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Labelled Background: Haemoptysis is a life-threatening complication of cystic fibrosis (CF). One treatment is bronchial artery embolisation (BAE) using embolic-microspheres (EMs). During BAE, pulmonary arteries can be seen on digital subtracted angiography while iodine containing contrast material injection is performed in the bronchial artery. This suggests that EMs could go from bronchial to nontarget pulmonary arteries. The aim was to evaluate if EMs could be found inside pulmonary arteries on lung explants after BAE in transplanted CF patients., Methods: Retrospective observational study including patients with CF who underwent lung transplantation and had previously needed BAE. Clinical, chest CT angiography, and angiographic data were reviewed from medical records. Pathology examination of lung explants was performed to analyze the EMs anatomical localisation., Results: Eight patients were included between 2013 and 2015, four males with a mean age of 29 (19-45) years. All patients had bronchial artery hypertrophy on CT and bronchial-to-pulmonary artery shunting during BAE. On pathology examination, EM ≤800 µm were found in the pulmonary arteries in all patients and were responsible for distal branch occlusions. Two pulmonary infarcts were observed on CT angiography after BAE and confirmed histopathologically., Conclusions: EM migration from the bronchial to pulmonary arteries is a common occurrence after BAE in patients with advanced stage CF. Although BAE is a highly effective means of controlling haemoptysis in CF, studies on the optimal particle size are needed to preserve pulmonary artery circulation, because these results suggest that low size EMs could lead to nontarget embolisation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands., Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays., Results: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband., Conclusion: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.

Thoracic ultrasound (TUS) is increasingly studied in neonatal respiratory distress but chest x-ray (CXR) remains the first-line exam. We aimed to evaluate its diagnostic performance for the investigation of unselected causes of neonatal respiratory distress in daily practice. We conducted a descriptive, prospective, and single-center diagnostic accuracy study in a tertiary hospital, including term and preterm newborns who needed a CXR because of respiratory conditions occurring at birth or during the first 24h of life. TUS was compared to the reference diagnosis, which was the association between the CXR results, the clinical initial context, and the patient's outcome. Fifty-two newborns were included and 104 hemi-thorax ultrasounds were analyzed. Sensitivity, specificity, positive and negative predictive values (PPV, NPV), diagnosis accuracy, as well as the positive and negative likelihood ratio of TUSs were 100% for respiratory distress syndrome (RDS), transient tachypnea of newborn (TTN), pneumomediastinum, meconium aspiration syndrome, and absence of pulmonary disease. TUS also showed 100% sensitivity and NPV for pneumothorax, but specificity was 97% and PPV was 50%. Kappa concordance between TUS and either CXR alone or the radiological/clinical gold standard was 0.79 and 0.95, respectively. CONCLUSION: TUS at the newborn's bedside is efficient for investigating the main neonatal respiratory diseases, especially for the confirmation of RDS or TTN and for the exclusion of differential diagnosis or complications., (Copyright © 2019 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability., Methods: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects., Results: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects., Conclusion: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.

Purpose: To assess the association of clinical and biological factors with extensive macular atrophy with pseudodrusen (EMAP) characterized by bilateral macular atrophy occurring in patients aged 50 to 60 years and a rapid progression to legal blindness within 5 to 10 years., Design: A national matched case-control study., Participants: Participants were recruited in 10 French Departments of Ophthalmology and their associated clinical investigation centers. All 115 patients with EMAP had symptoms before the age of 55 years due to bilateral extensive macular atrophy with a larger vertical axis and diffuse pseudodrusen. Three controls without age-related macular degeneration (AMD) or retinal disease at fundus examination were matched for each patient with EMAP by gender, age, and geographic area (in total 415)., Methods: Subjects and controls underwent an eye examination including color, red-free autofluorescent fundus photographs and spectral-domain optical coherence tomography with macular analysis. The interviews collected demographic, lifestyle, family and personal medical history, medications, and biological data. Associations of risk factors were estimated using conditional logistic regression., Main Outcome Measures: Extensive macular atrophy with pseudodrusen status (cases vs. controls)., Results: Extensive macular atrophy with pseudodrusen most frequently affected women (70 women, 45 men). After multivariate adjustment, family history of glaucoma or AMD was strongly associated with EMAP (odds ratio [OR], 2.3, P = 0.008 and OR, 1.5, P = 0.01, respectively). No association was found with cardiac diseases or their risk factors. Mild and moderate kidney disease and higher neutrophil rate were associated with a reduced risk of EMAP (OR, 0.58, P = 0.04; OR, 0.34, P = 0.01; and OR, 0.59, P = 0.003, respectively). On the contrary, eosinophilia (OR, 1.6; P = 0.0002), lymphocytosis (OR, 1.84; P = 0.0002), increased erythrocyte sedimentation rate (OR, 6.5; P = 0.0005), decreased CH50 (P = 0.001), and high plasma C3 level (P = 0.023) were significantly associated with a higher risk of EMAP., Conclusions: This study documents an association between EMAP and family history of AMD and glaucoma, a clear female predominance, and a systemic inflammatory profile. The reduced CH50 and increased C3 plasma values could reflect a more severe complement pathway dysfunction than in AMD, leading to early pseudodrusen and rapid development of geographic atrophy. There is no association of EMAP with AMD cardiac diseases or cardiac risks, including cigarette smoking., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To identify specific mutations causing North Carolina macular dystrophy (NCMD)., Design: Whole-genome sequencing coupled with reverse transcription polymerase chain reaction (RT-PCR) analysis of gene expression in human retinal cells., Participants: A total of 141 members of 12 families with NCMD and 261 unrelated control individuals., Methods: Genome sequencing was performed on 8 affected individuals from 3 families affected with chromosome 6-linked NCMD (MCDR1) and 2 individuals affected with chromosome 5-linked NCMD (MCDR3). Variants observed in the MCDR1 locus with frequencies <1% in published databases were confirmed using Sanger sequencing. Confirmed variants absent from all published databases were sought in 8 additional MCDR1 families and 261 controls. The RT-PCR analysis of selected genes was performed in stem cell-derived human retinal cells., Main Outcome Measures: Co-segregation of rare genetic variants with disease phenotype., Results: Five sequenced individuals with MCDR1-linked NCMD shared a haplotype of 14 rare variants spanning 1 Mb of the disease-causing allele. One of these variants (V1) was absent from all published databases and all 261 controls, but was found in 5 additional NCMD kindreds. This variant lies in a DNase 1 hypersensitivity site (DHS) upstream of both the PRDM13 and CCNC genes. Sanger sequencing of 1 kb centered on V1 was performed in the remaining 4 NCMD probands, and 2 additional novel single nucleotide variants (V2 in 3 families and V3 in 1 family) were identified in the DHS within 134 bp of the location of V1. A complete duplication of the PRDM13 gene was also discovered in a single family (V4). The RT-PCR analysis of PRDM13 expression in developing retinal cells revealed marked developmental regulation. Next-generation sequencing of 2 individuals with MCDR3-linked NCMD revealed a 900-kb duplication that included the entire IRX1 gene (V5). The 5 mutations V1 to V5 segregated perfectly in the 102 affected and 39 unaffected members of the 12 NCMD families., Conclusions: We identified 5 rare mutations, each capable of arresting human macular development. Four of these strongly implicate the involvement of PRDM13 in macular development, whereas the pathophysiologic mechanism of the fifth remains unknown but may involve the developmental dysregulation of IRX1., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the frequency of and to characterize the clinical spectrum and optical coherence tomography findings of vitelliform macular dystrophy linked to IMPG1 and IMPG2, 2 new causal genes expressed in the interphotoreceptor matrix., Design: Retrospective epidemiologic, clinical, electrophysiologic, and molecular genetic study., Participants: The database of a national referral center specialized in genetic sensory diseases was screened for patients with a macular vitelliform dystrophy without identified mutation or small deletion or large rearrangement in BEST1 and PRPH2 genes. Forty-nine families were included., Methods: Clinical, imaging, and electro-oculogram findings were reviewed. Mutation screening of IMPG1 and IMPG2 genes were performed systematically., Main Outcome Measures: Frequency, inheritance, and clinical pattern of vitelliform dystrophy associated with IMPG1 and IMPG2 mutations were characterized., Results: IMPG1 was the causal gene in 3 families (IMPG1 1-3, 11 patients) and IMPG2 in a fourth family (2 patients). With an autosomal dominant transmission, families 1 and 2 had the c.713T→G (p.Leu238Arg) mutation in IMPG1 and family 4 had the c.3230G→T (p.Cys1077Phe) mutation in IMPG2. Patients with IMPG1 or IMPG2 mutations had a late onset and moderate visual impairment (mean visual acuity, 20/40; mean age of onset, 42 years), even in the sporadic case of family 3 with a presumed recessive transmission (age at onset, 38 years; mean visual acuity, 20/50). Drusen-like lesions adjacent to the vitelliform deposits were observed in 9 of 13 patients. The vitelliform material was above the retinal pigment epithelium (RPE) at any stage of the macular dystrophy, and this epithelium was well preserved and maintained its classical reflectivity on spectral-domain optical coherence tomography (SD-OCT). Electro-oculogram results were normal or borderline in 9 cases., Conclusions: IMPG1 and IMPG2 are new causal genes in 8% of families negative for BEST1 and PRPH2 mutations. These genes should be screened in adult-onset vitelliform dystrophy with (1) moderate visual impairment, (2) drusen-like lesions, (3) normal reflectivity of the RPE line on SD-OCT, and (4) vitelliform deposits located between ellipsoid and interdigitation lines on SD-OCT. These clinical characteristics are not observed in the classical forms of BEST1 or PRPH2 vitelliform dystrophies., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The complex regional pain syndrome type 1 from the surgeon's point of view: description of the symptoms, imaging (nuclear medicine, MRI) and of the associated psychological context. Importance of the need for a multi-disciplinary organization from the diagnostic to the therapeutic care., (Copyright © 2011 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.)

Purpose: To evaluate a genetic approach of BEST1 and PRPH2 screening according to age of onset, family history, and Arden ratio in patients with juvenile vitelliform macular dystrophy (VMD2) or adult-onset vitelliform macular dystrophy (AVMD), which are characterized by autofluorescent deposits., Design: Clinical, electrophysiologic, and molecular retrospective study., Participants: The database of a clinic specialized in genetic sensory diseases was screened for patients with macular vitelliform dystrophy. Patients with an age of onset less than 40 years were included in the VMD2 group (25 unrelated patients), and patients with an age of onset more than 40 years were included in the AVMD group (19 unrelated patients)., Methods: Clinical, fundus photography, and electro-oculogram (EOG) findings were reviewed. Mutation screening of BEST1 and PRPH2 genes was systematically performed., Main Outcome Measures: Relevance of age of onset, family history, and Arden ratio were reviewed., Results: Patients with VMD2 carried a BEST1 mutation in 60% of the cases. Seven novel mutations in BEST1 (p.V9L, p.F80V, p.I73V, p.R130S, pF298C, pD302A, and p.179delN) were found. Patients with VMD2 with a positive family history or a reduced Arden ratio carried a BEST1 mutation in 70.5% of cases and in 83% if both criteria were fulfilled. Patients with AVMD carried a PRPH2 mutation in 10.5% of cases and did not carry a BEST1 mutation. The probability of finding a PRPH2 mutation increased in the case of a family history (2/5 patients). Electro-oculogram was normal in 3 of 15 patients with BEST1 mutations and reduced in the 3 patients with PRPH2 mutations., Conclusions: Age of onset is a major criterion to distinguish VMD2 from AVMD. Electro-oculogram is not as relevant because decreased or normal Arden ratios have been associated with mutations in both genes and diseases. A positive family history increased the probability of finding a mutation. BEST1 screening should be recommended to patients with an age of onset less than 40 years, and PRPH2 screening should be recommended to patients with an age of onset more than 40 years. For an onset between 30 and 40 years, PRPH2 can be screened if no mutation has been detected in BEST1., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: Kjellin's syndrome is a hereditary neuro-ophthalmologic syndrome. We describe the clinical phenotypes of 7 patients, identifying the responsible mutations for 4 of them. A 10-year ophthalmologic and neurologic follow-up of 5 patients allowed us to describe the disease's characteristics, early symptoms and progression, associated ocular signs, and retinal changes in carriers., Design: Retrospective clinical study and molecular genetics investigation., Participants: The records of 7 patients with Kjellin's syndrome were analyzed retrospectively., Methods: All patients underwent full neurologic and ophthalmologic examinations. The neurologic examinations included assessments of initial symptoms, intelligence quotient tests, psychologic tests, and either magnetic resonance imaging or computed tomography. The ophthalmologic examinations included visual acuity on an Early Treatment Diabetic Retinopathy Study chart, intraocular pressure color vision assessment, slit-lamp and fundus examination, Goldmann perimetry, fundus autofluorescence, optical coherence tomography and fluorescein angiography, electro-oculography, electroretinography, and flash visual evoked potentials. Direct sequencing of the SPG11 and SPG15 genes and gene-dosage analysis for the former were performed for 4 of these index patients., Main Outcome Measures: Identification of new mutations in the SPG11 gene, validating its implication in Kjellin's syndrome., Results: The first signs appear before the age of 10 years, with late verbal development and difficulty running and walking. Life expectancy is between 30 and 40 years. The secondary ophthalmologic symptoms only moderately affect visual acuity. In addition to the classic symptoms, 3 of the 7 patients displayed small whitish lens opacities, and 3 neurologically unaffected parents (father or mother), all heterozygous carriers, exhibited whitish retinal dots. All the patients who were tested carried SPG11, not SPG15, mutations., Conclusions: Neurologic signs of SPG11 mutations emerge in early infancy, with walking and language difficulties. Onset of paraplegia occurs at the end of the first decade or during the second decade. Retinal changes, an integral part of SPG11 mutations in this series of patients, are only observed once the paraplegia has become apparent., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

When Mozart died at the age of 36, was he suffering from the belated complications of a calcified extradural haematoma? This theory took shape during the identification process of the skull owned by the Mozarteum, when the print of calcified extradural haematoma was discovered on the left inner temporoparietal calvarial surface of the skull. This print looks like a rosette, with three distinct concentric areas. The first outer area is striated, the second middle one is granular and scattered with bony deposits, the third central one is marked with vascular grooves.