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Abstract Background Avoiding excessive antibiotic treatment duration is a fundamental goal in antimicrobial stewardship. Manual collection of data is a time-consuming process, but a semi-automated approach for data extraction has been shown feasible for community-acquired infections (CAI). Extraction of data however may be more challenging in hospital-acquired infections (HAI). The aim of this study is to explore whether semi-automated data extraction of treatment duration is also feasible and accurate for HAI. Methods Data from a university-affiliated hospital over the period 1-6-2020 until 1-6-2022 was used for this study. From the Electronic Health Record, raw data on prescriptions, registered indications and admissions was extracted and processed to define treatment courses. In addition, clinical notes including prescription instructions were obtained for the purpose of validation. The derived treatment course was compared to the registered indication and the actual length of treatment (LOT) in the clinical notes in a random sample of 5.7% of treatment courses, to assess the accuracy of the data for both CAI and HAI. Results Included were 10.564 treatment courses of which 73.1% were CAI and 26.8% HAI. The registered indication matched the diagnosis as recorded in the clinical notes in 79% of treatment courses (79.2% CAI, 78.5% HAI). Higher error rates were seen in urinary tract infections (UTIs) (29.0%) and respiratory tract infections (RTIs) (20.5%) compared to intra-abdominal infections (7.4%), or skin or soft tissue infections (11.1%), mainly due to incorrect specification of the type of UTI or RTI. The LOT was accurately extracted in 98.5% of courses (CAI 98.2%, HAI 99.3%) when compared to prescriptions in the EHR. In 21% of cases however the LOT did not match with the clinical notes, mainly if patients received treatment from other health care providers preceding or following the present course. Conclusion Semi-automatic data extraction can yield reliable information about the indication and LOT in treatment courses of hospitalized patients, for both HAI and CAI. This can provide stewardship programs with a surveillance tool for all in-hospital treated infections, which can be used to achieve stewardship goals.

Research has highlighted the relevance of biological measures in explaining antisocial behavior, but the inclusion of such measures in clinical practice is lagging behind. According to the integrative biopsychosocial model, biological measures should be studied together with psychological and social-environmental factors. In this data-driven study, we applied this comprehensive model to explain non-violent and violent delinquency of 876 at-risk youth (715 male, 9–27 years), by combining nine biological (autonomic-nervous-system; endocrinological), nine psychological, and seven social-environmental measures. Using latent-class-regression analysis we uncovered four distinct psychologically-driven biological clusters, which differed in non-violent and violent delinquency-risk, moderated by social-environmental variables: a biological–psychopathic traits; low problem; high problem; and biological–reactive group. Individual vulnerabilities to (non-)violent delinquency depended on social-environmental context that differed between clusters. These findings highlight the importance of biological and psychological factors, in the context of social-environmental factors, in explaining (non)-violent delinquency.

Objective: Congenital hypothyroidism (CH) is an inborn thyroid hormone (TH) deficiency mostly caused by thyroidal (primary CH) or hypothalamic/pituitary (central CH) disturbances. Most CH newborn screening (NBS) programs are thyroid-stimulating-hormone (TSH) based, thereby only detecting primary CH. The Dutch NBS is based on measuring total thyroxine (T4) from dried blood spots, aiming to detect primary and central CH at the cost of more false-positive referrals (FPRs) (positive predictive value (PPV) of 21% in 2007–2017). An artificial PPV of 26% was yielded when using a machine learning-based model on the adjusted dataset described based on the Dutch CH NBS. Recently, amino acids (AAs) and acylcarnitines (ACs) have been shown to be associated with TH concentration. We therefore aimed to investigate whether AAs and ACs measured during NBS can contribute to better performance of the CH screening in the Netherlands by using a revised machine learning-based model. Methods: Dutch NBS data between 2007 and 2017 (CH screening results, AAs and ACs) from 1079 FPRs, 515 newborns with primary (431) and central CH (84) and data from 1842 healthy controls were used. A random forest model including these data was developed. Results: The random forest model with an artificial sensitivity of 100% yielded a PPV of 48% and AUROC of 0.99. Besides T4 and TSH, tyrosine, and succinylacetone were the main parameters contributing to the model’s performance. Conclusions: The PPV improved significantly (26–48%) by adding several AAs and ACs to our machine learning-based model, suggesting that adding these parameters benefits the current algorithm.

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

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Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF

This article reports on one aspect of a nationally funded research project on contract cheating in Australian higher education. The project explored students' and educators' experiences of contract cheating, and the contextual factors that may influence it. This article reports the key findings from non-university higher education providers (NUHEPs). It compares survey responses from 961 students and 91 educators at four NUHEPs with previously reported findings from eight universities (14,086 students and 1,147 staff). NUHEP and university students report engaging in contract cheating in similar ways. However, while NUHEP educators spend more time teaching academic literacies and discussing contract cheating, NUHEP students are 12 times more likely than university students to report use of a professional academic writing service. Both NUHEP and university educators require systematic professional development regarding the relationship between the teaching and learning environment and students' contract cheating behaviour. NUHEPs need to be cognisant of students' vulnerability to commercial contract cheating services, and ensure they have access to timely academic and social support.

Contract cheating occurs when a student outsources their assessment to a third party, regardless of the third party's relationship with the student, or whether money is exchanged. In higher education, there is a widespread belief that assessment design is a solution to the problem of contract cheating and that authentic assessment tasks are particularly effective. This research analysed two datasets -- 221 assignment orders placed on academic custom writing websites and 198 assessment tasks in which contract cheating was detected -- to investigate if authentic assessment can assure academic integrity. The authenticity of assessments was determined using five factors derived from the literature: frequency, fidelity, complexity, real-world impact and feed forward. Our analysis found that assessment tasks with no, some, or all of the five authenticity factors are routinely outsourced by students.

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

Summary: Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different PHF8 predicted loss-of-function variants in eight individuals. Features of PHF8-XLID include ID and craniofacial dysmorphology. In this report we present 16 additional individuals with PHF8-XLID from 11 different families of diverse ancestry. We also present five individuals from four different families who have ID and a variant of unknown significance in PHF8 with no other explanatory variant in another gene. All affected individuals exhibited developmental delay and all but two had borderline to severe ID. Of the two who did not have ID, one had dyscalculia and the other had mild learning difficulties. Craniofacial findings such as hypertelorism, microcephaly, elongated face, ptosis, and mild facial asymmetry were found in some affected individuals. Orofacial clefting was seen in three individuals from our cohort, suggesting that this feature is less common than previously reported. Autism spectrum disorder and attention deficit hyperactivity disorder, which were not previously emphasized in PHF8-XLID, were frequently observed in affected individuals. This series expands the clinical phenotype of this rare ID syndrome caused by loss of PHF8 function.

This paper reports on findings from a large Australian research project that explored the relationship between contract cheating and assessment design. Using survey responses from 14,086 students and 1147 educators at eight universities, a multivariate analysis examined the influence of a range of factors on the likelihood that different assessment types would prompt considerations of contract cheating in students. Perceptions of likelihood were highest among students who speak a language other than English at home. Perceptions of likelihood were also higher among students who reported there to be lots of opportunities to cheat, and amongst students who were dissatisfied with the teaching and learning environment. Perceptions of likelihood for certain assessment types were also higher in commerce and engineering than in any other discipline. Overall, four assessment types were perceived by students to be the least likely to be outsourced, however these are also the least likely to be set by educators. The analysis indicates that educators are more likely to use these assessment tasks when they report positively on organisational support for teaching and learning.

If media reports are to be believed, Australian universities are facing a significant and growing problem of students outsourcing their assessment to third parties, a behaviour commonly known as 'contract cheating'. Teaching staff are integral to preventing and managing this emerging form of cheating, yet there has been little evidence-based research to inform changes to their practice. This paper reports on the findings of a large-scale survey of teaching staff in Australian universities on the topic of contract cheating. It investigated staff experiences with and attitudes towards student cheating, and their views on the individual, contextual and organisational factors that inhibit or support efforts to minimise it. Findings indicate that contract cheating could be addressed by improving key aspects of the teaching and learning environment, including the relationships between students and staff. Such improvements are likely to minimise cheating, and also improve detection when cheating occurs.

Recent Australian media scandals suggest that university students are increasingly outsourcing their assessments to third parties -- a behaviour known as 'contract cheating'. This paper reports on findings from a large survey of students from eight Australian universities (n = 14,086) which sought to explore students' experiences with and attitudes towards contract cheating, and the contextual factors that may influence this behaviour. A spectrum of seven outsourcing behaviours were investigated, and three significant variables were found to be associated with contract cheating: dissatisfaction with the teaching and learning environment, a perception that there are 'lots of opportunities to cheat', and speaking a Language Other than English (LOTE) at home. To minimise contract cheating, our evidence suggests that universities need to support the development of teaching and learning environments which nurture strong student--teacher relationships, reduce opportunities to cheat through curriculum and assessment design, and address the well-recognised language and learning needs of LOTE students.

For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

In many groups of animals the dominance hierarchy is linear. What mechanisms underlie this linearity of the dominance hierarchy is under debate. Linearity is often attributed to cognitively sophisticated processes, such as transitive inference and eavesdropping. An alternative explanation is that it develops via the winner-loser effect. This effect implies that after a fight has been decided the winner is more likely to win again, and the loser is more likely to lose again. Although it has been shown that dominance hierarchies may develop via the winner-loser effect, the degree of linearity of such hierarchies is unknown. The aim of the present study is to investigate whether a similar degree of linearity, like in real animals, may emerge as a consequence of the winner-loser effect and the socio-spatial structure of group members. For this purpose, we use the model DomWorld, in which agents group and compete and the outcome of conflicts is self-reinforcing. Here dominance hierarchies are shown to emerge. We analyse the dominance hierarchy, behavioural dynamics and network triad motifs in the model using analytical methods from a previous study on dominance in real hens. We show that when one parameter, representing the intensity of aggression, was set high in the model DomWorld, it reproduced many patterns of hierarchical development typical of groups of hens, such as its high linearity. When omitting from the model the winner-loser effect or spatial location of individuals, this resemblance decreased markedly. We conclude that the combination of the spatial structure and the winner-loser effect provide a plausible alternative for hierarchical linearity to processes that are cognitively more sophisticated. Further research should determine whether the winner-loser effect and spatial structure of group members also explains the characteristics of hierarchical development in other species with a different dominance style than hens.