Formally Verified Next-Generation Airborne Collision Avoidance Games in ACAS X

The design of aircraft collision avoidance algorithms is a subtle but important challenge that merits the need for provable safety guarantees. Obtaining such guarantees is nontrivial given the unpredictability of the interplay of the intruder aircraft decisions, the ownship pilot reactions, and the subtlety of the continuous motion dynamics of aircraft. Existing collision avoidance systems, such as TCAS and the Next-Generation Airborne Collision Avoidance System ACAS X, have been analyzed assuming severe restrictions on the intruder's flight maneuvers, limiting their safety guarantees in real-world scenarios where the intruder may change its course. This work takes a conceptually significant and practically relevant departure from existing ACAS X models by generalizing them to hybrid games with first-class representations of the ownship and intruder decisions coming from two independent players, enabling significantly advanced predictive power. By proving the existence of winning strategies for the resulting Adversarial ACAS X in differential game logic, collision-freedom is established for the rich encounters of ownship and intruder aircraft with independent decisions along differential equations for flight paths with evolving vertical/horizontal velocities. We present three classes of models of increasing complexity: single-advisory infinite-time models, bounded time models, and infinite time, multi-advisory models. Within each class of models, we identify symbolic conditions and prove that there then always is a possible ownship maneuver that will prevent a collision between the two aircraft

CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants

Purpose To expand the recent description of a new neurodevelopmental syndrome related to alterations in CDK19. Methods Individuals were identified through international collaboration. Functional studies included autophosphorylation assays for CDK19 Gly28Arg and Tyr32His variants and in vivo zebrafish assays of the CDK19(G28R) and CDK19(Y32H). Results We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19, including two recurrent changes at residues Tyr32 and Gly28. In vitro autophosphorylation and substrate phosphorylation assays revealed that kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein. Injection of CDK19 messenger RNA (mRNA) with either the Tyr32His or the Gly28Arg variants using in vivo zebrafish model significantly increased fraction of embryos with morphological abnormalities. Overall, the phenotype of the now 14 individuals with CDK19-related disorder includes universal developmental delay and facial dysmorphism, hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%). Conclusion CDK19 de novo missense variants are responsible for a novel neurodevelopmental disorder. Both kinase assay and zebrafish experiments showed that the pathogenetic mechanism may be more diverse than previously thought.Peer reviewe

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Investigating the Impact of Brief Outings on the Welfare of Dogs Living in US Shelters

Social isolation likely contributes to reduced welfare for shelter-living dogs. Several studies have established that time out of the kennel with a person can improve dogs’ behavior and reduce physiological measures of stress. This study assessed the effects of two-and-a-half-hour outings on the urinary cortisol levels and activity of dogs as they awaited adoption at four animal shelters. Dogs’ urine was collected before and after outings for cortisol:creatinine analysis, and accelerometer devices were used to measure dogs’ physical activity. In total, 164 dogs participated in this study, with 793 cortisol values and 3750 activity measures used in the statistical analyses. We found that dogs’ cortisol:creatinine ratios were significantly higher during the afternoon of the intervention but returned to pre-field trip levels the following day. Dogs’ minutes of low activity were significantly reduced, and high activity significantly increased during the outing. Although dogs’ cortisol and activity returned to baseline after the intervention, our findings suggest that short-term outings do not confer the same stress reduction benefits as previously shown with temporary fostering. Nevertheless, it is possible that these types of outing programs are beneficial to adoptions by increasing the visibility of dogs and should be further investigated to elucidate these effects

The Influence of Brief Outing and Temporary Fostering Programs on Shelter Dog Welfare

Human interaction is one of the most consistently effective interventions that can improve the welfare of shelter-living dogs. Time out of the kennel with a person has been shown to reduce physiological measures of stress as can leaving the shelter for a night or more in a foster home. In this study, we assessed the effects of brief outings and temporary fostering stays on dogs’ length of stay and outcomes. In total, we analyzed data of 1955 dogs from 51 animal shelters that received these interventions as well as 25,946 dogs residing at these shelters that served as our controls. We found that brief outings and temporary fostering stays increased dogs’ likelihood of adoption by 5.0 and 14.3 times, respectively. While their lengths of stay were longer in comparison to control dogs, this difference was present prior to the intervention. Additionally, we found that these programs were more successful when greater percentages of community members (as compared to volunteers and staff) were involved in caregiving as well as when programs were implemented by better-resourced shelters. As such, animal welfare organizations should consider implementing these fostering programs as evidence-based best practices that can positively impact the outcomes of shelter dogs

CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants

Purpose To expand the recent description of a new neurodevelopmental syndrome related to alterations in CDK19. Methods Individuals were identified through international collaboration. Functional studies included autophosphorylation assays for CDK19 Gly28Arg and Tyr32His variants and in vivo zebrafish assays of the CDK19(G28R) and CDK19(Y32H). Results We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19, including two recurrent changes at residues Tyr32 and Gly28. In vitro autophosphorylation and substrate phosphorylation assays revealed that kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein. Injection of CDK19 messenger RNA (mRNA) with either the Tyr32His or the Gly28Arg variants using in vivo zebrafish model significantly increased fraction of embryos with morphological abnormalities. Overall, the phenotype of the now 14 individuals with CDK19-related disorder includes universal developmental delay and facial dysmorphism, hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%). Conclusion CDK19 de novo missense variants are responsible for a novel neurodevelopmental disorder. Both kinase assay and zebrafish experiments showed that the pathogenetic mechanism may be more diverse than previously thought.Peer reviewe

Materials design and bonding:general discussion

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