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Emissions from internal combustion vehicles are currently not properly monitored throughout their life cycle. Remote emission sensing (RES) is a technology that can measure emissions under real driving conditions without contact. Current light extinction based RES systems are capable of providing emission factors for various gases, but lack accuracy for particulate matter (PM). Point Sampling (PS) is an extraction-based RES technique that can measure gases as well as various particle metrics such as black carbon or particle number. In this work, we evaluated the performance of a recently developed PS system and the state-of-the-art light extinction based remote sensing devices EDAR (HEAT) and ORSD (OPUS RSE) during co-location measurements. Validation measurements with portable emission measurement systems and emissions screening of several thousand cars in three European cities provide detailed insights into system's performance. Meteorological evaluations showed that the PS capture rate is strongly influenced by wind, but no other weather influences were found. Both light extinction based systems are unable to measure during rain. We found that all three systems tested were capable of screening NO x emissions from pre-Euro 6 diesel cars. Measurement results show the ability of the PS system to quantify high and low PM emitters equally well. The open-path RES systems (EDAR, ORSD) are capable of estimating PM emissions from pre-Euro 5 diesel cars. However, deficiencies of open-path RES systems are evident in the quantification of PM emissions from newer engine technologies (diesel Euro 5 and beyond) and from petrol cars. The PS system has a 2 to 5 times lower capture rate than open-path RES systems, but the PS measurement results are more accurate (more than 5 times for PM and more than 1.35 times for NO x ). The good accuracy of individual measurements makes PS a powerful tool for reliable high emitter identification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations., Design: Retrospective case series from academic referral centers., Participants: Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene., Methods: Whole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping., Main Outcome Measures: Clinical characterization of UM patients with germline alterations in known cancer genes., Results: We identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively)., Conclusions: The study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Family studies are an important but underreported source of information for reclassification of variants of uncertain significance (VUS). We evaluated outcomes of a patient-driven framework that offered familial VUS reclassification analysis to any adult with any clinically ascertained VUS from any laboratory in the United States., Methods: With guidance from FindMyVariant.org, participants recruited their own relatives for study participation. We genotyped relatives, calculated quantitative cosegregation likelihood ratios, and evaluated variant classifications using Tavtigian's unified framework for Bayesian analysis with American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. We report participation and VUS reclassification rates from the 50 families enrolled for at least one year and reclassification results for 112 variants from the larger 92-family cohort., Results: For the 50-family cohort, 6.7 relatives per family were invited to participate and 67% of relatives returned samples for genotyping. Sixty-one percent of VUS were reclassified, 84% of which were classified as benign or likely benign. Genotyping relatives identified a de novo variant, phase variants, and relatives with phenotypes highly specific for or incompatible with specific classifications., Conclusions: Motivated families can contribute to successful VUS reclassification at substantially higher rates than those previously published. Clinical laboratories could consider offering family studies to all patients with VUS.

Purpose: Screening multiple genes for inherited cancer predisposition expands opportunities for cancer prevention; however, reports of variants of uncertain significance (VUS) may limit clinical usefulness. We used an expert-driven approach, exploiting all available information, to evaluate multigene panels for inherited cancer predisposition in a clinical series that included multiple cancer types and complex family histories., Methods: For 1,462 sequential patients referred for testing by BROCA or ColoSeq multigene panels, genomic DNA was sequenced and variants were interpreted by multiple experts using International Agency for Research on Cancer guidelines and incorporating evolutionary conservation, known and predicted variant consequences, and personal and family cancer history. Diagnostic yield was evaluated for various presenting conditions and family-history profiles., Results: Of 1,462 patients, 12% carried damaging mutations in established cancer genes. Diagnostic yield varied by clinical presentation. Actionable results were identified for 13% of breast and colorectal cancer patients and for 4% of cancer-free subjects, based on their family histories of cancer. Incidental findings explaining cancer in neither the patient nor the family were present in 1.7% of subjects. Less than 1% of patients carried VUS in BRCA1 or BRCA2. For all genes combined, initial reports contained VUS for 10.5% of patients, which declined to 7.5% of patients after reclassification based on additional information., Conclusions: Individualized interpretation of gene panels is a complex medical activity. Interpretation by multiple experts in the context of personal and family histories maximizes actionable results and minimizes reports of VUS.Genet Med 18 10, 974-981.

Purpose: Single-exon inversions have rarely been described in clinical syndromes and are challenging to detect using Sanger sequencing. We report the case of a 40-year-old woman with adenomatous colon polyps too numerous to count and who had a complex inversion spanning the entire exon 10 in APC (the gene encoding for adenomatous polyposis coli), causing exon skipping and resulting in a frameshift and premature protein truncation., Methods: In this study, we employed complete APC gene sequencing using high-coverage next-generation sequencing by ColoSeq, analysis with BreakDancer and SLOPE software, and confirmatory transcript analysis., Results: ColoSeq identified a complex small genomic rearrangement consisting of an inversion that results in translational skipping of exon 10 in the APC gene. This mutation would not have been detected by traditional sequencing or gene-dosage methods., Conclusion: We report a case of adenomatous polyposis resulting from a complex single-exon inversion. Our report highlights the benefits of large-scale sequencing methods that capture intronic sequences with high enough depth of coverage-as well as the use of informatics tools-to enable detection of small pathogenic structural rearrangements.

Background: Endoscopic treatment of malignant central airway obstructions usually is done for palliation. The exact role of such a procedure as preparatory to operation remains controversial., Methods: From 1987 through 1996, 24 patients at our institution underwent tracheobronchial pulmonary resection after preliminary endoscopic treatment. During the same period, 304 patients underwent 449 operative rigid bronchoscopies for airway obstructions, most involving the use of a neodymium:yttrium-aluminum-garnet laser. The indications for operation were squamous cell carcinoma in 14 patients, bronchial gland tumors in 8 patients, and papillary thyroid cancer infiltrating the trachea in 2 patients. The total resection rate was 9.5% (5% for squamous cell carcinoma, 75% for low-grade malignant bronchial tumors, and 75% for papillary thyroid cancer). The median period between operative rigid bronchoscopy and operation was 18 days., Results: No complications were observed after endoscopic treatment. There were two perioperative deaths (adult respiratory distress syndrome after carinal resection and pulmonary embolism after pneumonectomy) and one major complication (poor postoperative pulmonary function after pneumonectomy). No anastomotic complications were observed in the tracheobronchoplastic procedures. Follow-up was possible in every patient but 1: 6 patients died at a median of 30.5 months after operation (range, 3 to 46 months), 2 patients are alive with disease, and the rest are alive without evidence of disease at a median of 21 months (range, 2 to 61 months)., Conclusions: Most patients who require endoscopic therapy for malignant airway obstructions are not candidates for operative resection. Preliminary endoscopic relief of obstruction can increase operability and improve surgical results in a highly selected group of patients.