Adding Natural Frequency Data to a Decision Aid for Colorectal Cancer Screening: Results of a Randomized Trial

Guidelines recommend that decision aids provide natural frequency data regarding baseline risk, risk reduction, and chances of false positives and negatives. Such quantitative information may confuse patients, especially those with low numeracy. We conducted a randomized trial to compare effects of 2 colorectal cancer (CRC) screening decision aids—one with and one without natural frequency data

Confirmation That MAT1A p.Ala259Val Mutation Causes Autosomal Dominant Hypermethioninemia

Methionine adenosyltransferase (MAT) I/III deficiency is an inborn error of metabolism caused by mutations in MAT1A, encoding the catalytic subunit of MAT responsible for the synthesis of S-adenosylmethionine, and is characterized by persistent hypermethioninemia. While historically considered a recessive disorder, a milder autosomal dominant form of MAT I/III deficiency occurs, though only the most common mutation p.Arg264His has ample evidence to prove dominant inheritance. We report a case of hypermethioninemia caused by the p.Ala259Val substitution and provide evidence of autosomal dominant inheritance by showing both maternal inheritance of the mutation and concomitant hypermethioninemia. The p.Ala259Val mutation falls in the dimer interface, and thus likely leads to dominant inheritance by a similar mechanism to that described in the previously reported dominant negative mutation, that is, by means of interference with subunits encoded by the wild-type allele

Presenting Stool Testing as the Default Option for Colorectal Cancer Screening: Results of a Randomized Trial

Individuals eligible for colorectal cancer (CRC) screening can choose from multiple approved tests, including colonoscopy and stool testing. The existence of multiple options allows patients to choose a preferred strategy but also may lead to indecision and delay. Behavioral economics suggests presenting one option as a default choice, i.e. the one that patients should receive if they do not wish to decide. We conducted a randomized trial to measure the impact of describing stool testing as the default option for CRC screening in a decision aid (DA)

Providing Quantitative Information and a Nudge to Undergo Stool Testing in a Colorectal Cancer Screening Decision Aid: A Randomized Clinical Trial

Background. Guidelines recommend that patient decision aids should provide quantitative information about probabilities of potential outcomes, but the impact of this information is unknown. Behavioral economics suggests that patients confused by quantitative information could benefit from a “nudge” towards one option. We conducted a pilot randomized trial to estimate the effect sizes of presenting quantitative information and a nudge. Methods. Primary care patients (n = 213) eligible for colorectal cancer screening viewed basic screening information and were randomized to view (a) quantitative information (quantitative module), (b) a nudge towards stool testing with the fecal immunochemical test (FIT) (nudge module), (c) neither a nor b, or (d) both a and b. Outcome measures were perceived colorectal cancer risk, screening intent, preferred test, and decision conflict, measured before and after viewing the decision aid, and screening behavior at 6 months. Results. Patients viewing the quantitative module were more likely to be screened than those who did not (P = 0.012). Patients viewing the nudge module had a greater increase in perceived colorectal cancer risk than those who did not (P = 0.041). Those viewing the quantitative module had a smaller increase in perceived risk than those who did not (P = 0.046), and the effect was moderated by numeracy. Among patients with high numeracy who did not view the nudge module, those who viewed the quantitative module had a greater increase in intent to undergo FIT (P = 0.028) than did those who did not. Limitations. The limitations of this study were the limited sample size and single healthcare system. Conclusions. Adding quantitative information to a decision aid increased uptake of colorectal cancer screening, while adding a nudge to undergo FIT did not increase uptake. Further research on quantitative information in decision aids is warranted

Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy.

PURPOSE: Pathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the nonspecific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy. METHODS: Using CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype. RESULTS: We identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype. CONCLUSIONS: We designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD-deficient individuals who could benefit from uridine therapy

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

AbstractDevelopmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy

Safety Evaluation of Hybrid Main-Line Toll Plazas

Traditional main-line toll plazas on expressways may have both safety and operational challenges. Although many studies have demonstrated the operational and environmental impacts of conversion from traditional toll plazas to a barrier-free system (open road tolling), research that quantifies the safety benefits of new tolling systems Ls lacking. This study evaluated the safety effectiveness of the conversion from a traditional main-line toll plaza design to a hybrid main-line toll plaza (HMTP) system. An 11M 11\u27 .system combines both open road tolling on the main line and separate traditional toll collection to the side. Various observational before-after studies were applied on VH main-line toll plazas (two directions) located on approximately 750 mi of loll roads in Florida; .V) of these were upgraded to the HMTP system. Ihr multivariate empirical Hayes method produced the best crash modification factors with low standard errors, and its results indicated that the conversion from traditional main-line toll plaza to HMTP showed an average crash reduction of 47%, 46%, and 54% for total crashes, fatal and injury Crashes, and property-damage-only crashes, respectively. The use of an HMTP system also significantly reduced rear-end crashes and lane-change-related crashes by an average of 65% and 55%, respectively. The ase of the HMTP system was proved to he an excellent solution to several trartic operations, environmental, and economic problems. The results of this study proved that the safety effectiveness was significantly improved across all locations that were upgraded to an HMTP system