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Germline de novo mutations can impact individual fitness, but their role in human male infertility is understudied. Trio-based exome sequencing identifies many new candidate genes affecting male fertility, including an essential regulator of male germ cell pre-mRNA splicing.

Abstract The translucency of dental ceramics [feldspathic ceramic (FC), lithium disilicate glass-ceramic (LD), zirconia-reinforced lithium silicate glass-ceramic (LS), and translucent zirconia (TZ)], in two thicknesses (1 and 2 mm), using different parameters was assessed. Translucency parameters ( TP ab *, TP00), contrast ratio (CR), light transmittance at 468 nm (T%), and light attenuation were determined. Data were analyzed by ANOVA, Tukey’s test, and Pearson correlations (α=0.05). CR ranged from 0.64 (LS-1 mm) to 0.96 (TZ-2 mm). TP ab * ranged from 3.7 (TZ-2 mm) to 32.2 (LS-1 mm). TP00 ranged from 3.0 (TZ-2 mm) to 26.4 (LS-1 mm). T% ranged from 14.9 (TZ-2 mm) to 75.2 (FC-1 mm). Light attenuation varied from 54% (LS-1 mm) to 84% (TZ-2 mm). There were significant strong negative correlations between CR and TP ab * (R=-0.997), CR and TP00 (R=-0.991), TP ab * and light attenuation (R=-0.888), and TP00 and light attenuation (R=-0.867). LS showed the highest translucency, whereas TZ showed the lowest translucency. When thickness increased, CR and light attenuation also increased, while TP and transmittance decreased.

Abstract Group A Streptococcus (Strep A) is a life-threatening human pathogen with no licensed vaccine. Here, we used a biopolymer particle (BP) approach to display repeats of Strep A vaccine candidate peptides p*17 and K4S2 derived from M and non-M protein, respectively. BPs densely displaying both peptides (BP-p*17-S2) were successfully assembled in one-step inside an engineered endotoxin-free Escherichia coli strain. Purified BP-p*17-S2 showed a spherical core-shell morphology with a biopolymer core and peptide shell. Upon formulation with aluminum hydroxide as adjuvant, BP-p*17-S2 exhibited a mean diameter of 2.9 µm and a positive surface charge of 22 mV. No cytotoxicity was detected when tested against HEK-293 cells. Stability studies showed that BP-p*17-S2 is ambient-temperature stable. Immunized mice showed no adverse reactions, while producing high titers of peptide specific antibodies and cytokines. This immune response could be correlated with protective immunity in an animal model of infection, i.e. intranasal challenge of mice with Strep A, where a significant reduction of >100-fold of pathogen burden in nose-associated lymphoid tissue, lung, and spleen was obtained. The cost-effective scalable manufacture of ambient-temperature stable BPs coated with Strep A peptides combined with their immunogenic properties offer an attractive alternative strategy to current Strep A vaccine development.

Streptococcus suis is a zoonotic pathogen affecting pigs and humans. This bacterium causes severe economic losses in the swine industry and poses a serious threat to public health and food safety. There is no effective commercial vaccine available for pigs or humans. In this study, we applied the biopolymer particle (BP) vaccine technology to incorporate seven conserved S. suis antigens (38 kDa protein (38), enolase (Enol), SSU1915, SSU1355, SSU0185, SSU1215, and SSU1773 (SSU1 and SSU2)). Two combinations of these antigens (38 and Enol; all SSU antigens designated as SSU1 and SSU2) were engineered to mediate production of BPs coated with either antigens 38 and Enol or SSU1 and SSU2 inside recombinant Escherichia coli. The isolated and purified empty BPs, 38-BP-Enol and SSU1-BP-SSU2, showed size ranges of 312–428 nm and 292–344 nm with and without the QuilA® adjuvant, respectively, and all showed a negative surface charge. Further characterization of purified BPs confirmed the presence of the expected antigen-comprising fusion proteins as assessed by tryptic peptide fingerprinting analysis using quadrupole time-of-flight mass spectrometry and immunoblotting. Vaccination with 38-BP-Enol and SSU1-BP-SSU2 formulated with and without QuilA® adjuvant induced significant antigen-specific humoral immune responses in mice. Antigen-coated BPs induced significant and specific Ig (IgM + IgG) and IgG immune responses (1.0 × 106–1.0 × 107) when compared with mice vaccinated with empty BPs. Functionality of the immune response was confirmed in challenge experiments using an acute murine S. suis infection model, which showed 100% survival of the 38-BP-Enol and SSU1-BP-SSU2 vaccinated mice compared to 70% survival when vaccinated with empty BPs. Overall, our data suggest that S. suis antigen-coated BPs could be developed into particulate vaccines that induce protective immunity against S. suis infections.

Despite numerous efforts to develop an effective vaccine against Pseudomonas aeruginosa, no vaccine has yet been approved for human use. This study investigates the utility of the P. aeruginosa inherently produced polyhydroxyalkanaote (PHA) inclusions and associated host–cell proteins (HCP) as a particulate vaccine platform. We further engineered PHA inclusions to display epitopes derived from the outer membrane proteins OprF/OprI/AlgE (Ag) or the type III secretion system translocator PopB. PHA and engineered PHA beads induced antigen-specific humoral, cell-mediated immune responses, anti-HCP and anti-polysaccharide Psl responses in mice. Antibodies mediated opsonophagocytic killing and serotype-independent protective immunity as shown by 100% survival upon challenge with P. aeruginosa in an acute pneumonia murine model. Vaccines were stable at 4 °C for at least one year. Overall, our data suggest that vaccination with subcellular empty PHA beads was sufficient to elicit multiple immune effectors that can prevent P. aeruginosa infection.

Abstract Background Stagnant flooding, where water of 25–50 cm remains until harvest time, is a major problem in rainfed lowland areas. Most of the Sub1 varieties, which can withstand around 2 weeks of complete submergence, perform poorly in these conditions. Hence, varieties tolerant of stagnant flooding are essential. Results This paper presents the first study to map QTLs associated with tolerance to stagnant flooding, along with a parallel study under normal irrigation, using an F7 mapping population consisting of 148 RILs derived from a cross of Ciherang-Sub1 and the stagnant-flooding tolerant line IR10F365. Phenotypic data was collected for 15 key traits under both environments. Additionally, survival rate was measured under stress conditions. Genotyping was performed using the Illumina Infinium genotyping platform with a 6 K SNP chip, resulting in 469 polymorphic SNPs. Under stress and irrigated conditions, 38 and 46 QTLs were identified, respectively. Clusters of QTLs were detected in both stress and normal conditions, especially on chromosomes 3 and 5. Conclusions Unique and common QTLs were identified and their physiological consequences are discussed. These beneficial QTLs can be used as targets for molecular breeding and can be further investigated to understand the underlying molecular mechanisms involved in stagnant flooding tolerance in rice.

In this study, we investigate the topology on B-algebras: an algebraic system of propositional logic. We define here the notion of topological B-algebras (briefly, TB-algebras) and some properties are investigated. A characterization of TB-algebras based on neighborhoods is provided. We also provide a filterbase that generates a unique B-topology, making a TB-algebra in which the filterbase is a neighborhood base of the constant element, provided that the given B-algebra is commutative. Finally, we investigate subalgebras of TB-algebras and introduce the notion of quotient TB-algebras of the given B-algebra.

Objectives: To determine the prevalence of increased serum fibrinogen levels and its association with cardiometabolic risk factors in overweight or obese children and adolescents. Methods: Cross-sectional study with 138 children and adolescents (overweight or obese) followed at a reference outpatient clinic of the public health care network. Fibrinogen concentration was divided into quartiles, and values above or equal to the third quartile were considered high. The association between high fibrinogen values and cardiometabolic risk factors was assessed using Pearson's chi-squared test or Fisher's exact test, as necessary. Logistic regression was used to adjust variables predictive of fibrinogen levels. Analyses were performed using SPSS version 22.0 and SAS software, considering a confidence interval of 95%. Results: Serum fibrinogen levels were elevated in 28.3% of individuals, showing association with the presence of high CRP (p = 0.003, PR: 2.41, 95% CI: 1.30–4.46) and the presence of four or more risk factors (p = 0.042; PR: 1.78, 95% CI: 1.00–3.17). After a logistic regression, only elevated CRP remained associated with altered fibrinogen levels (p = 0.024; PR: 1.32; 95% CI: 1.09–5.25). Conclusions: Increased fibrinogen was prevalent in the study population and was associated with ultrasensitive C-reactive protein and the presence of four or more cardiovascular risk factors; it should be included in the assessment of individuals at risk. Resumo: Objetivos: Verificar a prevalência de níveis séricos elevados de fibrinogênio e sua associação com os fatores de risco cardiometabólicos em crianças e adolescentes com sobrepeso ou obesidade. Métodos: Estudo transversal com 138 crianças e adolescentes (obesos ou com sobrepeso) acompanhados em um ambulatório de referência da rede pública. A concentração do fibrinogênio foi distribuída em quartis, sendo considerada elevada quando os valores eram iguais ou superiores ao terceiro quartil. A associação entre o valor elevado do fibrinogênio com os fatores de risco cardiometabólicos foi verificada através do teste qui-quadrado de Pearson ou teste exato de Fisher, quando necessário. A regressão logística foi utilizada para ajuste das variáveis preditoras do nível do fibrinogênio. As análises foram realizadas no SPSS 22.0 e SAS, considerando-se o intervalo de confiança de 95%. Resultados: Os níveis séricos de fibrinogênio estiveram elevados em 28.3% dos indivíduos, apresentando associação com a PCR elevada (RP: 2.41; IC 95%: 1.30–4.46, p = 0.003) e com a presença de quatro ou mais fatores de risco (RP: 1.78; IC 95%: 1.00–3.17; p = 0.042). Após a regressão logística, apenas o PCR elevado continuou associado ao fibrinogênio alterado (RP: 1.32; IC 95% 1.09–5.25; p = 0.024). Conclusões: O aumento do fibrinogênio foi prevalente na população estudada e esteve associado à proteína C reativa ultrassensível e ao número igual ou superior a quatro de fatores de risco cardiovasculares, devendo ser incluído na avaliação de indivíduos sob risco. Keywords: Fibrinogen, Obesity, Atherosclerosis, Children, Adolescents, Palavras-chave: Fibrinogênio, Obesidade, Aterosclerose, Crianças, Adolescentes

OBJETIVO: Verificar a relação entre a concentração de ácido úrico sérico de acordo com a presença ou não de esteatose hepática não alcoólica e/ou síndrome metabólica (SM) em crianças e adolescentes com sobrepeso ou obesidade. MÉTODOS: Estudo transversal desenvolvido no período de abril/2009 a março/2010, incluindo 129 crianças e adolescentes atendidos no Centro de Obesidade Infantil. Foi realizada antropometria, aferição da pressão arterial, dosagem dos exames laboratoriais e o diagnóstico de esteatose hepática por exame ultrassonográfico. Para o diagnóstico de SM, foram utilizados os critérios da National Cholesterol Education Program/Adult Treatment Panel III adaptados para faixa etária. Para avaliação da associação do ácido úrico com os grupos, foi realizado o teste do Qui-quadrado ou Fisher, adotando-se o intervalo de confiança de 95%. Para comparação de médias, utilizou-se o ANOVA One Way. Para o ajuste das variáveis foi utilizada a regressão logística múltipla. Os dados foram processados no SPSS versão 17. RESULTADOS: Níveis elevados de ácido úrico associaram-se significativamente à adolescência, SM e pressão arterial sistólica. O maior quartil de ácido úrico apresentou valores médios significativamente mais elevados de índice de massa corpórea, circunferência abdominal, pressão arterial sistólica, pressão arterial diastólica, triglicerídeos, colesterol total e HOMA-IR, e menor média do colesterol HDL. No modelo final só permaneceram associadas aos níveis de ácido úrico a faixa etária e a presença de síndrome metabólica. CONCLUSÕES: Níveis elevados de ácido úrico estiveram associados à síndrome metabólica e à adolescência, o que não foi observado com a esteatose hepática.

Objective: To investigate the association between serum uric acid concentration according to the presence or absence of non-alcoholic fatty liver disease (NAFLD) and/or metabolic syndrome (MS) in overweight or obese children and adolescents. Methods: This was a cross-sectional study conducted from April of 2009 to March of 2010, including 129 children and adolescents treated at the Center for Childhood Obesity. Anthropometric data, blood pressure measurements, and laboratory test results were obtained, and NAFLD diagnosis was made by ultrasound. The diagnosis of MS was made using the criteria of the National Cholesterol Education Program/Adult Treatment Panel III, adapted to age range. The chi-squared test or or Fisher's test were used to evaluate the association of uric acid with the groups, with a 95% confidence interval. One-way analysis of variance (ANOVA) was used for comparison of means. Multiple logistic regression was used for adjustment of variables. The data were analyzed with the Statistical Package for Social Sciences (SPSS), release 17. Results: High levels of uric acid were significantly associated with adolescence, MS, and systolic blood pressure. The highest quartile of uric acid showed significantly higher values of body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, triglycerides, total cholesterol, and homeostatic model assessment index (HOMA-IR), and lower mean values of HDL cholesterol. In the final model, only age range and the presence of MS remained associated with uric acid levels. Conclusions: High levels of uric acid were associated with MS and adolescence, which was not observed with NAFLD. Resumo: Objetivo: Verificar a relação entre a concentração de ácido úrico sérico de acordo com a presença ou não de esteatose hepática não alcoólica e/ou síndrome metabólica (SM) em crianças e adolescentes com sobrepeso ou obesidade. Métodos: Estudo transversal desenvolvido no período de abril/2009 a março/2010, incluindo 129 crianças e adolescentes atendidos no Centro de Obesidade Infantil. Foi realizada antropometria, aferição da pressão arterial, dosagem dos exames laboratoriais e o diagnóstico de esteatose hepática por exame ultrassonográfico. Para o diagnóstico de SM, foram utilizados os critérios da National Cholesterol Education Program/Adult Treatment Panel III adaptados para faixa etária. Para avaliação da associação do ácido úrico com os grupos, foi realizado o teste do Qui-quadrado ou Fisher, adotando-se o intervalo de confiança de 95%. Para comparação de médias, utilizou-se o ANOVA One Way. Para o ajuste das variáveis foi utilizada a regressão logística múltipla. Os dados foram processados no SPSS versão 17. Resultados: Níveis elevados de ácido úrico associaram-se significativamente à adolescência, SM e pressão arterial sistólica. O maior quartil de ácido úrico apresentou valores médios significativamente mais elevados de índice de massa corpórea, circunferência abdominal, pressão arterial sistólica, pressão arterial diastólica, triglicerídeos, colesterol total e HOMA-IR, e menor média do colesterol HDL. No modelo final só permaneceram associadas aos níveis de ácido úrico a faixa etária e a presença de síndrome metabólica. Conclusões: Níveis elevados de ácido úrico estiveram associados à síndrome metabólica e à adolescência, o que não foi observado com a esteatose hepática. Keywords: Uric acid, Metabolic syndrome X, Fatty liver, Cardiovascular diseases, Obesity, Palavras-chave: Ácido úrico, Síndrome X metabólica, Fígado gorduroso, Doenças cardiovasculares, Obesidade

Verificou-se o efeito do acondicionamento em saliva artificial na resistência à flexão e no tempo de vida de uma porcelana feldspática dentária. Os espécimes na forma de disco foram preparados por sinterização, usinagem e polimento e ensaiados pelo método da fadiga dinâmica para determinação dos parâmetros de crescimento de trinca subcrítico (SCG), com taxas de tensão de 0,01 a 100 MPa/s em meio de saliva artificial a 37 °C. Antes do ensaio de flexão biaxial, parte dos espécimes foi imersa em saliva artificial a 37 °C por 10 dias e outra parte foi mantida ao ar. O acondicionamento em saliva causou aumento de ~11% na resistência à flexão biaxial; aumento de 20% no módulo de Weibull; aumento de 20% no coeficiente de susceptibilidade ao fenômeno de SCG; aumento de 50% na resistência à flexão prevista no tempo de fratura de 1 ano; manutenção da tenacidade à fratura; e diminuição de 5% da dureza superficial. Os resultados indicaram que, ao menos no caso investigado, a exposição da porcelana à saliva não degrada as propriedades mecânicas e pode até aumentar a resistência à flexão e à propagação lenta de trincas.The effects of artificial saliva storage on flexural strength and lifetime prediction of a dental feldspathic porcelain were investigated. The disk-shaped specimens were sintered, machined and polished and then subjected to a dynamic fatigue test in order to determine the slow crack growth (SCG) parameters, by means of biaxial flexure tests at stress rates of 0.01 to 100 MPa/s. The specimens remained immersed in artificial saliva at 37 ºC during the whole test. Before the biaxial flexure strength test, some specimens were stored in artificial saliva at 37 ºC for 10 days while others were stored in air at ambient temperature. The specimens stored in artificial saliva presented an ~11% increase in biaxial flexure strength; a 20% increase in Weibull modulus; a 20% increase in SCG susceptibility coefficient; a 50% increase in the predicted flexural strength for a lifetime of 1 year, a 5% decrease in superficial hardness. Similar fracture toughness values were determined for groups stored in air and in artificial saliva. The results indicated that, at least in the present study, storage of a dental porcelain in artificial saliva did not decrease the mechanical properties investigated and can even increase the flexural strength value and the resistance to slow crack growth phenomenon.

In this paper we list several useful properties of central points in linear programming problems. We study the logarithmic barrier function, the analytic center and the central path, relating the proximity measures and scaled Euclidean distances defined for the primal and primal–dual problems. We study the Newton centering steps, and show how large the short steps used in path following algorithms can actually be, and what variation can be ensured for the barrier function in each iteration of such methods. We relate the primal and primal–dual Newton centering steps and propose a primal-only path following algorithm for linear programming. [ABSTRACT FROM AUTHOR]

ABSTRACT: Ruminants may be affected by a wide variety of central nervous system (CNS) diseases. Cerebrospinal fluid (CSF) analysis forms the basis for ante mortem diagnostic evaluation of ruminants with clinical signs involving the CNS. Despite its importance as a tool to aid diagnosis, data regarding CSF examinations in spontaneous cases of CNS diseases in ruminants from Brazil are limited, and most reports involve experimental studies. Therefore, this study aimed to report the results of CSF analysis in 58 ruminants showing signs of neurological disorders. CSF samples for analysis were obtained from 32 cattle, 20 sheep, and 6 goats by cerebello-medullary cistern (n=54) or lumbosacral space (n=4) puncture. These ruminants showed neurological signs related to viral (n=13), mycotic (n=3), or bacterial (n=15) infections, and toxic (n=21), traumatic (n=4), or congenital disorders (n=2). CSF analysis from ruminants with viral infections presented lymphocytic pleocytosis, even though CSF showed no changes in several cases of rabies. Neutrophilic pleocytosis, cloudiness, presence of fibrin clots, and abnormal coloration were evident in the CSF of most cases of CNS bacterial infection, such as meningoencephalitis, meningitis, abscesses, myelitis, and a case of conidiobolomycosis. On the other hand, CSF was unchanged in most cases of toxic disorders, as botulism and hepatic encephalopathy. Elevated CSF density was observed in 60% of ruminants diagnosed with polioencephalomalacia. Our findings show that evaluation of CSF is a valuable diagnostic tool when used in association with epidemiological, clinical and pathological findings for diagnosis of CNS diseases in ruminants.

ABSTRACT Parvovirus B19 (B19V) can be transmitted by the respiratory route, vertically - from the mother to the fetus - and via blood transfusion or organ transplantation. Infection by transfusion of blood or blood products occurs due to the resistance of B19V to viral inactivation methods. Our study evaluated the presence of B19V deoxyribonucleic acid (DNA) and the prevalence of anti-B19V class G immunoglobulin (IgG) in women of childbearing age blood donors of the Federal District, Brazil. Our results demonstrated the absence of B19V DNA in these blood donors. However, the seroprevalence for anti-B19V IgG was observed in 60.7% of this population. This study provides important data of B19V circulation in the Center-West of Brazil.

Fewer than half of individuals with a suspected Mendelian or monogenic condition receive a precise molecular diagnosis after comprehensive clinical genetic testing. Improvements in data quality and costs have heightened interest in using long-read sequencing (LRS) to streamline clinical genomic testing, but the absence of control data sets for variant filtering and prioritization has made tertiary analysis of LRS data challenging. To address this, the 1000 Genomes Project (1KGP) Oxford Nanopore Technologies Sequencing Consortium aims to generate LRS data from at least 800 of the 1KGP samples. Our goal is to use LRS to identify a broader spectrum of variation so we may improve our understanding of normal patterns of human variation. Here, we present data from analysis of the first 100 samples, representing all 5 superpopulations and 19 subpopulations. These samples, sequenced to an average depth of coverage of 37× and sequence read N50 of 54 kbp, have high concordance with previous studies for identifying single nucleotide and indel variants outside of homopolymer regions. Using multiple structural variant (SV) callers, we identify an average of 24,543 high-confidence SVs per genome, including shared and private SVs likely to disrupt gene function as well as pathogenic expansions within disease-associated repeats that were not detected using short reads. Evaluation of methylation signatures revealed expected patterns at known imprinted loci, samples with skewed X-inactivation patterns, and novel differentially methylated regions. All raw sequencing data, processed data, and summary statistics are publicly available, providing a valuable resource for the clinical genetics community to discover pathogenic SVs., (© 2024 Gustafson et al.; Published by Cold Spring Harbor Laboratory Press.)

Chagas disease (CD), a disease affecting millions globally, remains shrouded in scientific uncertainty, particularly regarding the role of the intestinal microbiota in disease progression. This study investigates the effects of antibiotic-induced microbiota depletion on parasite burden, immune responses, and clinical outcomes in BALB/c mice infected with either the Trypanosoma cruzi Colombiana or CL Brener strains. Mice were treated with a broad-spectrum antibiotic cocktail before infection, and parasite burden was quantified via qPCR at 30 and 100 days post-infection (dpi). Immune responses were analyzed using flow cytometry and ELISA, while histopathology was conducted on cardiac and intestinal tissues. Antibiotic treatment uncovered strain-specific correlations, with Colombiana infections affecting Bifidobacterium populations and CL Brener infections linked to Lactobacillus. Microbiota depletion initially reduced parasite burden in the heart and intestine, but an increase was observed in the chronic phase, except in the CL Brener-infected gut, where an early burden spike was followed by a decline. Antibiotic-induced bacterial shifts, such as reductions in Bacteroides and Bifidobacterium , promoted a more pro-inflammatory immune profile. These findings highlight the importance of microbiota and strain-specific factors in CD and suggest further research into microbiota manipulation as a potential therapeutic strategy.

Introduction: Hidradenitis suppurativa (HS) is a prevalent and persistent inflammatory skin disorder, lacking a known cure or effective biomarkers for early diagnosis at present. The genetic determinants of HS have not been fully documented, but it is believed to result from a combination of genetic and environmental factors., Methods: To identify relevant HS gene variants in sporadic HS patients, this study utilized longitudinal electronic health records (EHRs) and whole-exome sequencing. DNA exome sequencing data from 92,455 participant samples in the MyCode biobank, linked to Geisinger's EHR, were analyzed. This cohort included 1,092 HS cases and 91,363 healthy controls. The MyCode EHR has a median longitudinal follow-up of 15 years per participant, with an average of 87 clinical encounters, 687 laboratory tests, and 7 procedures., Results: There were 1,092 (901 females and 191 males) participants aged 14-89 years (median 47 years) with HS (L73.2), indicating a 1.18% prevalence and accounting for a 4.7:1 female-to-male ratio among the individuals presenting for clinical care. γ-secretase complex, syndromic, and autoinflammatory gene variants were assessed. Potential pathogenic variants were identified among 66 individuals in the HS genes studied. Molecularly, the estimated HS variant prevalence was 1:1,400 in the cohort, 12.3% of variant carriers had HS diagnosis in EHR., Conclusions: Using longitudinal EHR data, genomic screening identified HS-associated gene variants in a defined group of sporadic HS patients to augment the clinical diagnosis, particularly in cases of ambiguity. Based on this study, the field of skin disorders can benefit from a personalized approach to HS diagnosis using large-scale sequencing., (© 2024 S. Karger AG, Basel.)

Background: There is a need to understand the clinical decision-making and work practices within ostomy nursing care to support expanding nursing training., Objective: To develop and evaluate a new metric-based simulation for assessing ostomy nursing care using a human factors approach., Sample: This pilot study involved eleven stakeholders in the needs assessment, six nurse participants performing simulated ostomy care, and three independent observers assessing procedure reliability., Method: We conducted a needs assessment of ostomy nursing care and training, developed an enhanced metric-based simulation for ostomy appliance change procedures, and statistically evaluated its reliability for measuring the simulated tasks., Results: The enhanced metric-based simulation captured different tasks within four task categories: product selection; stoma and peristomal skin care; baseplate sizing and adhesion; and infection control strategies. The video review procedure was reliable for assessing continuous (average ICC≥0.96) and categorical (average κ>0.96) variables., Conclusion: The new metric-based simulation was suitable for characterizing a broad range of clinical decision-making and work practices in ostomy nursing care.

Background: Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated with Wolff-Parkinson-White syndrome. The goal of this study was to identify genetic variants within a large family with structurally normal hearts affected by SVT and Wolff-Parkinson-White syndrome and determine causality of the gene deficit in a corresponding mouse model., Methods: Whole exome sequencing performed on 2 distant members of a 3-generation family in which multiple members were affected by SVT or Wolff-Parkinson-White pattern (preexcitation) on ECG identified MRC2 as a candidate gene. Serial electrocardiograms, intracardiac electrophysiology studies, echocardiography, optical mapping studies, and histology were performed on both Mrc2 mutant and WT (wild-type) mice., Results: A rare HET (heterozygous) missense variant c.2969A>G;p.Glu990Gly (E990G) in MRC2 was identified as the leading candidate gene variant segregating with the cardiac phenotype following an autosomal-dominant Mendelian trait segregation pattern with variable expressivity. In vivo electrophysiology studies revealed reentrant SVT in E990G mice. Optical mapping studies in E990G mice demonstrated abnormal retrograde conduction, suggesting the presence of an accessory pathway. Histological analysis of E990G mouse hearts showed a disordered ECM (extracellular matrix) in the annulus fibrosus. Finally, Mrc2 knockdown in human cardiac fibroblasts enhanced accelerated cell migration., Conclusions: This study identified a rare nonsynonymous variant in the MRC2 gene in individuals with familial reentrant SVT, Wolff-Parkinson-White ECG pattern, and structurally normal hearts. Furthermore, Mrc2 knock-in mice revealed an increased incidence of reentrant SVT and bypass tract formation in the setting of preserved cardiac structure and function., Competing Interests: Dr Lupski has stock ownership in 23andMe (Sunnyvale, CA), is a paid consultant for the Regeneron Genetics Center (Tarrytown, NY), and is a coinventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories (Houston, TX). Dr Lupski serves on the Scientific Advisory Board of BG. Dr Wehrens is a cofounder and board member of Elex Biotech LLC, a start-up company developing RyR2 (ryanodine receptor type-2) modifying drugs for heart disease. Dr Wehrens is also a consultant at Pfizer and Rocket Pharmaceuticals. The other authors report no conflicts.

Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Patients, families, the healthcare system, and society as a whole are all significantly impacted by rare diseases (RDs). According to various classifications, there are currently up to 9,000 different rare diseases that have been recognized, and new diseases are discovered every month. Although very few people are affected by each uncommon disease individually, millions of people are thought to be impacted globally when all these conditions are considered. Therefore, RDs represent an important public health concern. Although crucial for clinical care, early and correct diagnosis is still difficult to achieve in many nations, especially those with low and middle incomes. Consequently, a sizeable amount of the overall burden of RD is attributable to undiagnosed RD (URD). Existing barriers and policy aspects impacting the care of patients with RD and URD remain to be investigated., Methods: To identify unmet needs and opportunities for patients with URD, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) conducted a survey among its members, who were from 20 different nations. The survey used a mix of multiple choice and dedicated open questions covering a variety of topics. To explore reported needs and analyze them in relation to national healthcare economical aspects, publicly available data on (a) World Bank ranking; (b) Current health expenditure per capita ; (c) GDP per capita ; (d) Domestic general government health expenditure (% of GDP); and (e) Life expectancy at birth, total (years) were incorporated in our study., Results: This study provides an in-depth evaluation of the unmet needs for 20 countries: low-income (3), middle-income (10), and high-income (7). When analyzing reported unmet needs, almost all countries ( N = 19) indicated that major barriers still exist when attempting to improve the care of patients with UR and/or URD; most countries report unmet needs related to the availability of specialized care and dedicated facilities. However, while the countries ranked as low income by the World Bank showed the highest prevalence of referred unmet needs across the different domains, no specific trend appeared when comparing the high, upper, and low-middle income nations. No overt trend was observed when separating countries by current health expenditure per capita , GDP per capita , domestic general government health expenditure (% of GDP) and life expectancy at birth, total (years). Conversely, both the GDP and domestic general government health expenditure for each country impacted the presence of ongoing research., Conclusion: We found that policy characteristics varied greatly with the type of health system and country. No overall pattern in terms of referral for unmet needs when separating countries by main economic or health indicators were observed. Our findings highlight the importance of identifying actionable points (e.g., implemented orphan drug acts or registries where not available) in order to improve the care and diagnosis of RDs and URDs on a global scale., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sciascia, Roccatello, Salvatore, Carta, Cellai, Ferrari, Lumaka, Groft, Alanay, Azam, Baynam, Cederroth, Cutiongco-de la Paz, Dissanayake, Giugliani, Gonzaga-Jauregui, Hettiarachchi, Kvlividze, Landoure, Makay, Melegh, Ozbek, Puri, Romero, Scaria, Jamuar, Shotelersuk, Gahl, Wiafe, Bodamer, Posada and Taruscio.)

Background: Druze individuals, like many genetically homogeneous and isolated populations, harbor recurring pathogenic variants (PV) in autosomal recessive (AR) disorders., Methods: Variant calling of whole-genome sequencing (WGS) of 40 Druze from the Human Genome Diversity Project (HGDP) was performed (HGDP-cohort). Additionally, we performed whole exome sequencing (WES) of 118 Druze individuals: 38 trios and 2 couples, representing geographically distinct clans (WES-cohort). Rates of validated PV were compared with rates in worldwide and Middle Eastern populations, from the gnomAD and dbSNP datasets., Results: Overall, 34 PVs were identified: 30 PVs in genes underlying AR disorders, 3 additional PVs were associated with autosomal dominant (AD) disorders, and 1 PV with X-linked-dominant inherited disorder in the WES cohort., Conclusions: The newly identified PVs associated with AR conditions should be considered for incorporation into prenatal-screening options offered to Druze individuals after an extension and validation of the results in a larger study.

Introduction: Rare diseases (RD) are a health priority worldwide, overall affecting hundreds of millions of people globally. Early and accurate diagnosis is essential to support clinical care but remains challenging in many countries, especially the low- and medium-income ones. Hence, undiagnosed RD (URD) account for a significant portion of the overall RD burden., Methods: In October 2020, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) launched a survey among its members, belonging to 20 countries across all continents, to map unmet needs and opportunities for patients with URD. The survey was based on questions with open answers and included eight different domains. Conflicting interpretations were resolved in contact with the partners involved., Results: All members responded to the survey. The results indicated that the scientific and medical centers make substantial efforts to respond to the unmet needs of patients. In most countries, there is a high awareness of RD issues. Scarcity of resources was highlighted as a major problem, leading to reduced availability of diagnostic expertise and research. Serious equity in accessibility to services were highlighted both within and between participating countries. Regulatory problems, including securing informed consent, difficulties in sending DNA to foreign laboratories, protection of intellectual property, and conflicts of interest on the part of service providers, remain issues of concern. Finally, most respondents stressed the need to strengthen international cooperation in terms of data sharing, clinical research, and diagnostic expertise for URD patients in low and medium income countries., Discussion: The survey highlighted that many countries experienced a discrepancy between the growing expertise and scientific value, the level of awareness and commitment on the part of relevant parties, and funding bodies. Country-tailored public health actions, including general syllabus of medical schools and of the education of other health professionals, are needed to reduce such gaps., Competing Interests: SW was employed by Rare Disease Ghana Initiative. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Taruscio, Salvatore, Lumaka, Carta, Cellai, Ferrari, Sciascia, Groft, Alanay, Azam, Baynam, Cederroth, Cutiongco-de la Paz, Dissanayake, Giugliani, Gonzaga-Jauregui, Hettiarachchi, Kvlividze, Landoure, Makay, Melegh, Ozbek, Puri, Romero, Scaria, Jamuar, Shotelersuk, Roccatello, Gahl, Wiafe, Bodamer and Posada.)

Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations (n = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations (n = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations (n = 19). Fifty-one patients (males, n = 27; females, n = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg -1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of -27.1% (37.4) (95% confidence interval -71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 ., (© 2023. The Author(s).)

Rare diseases (RDs) cause considerable death and disability in Latin America. Still, there is no consensus on their definition across the region. Patients with RDs face a diagnostic odyssey to find a correct diagnosis, which may last many years and creates a burden for caregivers, healthcare systems, and society. These diagnostic delays have repercussions on the health and economic burden created by RDs and continue to represent an unmet medical need. This review analyzes barriers to the widespread adoption of newborn screening (NBS) programs and early diagnostic methods for RDs in Latin America and provides recommendations to achieve this critical objective. Increasing the adoption of NBS programs and promoting early diagnosis of RDs are the first steps to improving health outcomes for patients living with RDs. A coordinated, multistakeholder effort from leaders of patient organizations, government, industry, medical societies, academia, and healthcare services is required to increase the adoption of NBS programs. Patients' best interests should remain the guiding principle for decisions regarding NBS implementation and early diagnosis for RDs., (Copyright © 2022 Giugliani, Castillo Taucher, Hafez, Oliveira, Rico-Restrepo, Rozenfeld, Zarante and Gonzaga-Jauregui.)

The genotyping of millions of human samples has made it possible to evaluate variants across the human genome for their possible association with risks for numerous diseases and other traits by using genome-wide association studies (GWASs). The associations between phenotype and genotype found in GWASs make possible the construction of polygenic scores (PGSs), which aim to predict a trait or disease outcome in an individual on the basis of their genotype (in the disease case, the term polygenic risk score [PRS] is often used). PGSs have shown promise for studying the biology of complex traits and as a tool for evaluating individual disease risks in clinical settings. Although the quantity and quality of data to compute PGSs are increasing, challenges remain in the technical aspects of developing PGSs and in the ethical and social issues that might arise from their use. This ASHG Guidance emphasizes three major themes for researchers working with or interested in the application of PGSs in their own research: (1) developing diverse research cohorts; (2) fostering robustness in the development, application, and interpretation of PGSs; and (3) improving the communication of PGS results and their implications to broad audiences., (Copyright © 2022. Published by Elsevier Inc.)

Mutations in nitrogen permease regulator-like 3 (NPRL3), a component of the GATOR1 complex within the mTOR pathway, are associated with epilepsy and malformations of cortical development. Little is known about the effects of NPRL3 loss on neuronal mTOR signalling and morphology, or cerebral cortical development and seizure susceptibility. We report the clinical phenotypic spectrum of a founder NPRL3 pedigree (c.349delG, p.Glu117LysFS; n = 133) among Old Order Mennonites dating to 1727. Next, as a strategy to define the role of NPRL3 in cortical development, CRISPR/Cas9 Nprl3 knockout in Neuro2a cells in vitro and in foetal mouse brain in vivo was used to assess the effects of Nprl3 knockout on mTOR activation, subcellular mTOR localization, nutrient signalling, cell morphology and aggregation, cerebral cortical cytoarchitecture and network integrity. The NPRL3 pedigree exhibited an epilepsy penetrance of 28% and heterogeneous clinical phenotypes with a range of epilepsy semiologies, i.e. focal or generalized onset, brain imaging abnormalities, i.e. polymicrogyria, focal cortical dysplasia or normal imaging, and EEG findings, e.g. focal, multi-focal or generalized spikes, focal or generalized slowing. Whole exome analysis comparing a seizure-free group (n = 37) to those with epilepsy (n = 24) to search for gene modifiers for epilepsy did not identify a unique genetic modifier that explained the variability in seizure penetrance in this cohort. Nprl3 knockout in vitro caused mTOR pathway hyperactivation, cell soma enlargement and the formation of cellular aggregates seen in time-lapse videos that were prevented with the mTOR inhibitors rapamycin or torin1. In Nprl3 knockout cells, mTOR remained localized on the lysosome in a constitutively active conformation, as evidenced by phosphorylation of ribosomal S6 and 4E-BP1 proteins, even under nutrient starvation (amino acid-free) conditions, demonstrating that Nprl3 loss decouples mTOR activation from neuronal metabolic state. To model human malformations of cortical development associated with NPRL3 variants, we created a focal Nprl3 knockout in foetal mouse cortex by in utero electroporation and found altered cortical lamination and white matter heterotopic neurons, effects which were prevented with rapamycin treatment. EEG recordings showed network hyperexcitability and reduced seizure threshold to pentylenetetrazol treatment. NPRL3 variants are linked to a highly variable clinical phenotype which we propose results from mTOR-dependent effects on cell structure, cortical development and network organization., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability., (© 2022. The Author(s).)

Purpose: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not., Methods: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship., Results: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants., Conclusion: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs., Competing Interests: Conflict of Interest A.Br. is a shareholder of and employed by Natera. A.Br. has also been an employee of Invitae and Quest Diagnostics commercial laboratories. A.R.C. and K.B. are shareholders of and employed by Illumina, Inc. A.Be. is a shareholder of and is employed by Invitae. B.B. has received research support from Biomarin Pharmaceuticals Inc. He is currently employed by and is a shareholder of Alnylam Pharmaceuticals, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

The vision of the American Society of Human Genetics (ASHG) is that people everywhere will realize the benefits of human genetics and genomics. Implicit in that vision is the importance of ensuring that the benefits of human genetics and genomics research are realized in ways that minimize harms and maximize benefits, a goal that can only be achieved through focused efforts to address health inequities and increase the representation of underrepresented communities in genetics and genomics research. This guidance is intended to advance community engagement as an approach that can be used across the research lifecycle. Community engagement uniquely offers researchers in human genetics and genomics an opportunity to pursue that vision successfully, including by addressing underrepresentation in genomics research., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Prenatal exome sequencing (ES) is currently indicated for fetal malformations. Some neurocognitive genetic disorders may not have a prenatal phenotype. We assessed the prevalence of prenatally detectable phenotypes among patients with neurocognitive syndromes diagnosed postnatally by ES., Methods: The medical files of a cohort of 138 patients diagnosed postnatally with a neurocognitive disorder using ES were reviewed for prenatal sonographic data. The Online Mendelian Inheritance in Man (OMIM) database was searched for prenatally detectable phenotypes for all genes identified., Results: Prenatal imaging data were available for 122 cases. Of these, 29 (23.75%) had fetal structural abnormalities and another 29 had other ultrasound abnormalities (fetal growth restriction, polyhydramnios, elevated nuchal translucency). In 30 patients, structural aberrations that were not diagnosed prenatally were detected at birth; in 21 (17.2%), the abnormalities could theoretically be detected prenatally by third-trimester/targeted scans. According to OMIM, 55.9% of the diagnosed genes were not associated with structural anomalies., Conclusions: Most patients (52.5%) with postnatally diagnosed neurocognitive disorders did not have prenatal sonographic findings indicating prenatal ES should be considered. The prevalence of specific prenatal phenotypes such as fetal growth restriction and polyhydramnios in our cohort suggests that additional prenatal findings should be assessed as possible indications for prenatal ES., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Background and Purpose: Muscular A-type lamin-interacting protein (MLIP) is most abundantly expressed in cardiac and skeletal muscle. In vitro and animal studies have shown its regulatory role in myoblast differentiation and in organization of myonuclear positioning in skeletal muscle, as well as in cardiomyocyte adaptation and cardiomyopathy. We report the association of biallelic truncating variation in the MLIP gene with human disease in five individuals from two unrelated pedigrees., Methods: Clinical evaluation and exome sequencing were performed in two unrelated families with elevated creatine kinase level., Results: Family 1. A 6-year-old girl born to consanguineous parents of Arab-Muslim origin presented with myalgia, early fatigue after mild-to-moderate physical exertion, and elevated creatine kinase levels up to 16,000 U/L. Exome sequencing revealed a novel homozygous nonsense variant, c.2530C>T; p.Arg844Ter, in the MLIP gene. Family 2. Three individuals from two distantly related families of Old Order Amish ancestry presented with elevated creatine kinase levels, one of whom also presented with abnormal electrocardiography results. On exome sequencing, all showed homozygosity for a novel nonsense MLIP variant c.1825A>T; p.Lys609Ter. Another individual from this pedigree, who had sinus arrhythmia and for whom creatine kinase level was not available, was also homozygous for this variant., Conclusions: Our findings suggest that biallelic truncating variants in MLIP result in myopathy characterized by hyperCKemia. Moreover, these cases of MLIP-related disease may indicate that at least in some instances this condition is associated with muscle decompensation and fatigability during low-to-moderate intensity muscle exertion as well as possible cardiac involvement., (© 2021 European Academy of Neurology.)

Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Background: Familial hypercholesterolemia (FH) due to a founder variant in Apolipoprotein B (ApoB R3500Q ) is reported in 12% of the Pennsylvania Amish community. By studying a cohort of ApoB R3500Q heterozygotes and homozygotes, we aimed to characterize the biochemical and cardiac imaging features in children and young adults with a common genetic background and similar lifestyle., Methods: We employed advanced lipid profile testing, carotid intima media thickness (CIMT), pulse wave velocity (PWV), and peripheral artery tonometry (PAT) to assess atherosclerosis in a cohort of Amish ApoB R3500Q heterozygotes (n = 13), homozygotes (n = 3), and their unaffected, age-matched siblings (n = 9). ApoB R3500Q homozygotes were not included in statistical comparisons., Results: LDL cholesterol (LDL-C) was significantly elevated among ApoB R3500Q heterozygotes compared to sibling controls, though several ApoB R3500Q heterozygotes had LDL-C levels in the normal range. LDL particles (LDL-P), small, dense LDL particles, and ApoB were also significantly elevated among subjects with ApoB R3500Q . Despite these differences in serum lipids and particles, CIMT and PWV were not significantly different between ApoB R3500Q heterozygotes and controls in age-adjusted analysis., Conclusions: We provide a detailed description of the serum lipids, atherosclerotic plaque burden, vascular stiffness, and endothelial function among children and young adults with FH due to heterozygous ApoB R3500Q . Fasting LDL-C was lower than what is seen with other forms of FH, and even normal in several ApoB R3500Q heterozygotes, emphasizing the importance of cascade genetic testing among related individuals for diagnosis. We found increased number of LDL particles among ApoB R3500Q heterozygotes but an absence of detectable atherosclerosis., (© 2022. The Author(s).)