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Collaborative skills are crucial in knowledge-rich domains, such as medical diagnosing. The Collaborative Diagnostic Reasoning (CDR) model emphasizes the importance of high-quality collaborative diagnostic activities (CDAs; e.g., evidence elicitation and sharing), influenced by content and collaboration knowledge as well as more general social skills, to achieve accurate, justified, and efficient diagnostic outcomes (Radkowitsch et al., 2022). However, it has not yet been empirically tested, and the relationships between individual characteristics, CDAs, and diagnostic outcomes remain largely unexplored. The aim of this study was to test the CDR model by analyzing data from three studies in a simulation-based environment and to better understand the construct and the processes involved (N = 504 intermediate medical students) using a structural equation model including indirect effects. We found various stable relationships between individual characteristics and CDAs, and between CDAs and diagnostic outcome, highlighting the multidimensional nature of CDR. While both content and collaboration knowledge were important for CDAs, none of the individual characteristics directly related to diagnostic outcome. The study suggests that CDAs are important factors in achieving successful diagnoses in collaborative contexts, particularly in simulation-based settings. CDAs are influenced by content and collaboration knowledge, highlighting the importance of understanding collaboration partners' knowledge. We propose revising the CDR model by assigning higher priority to collaboration knowledge compared with social skills, and dividing the CDAs into information elicitation and sharing, with sharing being more transactive. Training should focus on the development of CDAs to improve CDR skills.

Abstract Background Pulmonary arterial hypertension is a life-threatening progressive disorder characterised by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery). Although treatable, there is no known cure for this rare disorder, and its exact cause is unknown. Mutations in the bone morphogenetic protein receptor type-2 (BMPR2) are the most common genetic cause of familial pulmonary arterial hypertension. This study represents the first-ever trial of treatments aimed at directly rescuing the BMPR2 pathway, repurposing two drugs that have shown promise at restoring levels of BMPR2 signalling: hydroxychloroquine and phenylbutyrate. Methods This three-armed phase II precision medicine study will investigate BMPR2 target engagement and explore the efficacy of two repurposed therapies in pulmonary arterial hypertension patients with BMPR2 mutations. Patients will be stratified based on two BMPR2 mutation classes: missense and haploinsufficient mutations. Eligible subjects will be randomised to one of the three arms (two active therapy arms and a placebo arm, all plus standard of care) following a Bayesian response-adaptive design implemented independently in each stratum and updated in response to a novel panel of primary biomarkers designed to assess biological modification of the disease. Discussion The results of this trial will provide the first randomised evidence of the efficacy of these therapies to rescue BMPR2 function and will efficiently explore the potential for a differential response of these therapies per mutation class to address causes rather than consequences of this rare disease. Trial registration The study has been registered with ISRCTN (ISRCTN10304915, 22/09/2023).

ABSTRACT: Dietary carbohydrate manipulation can be used to reduce enteric CH4 emission, but few studies have focused on the interaction of the different types of carbohydrates that can affect feed intake and ruminal fermentation. Understanding this interaction is necessary to make the most out of CH4 mitigation feeding strategies using different dietary carbohydrates. The aim of this study was to test the effect on enteric CH4 emission, feed intake, and milk production response when cows were fed either grass-clover silage (GCS) or corn silage (CS) as the sole forage source (55% of dry matter, DM), in combination with either barley (BAR) or dried beet pulp (DBP) as a concentrate (21.5% of DM). A total of 24 (half first-parity and half second-parity) cows were used in a crossover design with 2 periods of 21 d each, receiving 2 of 4 diets obtained from a 2 × 2 factorial arrangement of the experimental diet. Feed intake, CH4 emission metrics, and milk production were recorded at the end of the experimental periods. The diets had NDF concentrations between 258 and 340 g/kg of DM and starch concentrations between 340 and 7.45 g/kg of DM (CS-BAR and GCS-DBP, respectively). The effects of silage and concentrate on dry matter intake (DMI) were additive, with the highest feed intake in cows fed CS-BAR, followed by cows fed CS-DBP, GCS-BAR, and GCS-DBP (21.2, 19.9, 19.1, and 18.3 kg/d, respectively). Energy corrected milk (ECM) yield was not affected by silage source in first parity cows, but it was higher for cows fed CS than cows fed GCS in second parity. The effects of silage and concentrate on CH4 production (g/d), yield (g/kg of DMI), and intensity (g/kg of ECM) were not additive, as cows fed GCS had similar responses regardless of the concentrate used, but cows fed CS had lower CH4 production, yield, and intensity when fed BAR instead of DBP. The lower CH4 production, yield, and intensity in cows fed CS-BAR compared with other diets could be partially explained by the nonlinear relationship between ruminal VFA and carbohydrates (NDF and starch) concentration reported in the literature; however, we observed a linear relationship between the acetate/propionate ratio and CH4 yield, suggesting possible other effects. The effects of silage and concentrate on the ruminal VFA were additive in first parity cows, but not in second parity cows. The interaction between dietary carbohydrate type and parity might indicate an effect of feed intake or the energy balance of the cow. Feeding cows silage and concentrate both rich in starch can result in the lowest enteric CH4 emission.

Abstract Determining the genetic architecture of Alzheimer’s disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Abstract Background Primary hypogonadism is a recognised complication in survivors of testicular cancer. However, secondary hypogonadism can result from other causes that suppress the hypothalamic-pituitary axis, including obesity, high dose glucocorticoids, chronic end organ failure, and diabetes. The aim of this study was to explore low total serum testosterone in Australian survivors of testicular cancer and examine associations with body mass index, age, and prior chemotherapy use. Methods Clinical data including height, weight, diagnosis, treatment, and hormonal evaluations during follow-up were extracted from the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group Chemocog study (2007-2012), accompanied by data from two Australian, high-volume testicular cancer centres included in the iTestis testicular cancer registry (2012-2019). Low testosterone was defined by a serum concentration of testosterone (T) 8 IU/L, otherwise as secondary. Results Two hundred eighty-five individuals with either stage 1 or advanced testicular cancer were included. Of these, 105 (37%) were treated with orchidectomy and chemotherapy. Forty-nine (17%) met criteria for low testosterone during follow-up: 21 (43%) had primary and 27 (55%) had secondary low testosterone. Survivors of testicular cancer with higher body mass index were more likely to display low testosterone, both primary (p = 0.032) and secondary (p = 0.028). Our data did not show evidence of an association between older age or chemotherapy use and low testosterone in our cohort. Conclusions Low total serum testosterone was common in survivors of testicular cancer, and associated with a higher body mass index prior to orchidectomy, suggesting that elevated body mass index may contribute to low testosterone in this population, and that body weight, diet, and exercise should be addressed in testicular cancer follow-up.

Purpose: Children progress from making grapheme-phoneme connections to making grapho-syllabic connections before whole-word connections during reading development (Ehri, 2005a). More is known about the development of grapheme--phoneme connections than is known about grapho-syllabic connections. Therefore, we explored the trajectory of syllable use in English developing readers during oral reading. Method: Fifty-one English-speaking children (mean age: 8.9 years, 55% females, 88% monolinguals) in year groups three, four, and five read aloud sentences with an embedded target word, while their eye movements and voices were recorded. The targets contained six letters and were either one or two syllables. Result: Children in grade five had shorter gaze duration, shorter articulation duration, and larger spatial eye-voice span (EVS) than children in grade four. Children in grades three and four did not significantly differ on these measures. A syllable number effect was found for gaze duration but not for articulation duration and spatial EVS. Interestingly, one-syllable words took longer to process compared to two-syllable words, suggesting that more syllables may not always signify greater processing difficulty. Conclusion: Overall, children are sensitive to sublexical reading units; however, due to sample and stimuli limitations, these findings should be interpreted with caution and further research conducted.

Description of the subject. Lipolytic enzymes are widely distributed and fulfil important physiological functions in the microorganisms inhabiting diverse environments. Soils are rich, diversified environments containing microbial communities that remain largely unknown. Objectives. This work aimed to discover new lipolytic enzymes. Method. New enzymes were found by functional screening of two seasonal metagenomic libraries (a winter and a spring library) constructed from an agricultural soil. Screens were performed on 2xYT medium supplemented with 3% lipase reagent. Results. Nineteen positive clones were isolated. Analysis of the corresponding inserts led to identifying 23 putative lipolytic enzymes (13 for the winter library and 10 for the spring library) displaying between 31% and 62% identity to known enzymes and belonging to seven different families. Conclusions. As enzymes show low identity to known enzymes, the encoded enzymes may display novel biochemical features.