Aims: To investigate quantitatively, relationships between chemical structure and reported occupational asthma hazard for low molecular weight (LMW) organic compounds; to develop and validate a model linking asthma hazard with chemical substructure; and to generate mechanistic hypotheses that might explain the relationships. Methods: A learning dataset used 78 LMW chemical asthmagens reported in the literature before 1995, and 301 control compounds with recognised occupational exposures and hazards other than respiratory sensitisation. The chemical structures of the asthmagens and control compounds were characterised by the presence of chemical substructure fragments. Odds ratios were calculated for these fragments to determine which were associated with a likelihood of being reported as an occupational asthmagen. Logistic regression modelling was used to identify the independent contribution of these substructures. A post-1995 set of 21 asthmagens and 77 controls were selected to externally validate the model. Results: Nitrogen or oxygen containing functional groups such as isocyanate, amine, acid anhydride, and carbonyl were associated with an occupational asthma hazard, particularly when the functional group was present twice or more in the same molecule. A logistic regression model using only statistically significant independent variables for occupational asthma hazard correctly assigned 90% of the model development set. The external validation showed a sensitivity of 86% and specificity of 99%. Conclusions: Although a wide variety of chemical structures are associated with occupational asthma, bifunctional reactivity is strongly associated with occupational asthma hazard across a range of chemical substructures. This suggests that chemical cross-linking is an important molecular mechanism leading to the development of occupational asthma. The logistic regression model is freely available on the internet and may offer a useful but inexpensive adjunct to the prediction of occupational asthma hazard.
In hereditary cancer, multigene panel testing is currently replacing older single‐gene approaches. Patients whose tests were previously uninformative could benefit from updated testing. Research suggests that patients desire to be recontacted about updated genetic testing, but few studies have tested the efficacy of recontact efforts. This study investigated the outcomes of a recontact effort in a hereditary cancer clinic and explored the impact of four different recontact letters, randomized in a 2X2 factorial design. Patients who had negative genetic testing for single genes or conditions were mailed letters inviting them to schedule an appointment to discuss updated testing. Patients were randomized to receive one of four letters and each letter emphasized different implications of updated multigene genetic testing: (a) personal medical management implications, (b) implications for family members, (c) both personal and family implications or (d) a control letter. The proportion of patients who arrived for appointments was assessed approximately 7 months after mailing along with associations with patient demographics and type of letter received. Letters were mailed to 586 patients who had initial testing between 2001 and 2015. Most patients were white (78%) and female (97%) with private insurance (65%). At 7 months, 25 patients (4.3%, 95% CI: 2.6% to 5.9%) had arrived for an appointment. Older age was significantly associated with response rate (p = .01), while type of recontact letter was not (p = .54). This study suggests that recontacting patients about updated genetic testing by mail does not yield a large response. It also suggests that personal and/or familial implications do not seem to be significant factors that determine response rate. Nevertheless, results provide meaningful information for cancer clinics about the outcomes of recontact efforts via informational letter.
Various low molecular weight substances cause occupational asthma, and there is scope for studying their chemical properties in relation to their propensity to cause this condition. Twenty-nine organic substances (molecular weight < 250), with or without oxygen or nitrogen atoms, were compared to control hazardous substances obtained from the list of occupational exposure limits. There were significantly more reactive groups in the active chemicals than in the controls. Carbon to nitrogen double bonds were also significantly over-represented in the active chemicals. If confirmed in a fuller study, these data could yield useful information on the causation of occupational asthma and on the hazard assessment of novel chemical entities.
Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and one was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1 -related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.
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