ment in an online resource (Tweets), in forms such as , , , and . Based on previous research on morphological productivity and boundary strength (Hay, 2002; Hay & Baayen, 2002, 2005), we hypothesized that morphological segmentability should affect the choice between vs. , vs. , and vs. <-mint>. An analysis of roughly 23,000 non-standard spellings is consistent with that hypothesis, underscoring the usefulness of spelling variation as a source of evidence for morphological segmentability and for the role of morphological representations in language production and comprehension.

Research on age-related changes in speech has primarily focused on comparing “young” vs. “elderly” adults. Yet, listeners are able to guess talker age more accurately than a binary distinction would imply, suggesting that acoustic characteristics of speech change continually and gradually throughout adulthood. We describe acoustic properties of vowels produced by eleven talkers based on naturalistic speech samples spanning a period of 28 years, from ages 21 to 49. We find that the position of vowels in F1/F2 space shifts towards the periphery with increasing talker age. Based on Generalized Additive Mixed Effects models, we show that this shift is not fully attributable to changes in vowel duration or to segmental context. We discuss the implications of our results for research on aging and speech, and for research in which durational shortening and spectral characteristics of vowels are assumed to reflect a unitary process of phonetic reduction.

Pseudowords have long served as key tools in psycholinguistic investigations of the lexicon. A common assumption underlying the use of pseudowords is that they are devoid of meaning: Comparing words and pseudowords may then shed light on how meaningful linguistic elements are processed differently from meaningless sound strings. However, pseudowords may in fact carry meaning. On the basis of a computational model of lexical processing, linear discriminative learning (LDL Baayen et al., Complexity, 2019, 1-39, 2019), we compute numeric vectors representing the semantics of pseudowords. We demonstrate that quantitative measures gauging the semantic neighborhoods of pseudowords predict reaction times in the Massive Auditory Lexical Decision (MALD) database (Tucker et al., 2018). We also show that the model successfully predicts the acoustic durations of pseudowords. Importantly, model predictions hinge on the hypothesis that the mechanisms underlying speech production and comprehension interact. Thus, pseudowords emerge as an outstanding tool for gauging the resonance between production and comprehension. Many pseudowords in the MALD database contain inflectional suffixes. Unlike many contemporary models, LDL captures the semantic commonalities of forms sharing inflectional exponents without using the linguistic construct of morphemes. We discuss methodological and theoretical implications for models of lexical processing and morphological theory. The results of this study, complementing those on real words reported in Baayen et al., (Complexity, 2019, 1-39, 2019), thus provide further evidence for the usefulness of LDL both as a cognitive model of the mental lexicon, and as a tool for generating new quantitative measures that are predictive for human lexical processing.

PurposeIn this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).MethodsFollowing next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.ResultsAll patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.ConclusionHeterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.

Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1 beta subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

PURPOSE: Seminal vesicle-sparing radical cystectomy has been reported to improve short-term functional results without compromising oncological outcomes. However, there is still a lack of data on long-term outcomes after seminal vesicle-sparing radical cystectomy. The aim of this study was to compare oncological and functional outcomes in patients after seminal vesicle-sparing vs nonseminal vesicle-sparing radical cystectomy. MATERIALS AND METHODS: Oncological and functional outcomes of 470 consecutive patients after radical cystectomy and orthotopic ileal reservoir from 2000 to 2017 were evaluated. They were stratified into 6 groups according to nerve-sparing and seminal vesicle-sparing status as attempted during surgery: no sparing at all (55), unilateral nerve sparing (159), bilateral nerve sparing (132), unilateral seminal vesicle-sparing and unilateral nerve sparing (30), unilateral seminal vesicle sparing and bilateral nerve sparing (45), and bilateral seminal vesicle sparing (49) and used propensity modeling to adjust for preoperative differences. RESULTS: Median followup among the entire cohort was 64 months. Among the 6 groups, our analysis showed no difference in local recurrence-free survival (p=0.173). However, progression-free, cancer-specific and overall survival were more favorable in patients with seminal vesicle-sparing radical cystectomy (p <0.001, p=0.006 and p <0.001, respectively). Proportions of patients with erectile function recovery were higher in the seminal vesicle-sparing groups at all time points in all analyses, respectively, with pronounced earlier recovery in patients with bilateral seminal vesicle sparing. Importantly, patients with seminal vesicle sparing were significantly less in need of erectile aids to achieve erection and intercourse. Over the whole period, daytime urinary-continence was significantly better in the seminal vesicle sparing groups (OR 2.64 to 5.21). CONCLUSIONS: In a highly selected group of patients, seminal ves

Pseudowords have long served as key tools in psycholinguistic investigations of the lexicon. A common assumption underlying the use of pseudowords is that they are devoid of meaning: Comparing words and pseudowords may then shed light on how meaningful linguistic elements are processed differently from meaningless sound strings. However, pseudowords may in fact carry meaning. On the basis of a computational model of lexical processing, linear discriminative learning (LDL Baayen et al., Complexity, 2019, 1-39, 2019), we compute numeric vectors representing the semantics of pseudowords. We demonstrate that quantitative measures gauging the semantic neighborhoods of pseudowords predict reaction times in the Massive Auditory Lexical Decision (MALD) database (Tucker et al., 2018). We also show that the model successfully predicts the acoustic durations of pseudowords. Importantly, model predictions hinge on the hypothesis that the mechanisms underlying speech production and comprehension interact. Thus, pseudowords emerge as an outstanding tool for gauging the resonance between production and comprehension. Many pseudowords in the MALD database contain inflectional suffixes. Unlike many contemporary models, LDL captures the semantic commonalities of forms sharing inflectional exponents without using the linguistic construct of morphemes. We discuss methodological and theoretical implications for models of lexical processing and morphological theory. The results of this study, complementing those on real words reported in Baayen et al., (Complexity, 2019, 1-39, 2019), thus provide further evidence for the usefulness of LDL both as a cognitive model of the mental lexicon, and as a tool for generating new quantitative measures that are predictive for human lexical processing.

PurposeIn this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).MethodsFollowing next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.ResultsAll patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.ConclusionHeterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.

PurposeThe NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices.MethodsWe analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods.ResultsOf 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling.ConclusionInvestigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.

Lysosomal free sialic acid storage disorder (FSASD) is an extremely rare, autosomal recessive, neurodegenerative, multisystemic disorder caused by defects in the lysosomal sialic acid membrane exporter SLC17A5 (sialin). SLC17A5 defects cause free sialic acid and some other acidic hexoses to accumulate in lysosomes, resulting in enlarged lysosomes in some cell types and 10-100-fold increased urinary excretion of free sialic acid. Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia. Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features. Around 200 FSASD cases are reported worldwide, with the clinical spectrum ranging from a severe infantile onset form, often lethal in early childhood, to a mild, less severe form with subjects living into adulthood, also called Salla disease. The pathobiology of FSASD remains poorly understood and FSASD is likely underdiagnosed. Known patients have experienced a diagnostic delay due to the rarity of the disorder, absence of routine urine sialic acid testing, and non-specific clinical symptoms, including developmental delay, ataxia and infantile hypomyelination. There is no approved therapy for FSASD. We initiated a multidisciplinary collaborative effort involving worldwide academic clinical and scientific FSASD experts, the National Institutes of Health (USA), and the FSASD patient advocacy group (Salla Treatment and Research [S.T.A.R.] Foundation) to overcome the scientific, clinical and financial challenges facing the development of new treatments for FSASD. We aim to collect data that incentivize industry to further develop, obtain approval for, and commercialize FSASD treatments. This review summarizes current aspects of FSASD diagnosis, prevalence, etiology, and disease models, as well as challenges on the path to therapeutic approaches

Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1 beta subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

OBJECTIVES We report validation of OsiriX® —an image processing freeware—to measure multi-slice computed tomography-derived annulus diameters for preprocedural transcatheter aortic valve implantation planning. METHODS A total of 137 patients (82 ± 6.5 years, 42.3% male, logistic EuroSCORE 24.1 ± 14.2%) with severe aortic stenosis at high surgical risk underwent transcatheter aortic valve implantation assessment: transoesophageal echocardiography, angiography and multi-slice computed tomography. Retrospectively, 3D multi-slice computed tomography reconstructions were generated using OsiriX and the reliability evaluated regarding inter- and intraobserver variability, intermodality correlation and estimation of the clinical impact on transcatheter aortic valve implantation sizing. RESULTS Reliability of the novel OsiriX software was high with an interobserver mean difference of 0.6 ± 1.4 mm and intraclass correlation of absolute agreement of 0.84 (95% confidence interval 0.74-0.90). The intermodality accuracy between OsiriX measurements and conventional 2D computed tomography reconstructions, transoesophageal echocardiography and angiography revealed significantly larger sizing with OsiriX, with a mean difference to 2D computed tomography of 0.4 ± 2.2 mm, which would have changed valve sizing in 38% of patients. In 28%, a larger size would have been chosen, and this correlated highly with the occurrence of postoperative severe aortic regurgitation (P < 0.001). CONCLUSIONS While OsiriX measurements are an accurate and reproducible assessment of the aortic annulus, there are distinct and clinically relevant differences in aortic annulus dimensions between OsiriX measurements and previously standard imaging modalities. Sizing with OsiriX resulted in a larger perimeter compared with conventional 2D imaging. Careful assessment of valve size will take into account multiple imaging modalities.

Narrow-gap semiconductors with strong spin-orbit coupling such as bismuth tellurohalides have become popular candidates for spintronic applications. But driving spin-polarized photocurrents in these materials with circularly polarized light requires picosecond lifetimes of the photoexcited carriers and low spin-flip scattering rates. In search of these essential ingredients, we conducted an extensive study of the carrier dynamics on the Te-terminated surface of BiTeI, which exhibits a giant Rashba splitting of both surface and bulk states. We observe a complex interplay of surface and bulk dynamics after photoexcitation. Carriers are rapidly rearranged in momentum space by quasielastic phonon and defect scattering, while a phonon bottleneck leads to a slow equilibration between bulk electrons and lattice. The particular band dispersion opens an inelastic decay channel for hot carriers in the form of plasmon excitations, which are immanent to Rashba-split systems. These ultrafast scattering processes effectively redistribute excited carriers in momentum and energy space and thereby inhibit spin-polarized photocurrents.

The premise of Open Science is that research and medical management will progress faster if data and knowledge are openly shared. The value of Open Science is nowhere more important and appreciated than in the rare disease (RD) community. Research into RDs has been limited by insufficient patient data and resources, a paucity of trained disease experts, and lack of therapeutics, leading to long delays in diagnosis and treatment. These issues can be ameliorated by following the principles and practices of sharing that are intrinsic to Open Science. Here, we describe how the RD community has adopted the core pillars of Open Science, adding new initiatives to promote care and research for RD patients and, ultimately, for all of medicine. We also present recommendations that can advance Open Science more globally.

The premise of Open Science is that research and medical management will progress faster if data and knowledge are openly shared. The value of Open Science is nowhere more important and appreciated than in the rare disease (RD) community. Research into RDs has been limited by insufficient patient data and resources, a paucity of trained disease experts, and lack of therapeutics, leading to long delays in diagnosis and treatment. These issues can be ameliorated by following the principles and practices of sharing that are intrinsic to Open Science. Here, we describe how the RD community has adopted the core pillars of Open Science, adding new initiatives to promote care and research for RD patients and, ultimately, for all of medicine. We also present recommendations that can advance Open Science more globally.

Code-switching has been found to incur a processing cost in auditory comprehension. However, listeners may have access to anticipatory phonetic cues to code-switches (Piccinini & Garellek, 2014; Fricke et al., 2016), thus mitigating switch cost. We investigated effects of withholding anticipatory phonetic cues on code-switched word recognition by splicing English-to-Mandarin code-switches into unilingual English sentences. In a concept monitoring experiment, Mandarin-English bilinguals took longer to recognize code-switches, suggesting a switch cost. In an eye tracking experiment, the average proportion of all participants' looks to pictures corresponding to sentence-medial code-switches decreased when cues were withheld. Acoustic analysis of stimuli revealed tone-specific pitch contours before English-to-Mandarin code-switches, consistent with previous work on tonal coarticulation. We conclude that withholding anticipatory phonetic cues can negatively affect code-switched recognition: therefore, bilingual listeners use phonetic cues in processing code-switches under normal conditions. We discuss the implications of tonal coarticulation for mechanisms underlying phonetic cues to code-switching.

Bilinguals alternate frequently between languages, but many psycholinguistic studies on code-switching have reported a “switch cost”, i.e. an increased processing difficulty, in production (Meuter & Allport, 1999; Thomas & Allport, 2000; Costa & Santesteban, 2004; Gollan & Ferreira, 2009, although see Kleinman & Gollan, 2016), recognition (Soares & Grosjean, 1984), and comprehension (Olson, 2017). This dissertation involves three experiments investigating the factors modulating switch cost in the auditory comprehension of Mandarin and English code-switched words. First, recent research suggests that subtle phonetic differences between the pronunciation of code-switched utterances and unilingual utterances might act as anticipatory cues to code-switches for listeners (Piccinini & Garellek, 2014; Fricke, Kroll & Dussias, 2016), which could mitigate switch cost. Second, an “asymmetric switch cost,” or higher switch cost for the dominant first language (L1) compared to the second language (L2), has been reported for auditory comprehension of Spanish-English code-switches (Olson, 2017). Additionally, Mandarin-English bilinguals judge switches from English-to-Mandarin as infrequent compared to Mandarin-to-English switches (Lu, 1991; Ong & Zhang, 2010). Thus, Mandarin-English switching could be subject to a cost asymmetry driven not just by dominance but by frequency.Experiments 1 and 2 test the effects of withholding anticipatory phonetic cues on code-switched recognition by splicing English-to-Mandarin code-switches into unilingual English sentence contexts. Experiment 1 measured Mandarin-English bilinguals’ (N=42) reaction times in a concept monitoring task where they had to press a button when they heard a pictured object mentioned in an auditorily presented English sentence. The target word was either code-switched (i.e., in Mandarin) or unswitched. RTs were slower when the target was a code-switch, suggesting a switch cost. Experim

Contains fulltext : 220722.pdf (Publisher’s version ) (Closed access)

A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain-containing endocytic trafficking adaptor 1 and 2 (PHETA1/2; also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here, we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, phetal and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentation of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient. This article has an associated First Person interview with the first author of the paper.

A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain-containing endocytic trafficking adaptor 1 and 2 (PHETA1/2; also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here, we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, phetal and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentation of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient. This article has an associated First Person interview with the first author of the paper.

IMPORTANCE: Whether intervention should be performed in patients with asymptomatic severe aortic stenosis (AS) remains debated. OBJECTIVE: To meta-analyze the natural history of asymptomatic severe AS and examine the association of early intervention with survival. DATA SOURCES: PubMed, Embase, and Cochrane databases were searched from inception to February 1, 2020. STUDY SELECTION: Observational studies of adult patients with asymptomatic severe AS. DATA EXTRACTION AND SYNTHESIS: Two investigators independently extracted study and patient characteristics, follow-up time, events, and prognostic indicators of events. Random-effects models were used to derive pooled estimates. MAIN OUTCOMES AND MEASURES: The meta-analysis on natural history was performed on the primary end point of all-cause death occurring during a conservative treatment period, with secondary end points consisting of cardiac death, death due to heart failure, sudden death, development of symptoms, development of an indication for aortic valve intervention, and aortic valve intervention. The primary end point for the meta-analysis of early intervention vs a conservative strategy was all-cause death during long-term follow-up. Finally, meta-analysis was performed on the association of prognostic indicators with the composite of death or aortic valve intervention found in multivariable models. RESULTS: A total of 29 studies with 4075 patients with 11 901 years of follow-up were included. Pooled rates per 100 patients per year were 4.8 (95% CI, 3.6-6.4) for all-cause death, 3.0 (95% CI, 2.2-4.1) for cardiac death, 2.0 (95% CI, 1.3-3.1) for death due to heart failure, 1.1 (95% CI, 0.6-2.1) for sudden death, 18.1 (95% CI, 12.8-25.4) for an indication for aortic valve intervention, 18.5 (95% CI, 13.4-25.5) for development of symptoms, and 19.2 (95% CI, 15.5-23.8) for aortic valve intervention. Early intervention was associated with a significant reduction in long-term mortality (hazard ratio, 0.38; 95% CI

Bilinguals alternate frequently between languages, but many psycholinguistic studies on code-switching have reported a “switch cost”, i.e. an increased processing difficulty, in production (Meuter & Allport, 1999; Thomas & Allport, 2000; Costa & Santesteban, 2004; Gollan & Ferreira, 2009, although see Kleinman & Gollan, 2016), recognition (Soares & Grosjean, 1984), and comprehension (Olson, 2017). This dissertation involves three experiments investigating the factors modulating switch cost in the auditory comprehension of Mandarin and English code-switched words. First, recent research suggests that subtle phonetic differences between the pronunciation of code-switched utterances and unilingual utterances might act as anticipatory cues to code-switches for listeners (Piccinini & Garellek, 2014; Fricke, Kroll & Dussias, 2016), which could mitigate switch cost. Second, an “asymmetric switch cost,” or higher switch cost for the dominant first language (L1) compared to the second language (L2), has been reported for auditory comprehension of Spanish-English code-switches (Olson, 2017). Additionally, Mandarin-English bilinguals judge switches from English-to-Mandarin as infrequent compared to Mandarin-to-English switches (Lu, 1991; Ong & Zhang, 2010). Thus, Mandarin-English switching could be subject to a cost asymmetry driven not just by dominance but by frequency.Experiments 1 and 2 test the effects of withholding anticipatory phonetic cues on code-switched recognition by splicing English-to-Mandarin code-switches into unilingual English sentence contexts. Experiment 1 measured Mandarin-English bilinguals’ (N=42) reaction times in a concept monitoring task where they had to press a button when they heard a pictured object mentioned in an auditorily presented English sentence. The target word was either code-switched (i.e., in Mandarin) or unswitched. RTs were slower when the target was a code-switch, suggesting a switch cost. Experim

Code-switching has been found to incur a processing cost in auditory comprehension. However, listeners may have access to anticipatory phonetic cues to code-switches (Piccinini & Garellek, 2014; Fricke et al., 2016), thus mitigating switch cost. We investigated effects of withholding anticipatory phonetic cues on code-switched word recognition by splicing English-to-Mandarin code-switches into unilingual English sentences. In a concept monitoring experiment, Mandarin-English bilinguals took longer to recognize code-switches, suggesting a switch cost. In an eye tracking experiment, the average proportion of all participants' looks to pictures corresponding to sentence-medial code-switches decreased when cues were withheld. Acoustic analysis of stimuli revealed tone-specific pitch contours before English-to-Mandarin code-switches, consistent with previous work on tonal coarticulation. We conclude that withholding anticipatory phonetic cues can negatively affect code-switched recognition: therefore, bilingual listeners use phonetic cues in processing code-switches under normal conditions. We discuss the implications of tonal coarticulation for mechanisms underlying phonetic cues to code-switching.

Contains fulltext : 220722.pdf (Publisher’s version ) (Closed access)

The premise of Open Science is that research and medical management will progress faster if data and knowledge are openly shared. The value of Open Science is nowhere more important and appreciated than in the rare disease (RD) community. Research into RDs has been limited by insufficient patient data and resources, a paucity of trained disease experts, and lack of therapeutics, leading to long delays in diagnosis and treatment. These issues can be ameliorated by following the principles and practices of sharing that are intrinsic to Open Science. Here, we describe how the RD community has adopted the core pillars of Open Science, adding new initiatives to promote care and research for RD patients and, ultimately, for all of medicine. We also present recommendations that can advance Open Science more globally.

A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain-containing endocytic trafficking adaptor 1 and 2 (PHETA1/2; also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here, we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, phetal and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentation of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient. This article has an associated First Person interview with the first author of the paper.

The premise of Open Science is that research and medical management will progress faster if data and knowledge are openly shared. The value of Open Science is nowhere more important and appreciated than in the rare disease (RD) community. Research into RDs has been limited by insufficient patient data and resources, a paucity of trained disease experts, and lack of therapeutics, leading to long delays in diagnosis and treatment. These issues can be ameliorated by following the principles and practices of sharing that are intrinsic to Open Science. Here, we describe how the RD community has adopted the core pillars of Open Science, adding new initiatives to promote care and research for RD patients and, ultimately, for all of medicine. We also present recommendations that can advance Open Science more globally.

The 11(th) International Conference on Rare Diseases and Orphan Drugs (ICORD), South Africa, included the Africa-Rare initiative launch and facilitated multi-stakeholder engagement in the challenges facing, and opportunities for, Africans living with rare diseases. The following ICORD Global Call to Action, developed in collaboration with the International Rare Diseases Research Consortium, synthesizes the outcomes of the deliberations and emphasizes the international collaborative efforts required to address the global effects of rare diseases on public health.