Purpose
Stargardt disease (STGD1) is caused by biallelic mutations in ABCA4, but many patients are genetically unsolved due to insensitive mutation‐scanning methods. We aimed to develop a ...cost‐effective sequencing method for ABCA4 exons and regions carrying known causal deep‐intronic variants.
Methods
Fifty exons and 12 regions containing 14 deep‐intronic variants of ABCA4 were sequenced using double‐tiled single molecule Molecular Inversion Probe (smMIP)‐based next‐generation sequencing. DNAs of 16 STGD1 cases carrying 29 ABCA4 alleles and of four healthy persons were sequenced using 483 smMIPs. Thereafter, DNAs of 411 STGD1 cases with one or no ABCA4 variant were sequenced. The effect of novel noncoding variants on splicing was analyzed using in vitro splice assays.
Results
Thirty‐four ABCA4 variants previously identified in 16 STGD1 cases were reliably identified. In 155/411 probands (38%), two causal variants were identified. We identified 11 deep‐intronic variants present in 62 alleles. Two known and two new noncanonical splice site variants showed splice defects, and one novel deep‐intronic variant (c.4539+2065C>G) resulted in a 170‐nt mRNA pseudoexon insertion (p.Arg1514Lysfs*35,=).
Conclusions
smMIPs‐based sequence analysis of coding and selected noncoding regions of ABCA4 enabled cost‐effective mutation detection in STGD1 cases in previously unsolved cases.
In most reported cases of lung trauma with water proofing products, volatile organic compounds (VOC) have a prominent role. Here we report on a case involving ten workers exposed to a sprayed product ...containing nanoparticles in a water solution with only a few percent VOC.
Ten workers suffered from respiratory symptoms following spray impregnation of hardwood furniture using a waterproofing product that contained positively charged fluorinated acrylate copolymer solid cores with a median diameter of 70 nm (1.3 w%) in aqueous suspension with 3.3 w% VOC and 0.3 w% quaternary ammonium. The worker who applied one liter of the product in a wood workshop, using an air mix spray gun, did not report any health complaints. Another worker, who entered the workshop 3 h later and had rolled and smoked two cigarettes, was hospitalized with severe chemical pneumonitis. A chest X-ray (CXR) showed bilateral infiltrative impairment in the lower lobe regions. On the next day a second CXR showed increased patchiness marking in all fields. A high-resolution Computer Tomography (CT)-scan demonstrated extensive bilateral areas of ground-glass opacities predominantly in the lower regions of the upper lobes, the right middle lobe and the apical regions of the lower lobes, compatible with severe chemical pneumonitis. On the following morning, nine workers in an adjacent workplace in the same building, experienced dry cough, chest tightness and substernal pain upon physical exercise. Reconstruction of the spray application in a climate chamber confirmed trimethyl silanol, glycol ethers and fluoroalkenes in the gas phase. Immediately after the spray application, aerosols were observed at a maximum concentration of 6.3 × 10
cm
. Mass concentrations were 0.095 and 10 mg/m
in the size ranges 5.6-560 nm and 0.22-30 μm, respectively, decreasing to less than 10 μg/m
in both size ranges after 15 h.
The hospitalized worker had smoked cigarettes contaminated with fluoropolymers which is a plausible explanation for the lung trauma. Respiratory symptoms in the nine workers may be caused by inhalation of particles that became airborne by resuspension from surfaces when workers entered the adjacent workplace the next day. A contribution from VOC appears less likely because measurements and modelling showed that concentrations in the mg/m
range could have occurred only if the building was assumed to be completely airtight.
The Russia-Ukraine war is a multifaceted beast. It ranges from fighting on the ground to high diplomacy, from domestic anti-war protests to international weapon supplies, from justification through ...sham referenda to coercion via economic sabotage, and from operational misdirection to covering up war crimes. There are close connections between these facets: the collapse of a front leads to the discovery of mass graves; the delivery of weapon systems depends on Zelensky’s appeal to the international community; sham referenda followed by annexation enable accusations of unwillingly mobilised soldiers who refuse to defend the motherland. This volume sheds light on the Russia-Ukraine war, exploring this multitude of facets and their interconnections. Bringing together the expertise of our colleagues at the Netherlands Defense Academy (NLDA) allows us to adopt a distinctively interdisciplinary approach, offering uniquely comprehensive and timely reflections on this armed conflict. The 27 chapters in this volume are centered around five themes. The first section covers historical and contemporary narratives, intelligence, digital technologies, and communication strategies. The second provides in-depth analyses of the operational aspects of the war, including warfighting on land, at sea, in the air, as well as in the space and cyber domains. The third section on international involvement covers topics such as sanctions, burden sharing, arms support and implications of the war on international institutions and the world order. The fourth provides analyses of the normative framework that applies to the Russia-Ukraine war. Finally, the fifth section deals with the way armed forces can transform their organisations and learn from this war, and concludes with questions on how and when the Russia-Ukraine war might end.
Ten workers suffered from respiratory complaints after spray impregnation of hardwood furniture with a waterproofing product that contained a fluorinated acrylate copolymer in an aqueous suspension. ...One litre of the product was sprayed during 4 min inside a workshop area with a volume of ca. 2 400 m3. A worker, who entered the workshop 3 h after the impregnation, was hospitalised with dyspnea, severe hypoxia, cough, blank sputum, fever, tremors and tingling extremities. Later a severe chemical pneumonitis was diagnosed. On the following morning, 15 h after the impregnation, nine workers in an adjacent room of 1 200 m3 in the same building experienced the following respiratory symptoms: dry cough, chest tightness and sub-sternal chest pain. No other sources of causative exposure could be identified. Reconstruction of the spray application in a 20 m3 steel chamber showed trimethyl silanol, glycol ethers and fluoroalkenes as major volatile organic compounds (VOCs). The fluoroalkenes reached their maximum concentrations 1-2 h after application and persisted in the gas phase along with trimethyl silanol and the glycol ethers. Immediately after the spray application aerosols were observed in a maximum concentration of 6.3 104 cm-3 (5.6 to 560 nm). Mass concentrations were 0.095 and 10 mg/m3 in the size ranges 5.6 to 560 nm and 0.22 to 30 mu m, respectively. After 15 h the mass concentrations of the airborne particle had decreased to values less than 10 mu g/m3 in both size ranges. The worker who developed chemical pneumonitis was a smoker. We hypothesise that rolling and smoking cigarettes contaminated with fluoropolymer was causative. The respiratory symptoms in the 9 workers exposed 15 hours after the spray event may be caused by combined exposure to trimethyl silanol, glycol ethers and fluoroalkenes, which persisted in the gas phase up to 24 h after application of the product.
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