Reconstruction of a genome-scale metabolic model and in-silico flux analysis of Aspergillus tubingensis: a non-mycotoxinogenic citric acid-producing fungus.

BACKGROUND: Aspergillus tubingensis is a citric acid-producing fungus that can utilize sugars in hydrolysate of lignocellulosic biomass such as sugarcane bagasse and, unlike A. niger, does not produce mycotoxins. To date, no attempt has been made to model its metabolism at genome scale. RESULTS: Here, we utilized the whole-genome sequence (34.96 Mb length) and the measured biomass composition to reconstruct a genome-scale metabolic model (GSMM) of A. tubingensis DJU120 strain. The model, named iMK1652, consists of 1652 genes, 1657 metabolites and 2039 reactions distributed over four cellular compartments. The model has been extensively curated manually. This included removal of dead-end metabolites and generic reactions, addition of secondary metabolite pathways and several transporters. Several mycotoxin synthesis pathways were either absent or incomplete in the genome, providing a genomic basis for the non-toxinogenic nature of this species. The model was further refined based on the experimental phenotypic microarray (Biolog) data. The model closely captured DJU120 fermentative data on glucose, xylose, and phosphate consumption, as well as citric acid and biomass production, showing its applicability to capture citric acid fermentation of lignocellulosic biomass hydrolysate. CONCLUSIONS: The model offers a framework to conduct metabolic systems biology investigations and can act as a scaffold for integrative modelling of A. tubingensis.

Photo-Induced Charge State Dynamics of the Neutral and Negatively Charged Silicon Vacancy Centers in Room-Temperature Diamond.

The silicon vacancy (SiV) center in diamond is drawing much attention due to its optical and spin properties, attractive for quantum information processing and sensing. Comparatively little is known, however, about the dynamics governing SiV charge state interconversion mainly due to challenges associated with generating, stabilizing, and characterizing all possible charge states, particularly at room temperature. Here, multi-color confocal microscopy and density functional theory are used to examine photo-induced SiV recombination - from neutral, to single-, to double-negatively charged - over a broad spectral window in chemical-vapor-deposition (CVD) diamond under ambient conditions. For the SiV0 to SiV- transition, a linear growth of the photo-recombination rate with laser power at all observed wavelengths is found, a hallmark of single photon dynamics. Laser excitation of SiV‒, on the other hand, yields only fractional recombination into SiV2‒, a finding that is interpreted in terms of a photo-activated electron tunneling process from proximal nitrogen atoms.

When not hitting your sales target is 'the end of the world': Examining the effects of rational emotive behaviour therapy on the irrational beliefs and emotional reactivity of UK-based sales professionals.

Against the backdrop of the COVID-19 pandemic, workplace wellbeing is a key priority for employers. Severe market and health conditions continue to bring inevitable problems that could be reduced with the application of psychological interventions to prevent mental and physical health issues, making this study a highly pertinent and valuable contribution to the field. This paper reports the effects of a rational emotive behaviour therapy (REBT) programme on the irrational beliefs and emotional reactivity of 56 office-based sales professionals located in the northwest region of the UK. A pre-test, post-test experimental design was utilised, and a mixed model ANOVA (repeated measures) was adopted to assess changes in mean differences concerning irrational beliefs and emotional reactivity at pre and post-test stages for the intervention group, in comparison to a control group. Results indicate that those in the REBT group reported significant reductions in irrational beliefs and emotional reactivity, whilst those in the control group reported no such changes. It is recommended that future research studies consider utilizing a mixed methods design and focus on a strategic collaboration of organisational and individual level interventions for improving the psychological wellbeing and performance of sales personnel.

Marine cyanobacterial biomass is an efficient feedstock for fungal bioprocesses.

BACKGROUND: Marine cyanobacteria offer many sustainability advantages, such as the ability to fix atmospheric CO2, very fast growth and no dependence on freshwater for culture. Cyanobacterial biomass is a rich source of sugars and proteins, two essential nutrients for culturing any heterotroph. However, no previous study has evaluated their application as a feedstock for fungal bioprocesses. RESULTS: In this work, we cultured the marine cyanobacterium Synechococcus sp. PCC 7002 in a 3-L externally illuminated bioreactor with working volume of 2 L with a biomass productivity of ~ 0.8 g L-1 day-1. Hydrolysis of the biomass with acids released proteins and hydrolyzed glycogen while hydrolysis of the biomass with base released only proteins but did not hydrolyze glycogen. Among the different acids tested, treatment with HNO3 led to the highest release of proteins and glucose. Cyanobacterial biomass hydrolysate (CBH) prepared in HNO3 was used as a medium to produce cellulase enzyme by the Penicillium funiculosum OAO3 strain while CBH prepared in HCl and treated with charcoal was used as a medium for citric acid by Aspergillus tubingensis. Approximately 50% higher titers of both products were obtained compared to traditional media. CONCLUSIONS: These results show that the hydrolysate of marine cyanobacteria is an effective source of nutrients/proteins for fungal bioprocesses.

Maternal plasma cortisol's effect on offspring birth weight: a Mendelian Randomisation study.

BACKGROUND: Observational studies and randomized controlled trials have found evidence that higher maternal circulating cortisol levels in pregnancy are associated with lower offspring birth weight. However, it is possible that the observational associations are due to residual confounding. METHODS: We performed two-sample Mendelian Randomisation (MR) using a single genetic variant (rs9989237) associated with morning plasma cortisol (GWAS; sample 1; N = 25,314). The association between this maternal genetic variant and offspring birth weight, adjusted for fetal genotype, was obtained from the published EGG Consortium and UK Biobank meta-analysis (GWAS; sample 2; N = up to 406,063) and a Wald ratio was used to estimate the causal effect. We also performed an alternative analysis using all GWAS reported cortisol variants that takes account of linkage disequilibrium. We also tested the genetic variant's effect on pregnancy cortisol and performed PheWas to search for potential pleiotropic effects. RESULTS: The estimated effect of maternal circulating cortisol on birth weight was a 50 gram (95% CI, -109 to 10) lower birth weight per 1 SD higher log-transformed maternal circulating cortisol levels, using a single variant. The alternative analysis gave similar results (-33 grams (95% CI, -77 to 11)). The effect of the cortisol variant on pregnancy cortisol was 2-fold weaker than in the original GWAS, and evidence was found of pleiotropy. CONCLUSIONS: Our findings provide some evidence that higher maternal morning plasma cortisol causes lower birth weight. Identification of more independent genetic instruments for morning plasma cortisol are necessary to explore the potential bias identified.

Neurodevelopmental outcomes in children and adults with Fetal Valproate Spectrum Disorder: A contribution from the ConcePTION project.

AIM: To describe the neurodevelopmental phenotype of older children and adults with a diagnosis of Fetal Valproate Spectrum Disorder (FVSD). METHODS: In this cross-sectional study, 90 caregivers were recruited and completed a series of questionnaires regarding the neurodevelopmental outcomes of 146 individuals aged 7-37 years (M = 18.1), including individuals with a formal diagnosis of FVSD (n = 99), individuals exposed to Valproate but without an FVSD diagnosis (n = 24), and individuals not exposed to Valproate (N = 23). The mean dose of valproate exposure for individuals with an FVSD diagnosis was 1470 mg/day. RESULTS: Individuals with a diagnosis of FVSD showed significantly higher levels of moderate (43.4%) and severe (14.4%) cognitive impairment than other groups (p = 0.003), high levels of required formal educational support (77.6%), and poorer academic competence than individuals not exposed to Valproate (p = 0.001). Overall psychosocial problems (p = 0.02), internalising problems (p = 0.05) and attention problems (p = 0.001), but not externalising problems, were elevated in individuals with a diagnosis of FVSD. Rates of neurodevelopmental disorders, particularly autistic spectrum disorders (62.9%) and sensory problems (80.6%) are particularly central to the FVSD phenotype. There was no evidence of a statistical dose-dependent effect, possibly due to the high mean dose of exposure having a uniformly negative impact across the sample. Individuals with FVSD had required a significant number of health and child development services. INTERPRETATION: Children and young adults with a diagnosis of FVSD are at an increased risk of a range of altered neurodevelopmental outcomes, highlighting the need for a multidisciplinary approach to clinical management across the lifespan.

Childhood cancer incidence & survival in Aotearoa, New Zealand 2010-2019.

OBJECTIVE: To provide updated estimates of childhood cancer incidence and survival in Aotearoa, New Zealand. METHOD: Registrations for children under the age of 15 years diagnosed with cancer between 2010 and 2019 were extracted from the New Zealand Children's Cancer Registry. Cases were stratified by age, sex, prioritised ethnicity (Maori, Pacific peoples, and non-Maori) and cancer type. Age-standardised incidence rates (ASRs) per million person years and observed survival rates were calculated. RESULTS: During the study period, 1522 children were diagnosed with cancer providing an ASR of 169.1 per million per year (95 % Confidence Interval, CI: 157.0-181.2). For all childhood cancers combined, survival at 5-years was 85.6 % (95 % CI 83.7-87.3). There was a gap in 5-year survival between Maori (80.9 %, 95 % CI 76.5-84.6), Pacific peoples (82.6 %, 95 % CI 75.6-87,7) and Non-Maori (87.8 %, 95 % CI 85.6-89.7) In both adjusted and unadjusted models, this difference in survival was most marked (p < 0.05) among children who were 10-14 years of age at diagnosis. CONCLUSION: Childhood cancer incidence and survival rates in Aotearoa, New Zealand remain comparable to other high-income countries. Further research is required to understand the survival difference between ethnic groups.

Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies.

Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance.

Child, parent, and family mental health and functioning in Australia during COVID-19: comparison to pre-pandemic data.

The COVID-19 pandemic presents significant risks to population mental health. Despite evidence of detrimental effects for adults, there has been limited examination of the impact of COVID-19 on parents and children specifically. We aim to examine patterns of parent and child (0-18 years) mental health, parent substance use, couple conflict, parenting practices, and family functioning during COVID-19, compared to pre-pandemic data, and to identify families most at risk of poor outcomes according to pre-existing demographic and individual factors, and COVID-19 stressors. Participants were Australian mothers (81%) and fathers aged 18 years and over who were parents of a child 0-18 years (N = 2365). Parents completed an online self-report survey during 'stage three' COVID-19 restrictions in April 2020. Data were compared to pre-pandemic data from four Australian population-based cohorts. Compared to pre-pandemic estimates, during the pandemic period parents reported higher rates of parent depression, anxiety, and stress (Cohen's d = 0.26-0.81, all p < 0.001), higher parenting irritability (d = 0.17-0.46, all p < 0.001), lower family positive expressiveness (d = - 0.18, p < 0.001), and higher alcohol consumption (22% vs 12% drinking four or more days per week, p < 0.001). In multivariable analyses, we consistently found that younger parent age, increased financial deprivation, pre-existing parent and child physical and mental health conditions, COVID-19 psychological and environmental stressors, and housing dissatisfaction were associated with worse parent and child functioning and more strained family relationships. Our data suggest wide-ranging, detrimental family impacts associated with the COVID-19 pandemic; and support policy actions to assist families with financial supports, leave entitlements, and social housing.

Modeling N-Glycosylation: A Systems Biology Approach for Evaluating Changes in the Steady-State Organization of Golgi-Resident Proteins.

The organization of Golgi-resident proteins is crucial for sorting molecules within the secretory pathway and regulating posttranslational modifications. However, evaluating changes to Golgi organization can be challenging, often requiring extensive experimental investigations. Here, we propose a systems biology approach in which changes to Golgi-resident protein sorting and localization can be deduced using cellular N-glycan profiles as the only experimental input.The approach detailed here utilizes the influence of Golgi organization on N-glycan biosynthesis to investigate the mechanisms involved in establishing and maintaining Golgi organization. While N-glycosylation is carried out in a non-template-driven manner, the distribution of N-glycan biosynthetic enzymes within the Golgi ensures this process is not completely random. Therefore, changes to N-glycan profiles provide clues into how altered cell phenotypes affect the sorting and localization of Golgi-resident proteins. Here, we generate a stochastic simulation of N-glycan biosynthesis to produce a simulated glycan profile similar to that obtained experimentally and then combine this with Bayesian fitting to enable inference of changes in enzyme amounts and localizations. Alterations to Golgi organization are evaluated by calculating how the fitted enzyme parameters shift when moving from simulating the glycan profile of one cellular state (e.g., a wild type) to an altered cellular state (e.g., a mutant). Our approach illustrates how an iterative combination of mathematical systems biology and minimal experimental cell biology can be utilized to maximally integrate biological knowledge to gain insightful knowledge of the underlying mechanisms in a manner inaccessible to either alone.

The Effects of Antibiotic Combination Treatments on Pseudomonas aeruginosa Tolerance Evolution and Coexistence with Stenotrophomonas maltophilia.

The Pseudomonas aeruginosa bacterium is a common pathogen of cystic fibrosis (CF) patients due to its ability to evolve resistance to antibiotics during treatments. While P. aeruginosa resistance evolution is well-characterized in monocultures, it is less well-understood in polymicrobial CF infections. Here, we investigated how exposure to ciprofloxacin, colistin, or tobramycin antibiotics, administered at sub-minimum inhibitory concentration (MIC) doses, both alone and in combination, shaped the tolerance evolution of P. aeruginosa (PAO1 lab and clinical CF LESB58 strains) in the absence and presence of a commonly co-occurring species, Stenotrophomonas maltophilia. The increases in antibiotic tolerances were primarily driven by the presence of that antibiotic in the treatment. We observed a reciprocal cross-tolerance between ciprofloxacin and tobramycin, and, when combined, the selected antibiotics increased the MICs for all of the antibiotics. Though the presence of S. maltophilia did not affect the tolerance or the MIC evolution, it drove P. aeruginosa into extinction more frequently in the presence of tobramycin due to its relatively greater innate tobramycin tolerance. In contrast, P. aeruginosa dominated and drove S. maltophilia extinct in most other treatments. Together, our findings suggest that besides driving high-level antibiotic tolerance evolution, sub-MIC antibiotic exposure can alter competitive bacterial interactions, leading to target pathogen extinctions in multispecies communities. IMPORTANCE Cystic fibrosis (CF) is a genetic condition that results in thick mucus secretions in the lungs that are susceptible to chronic bacterial infections. The bacterial pathogen Pseudomonas aeruginosa is often associated with morbidity in CF and is difficult to treat due to its high resistance to antibiotics. The resistance evolution of Pseudomonas aeruginosa is poorly understood in polymicrobial infections that are typical of CF. To study this, we exposed P. aeruginosa to sublethal concentrations of ciprofloxacin, colistin, or tobramycin antibiotics in the absence and presence of a commonly co-occurring CF species, Stenotrophomonas maltophilia. We found that low-level antibiotic concentrations selected for high-level antibiotic resistance. While P. aeruginosa dominated in most antibiotic treatments, S. maltophilia drove it into extinction in the presence of tobramycin due to an innately higher tobramycin resistance. Our findings suggest that, besides driving high-level antibiotic tolerance evolution, sublethal antibiotic exposure can magnify competition in bacterial communities, which can lead to target pathogen extinctions in multispecies communities.

Effects of the COVID-19 lockdown on mental health in a UK student sample.

BACKGROUND: The COVID-19 pandemic and the resulting restrictions placed upon society have had a profound impact on both physical and mental health, particularly for young people. AIMS: The current study assesses the impact of COVID-19 on student mental health. METHOD: Four hundred and thirty four first year Undergraduate students completed a battery of self-report questionnaires (PHQ-P, GAD-7 and SAS-SV) to assess for depression, anxiety and mobile phone addiction respectively with data being collected over a 2 year period. The data from each year was compared (216 and 218 students respectively). RESULTS: A MANOVA revealed that COVID-19 had a significant impact on self-reported levels of depression, anxiety and smartphone addiction-which all significantly increased from the 2020 to the 2021 group. The percentage of students who had a score which warranted a classification of clinical depression increased from 30 to 44%, and for anxiety increased from 22 to 27%-those students who showed a comorbidity across the two rose from 12 to 21%. Smartphone addiction levels rose from 39 to 50%. Correlational analysis showed a significant relationship between Smartphone usage and depression and anxiety. CONCLUSIONS: This research suggests that COVID-19 has had a major impact upon student mental health, and smartphone addiction. The importance of identifying predictive factors of depression and anxiety is emphasised, and suggestions for intervention are discussed.

Integration of Aspergillus niger transcriptomic profile with metabolic model identifies potential targets to optimise citric acid production from lignocellulosic hydrolysate.

BACKGROUND: Citric acid is typically produced industrially by Aspergillus niger-mediated fermentation of a sucrose-based feedstock, such as molasses. The fungus Aspergillus niger has the potential to utilise lignocellulosic biomass, such as bagasse, for industrial-scale citric acid production, but realising this potential requires strain optimisation. Systems biology can accelerate strain engineering by systematic target identification, facilitated by methods for the integration of omics data into a high-quality metabolic model. In this work, we perform transcriptomic analysis to determine the temporal expression changes during fermentation of bagasse hydrolysate and develop an evolutionary algorithm to integrate the transcriptomic data with the available metabolic model to identify potential targets for strain engineering. RESULTS: The novel integrated procedure matures our understanding of suboptimal citric acid production and reveals potential targets for strain engineering, including targets consistent with the literature such as the up-regulation of citrate export and pyruvate carboxylase as well as novel targets such as the down-regulation of inorganic diphosphatase. CONCLUSIONS: In this study, we demonstrate the production of citric acid from lignocellulosic hydrolysate and show how transcriptomic data across multiple timepoints can be coupled with evolutionary and metabolic modelling to identify potential targets for further engineering to maximise productivity from a chosen feedstock. The in silico strategies employed in this study can be applied to other biotechnological goals, assisting efforts to harness the potential of microorganisms for bio-based production of valuable chemicals.

Performance of ultrasound in the diagnosis of cholecystitis: not so (ultra)sound?

INTRODUCTION: Ultrasound has long been the radiological investigation of choice for right upper quadrant pain in the detection of gallstones and cholecystitis. However, previously reported sensitivity, specificity and other diagnostic metrics have varied widely and the underlying patient numbers have been small. We present robust and exhaustive diagnostic metrics based on a large series of 795 patients. METHODS: All laparoscopic cholecystectomies at Portsmouth Hospitals University were prospectively logged between 2017 and 2020. Ultrasound findings, Nassar operative difficulty and histopathological findings were all collected in addition to patient biometrics. RESULTS: In our large patient series, the sensitivity of ultrasound for cholecystitis was lower than previously reported at 75.7% for acute cholecystitis, 34.6% for chronic cholecystitis and 42.7% overall. Moreover, we show that sensitivity degrades with the time between ultrasound and cholecystectomy, falling below 50% at 140 days. Finally, we show that ultrasound strongly predicts the Nassar difficulty grade of cholecystectomy and that its ability to do so is greatest when the interval between ultrasound and cholecystectomy is less than 27 days. CONCLUSIONS: We present robust diagnostic metrics for ultrasound in the diagnosis of cholecystitis. These should caution the clinician that ultrasound may miss a quarter of cases of acute cholecystitis and over half of all cases of cholecystitis. Conversely, the finding of a thickened gallbladder wall on ultrasound can predict a 'difficult cholecystectomy' and highlight the need for appropriate expertise and resources. Both this prediction and the diagnostic sensitivity are best if the ultrasound is done less than 27 days before cholecystectomy.

Inter-species interactions alter antibiotic efficacy in bacterial communities.

The efficacy of antibiotic treatments targeting polymicrobial communities is not well predicted by conventional in vitro susceptibility testing based on determining minimum inhibitory concentration (MIC) in monocultures. One reason for this is that inter-species interactions can alter the community members' susceptibility to antibiotics. Here we quantify, and identify mechanisms for, community-modulated changes of efficacy for clinically relevant antibiotics against the pathogen Pseudomonas aeruginosa in model cystic fibrosis (CF) lung communities derived from clinical samples. We demonstrate that multi-drug resistant Stenotrophomonas maltophilia can provide high levels of antibiotic protection to otherwise sensitive P. aeruginosa. Exposure protection to imipenem was provided by chromosomally encoded metallo-ß-lactamase that detoxified the environment; protection was dependent upon S. maltophilia cell density and was provided by S. maltophilia strains isolated from CF sputum, increasing the MIC of P. aeruginosa by up to 16-fold. In contrast, the presence of S. maltophilia provided no protection against meropenem, another routinely used carbapenem. Mathematical ordinary differential equation modelling shows that the level of exposure protection provided against different carbapenems can be explained by differences in antibiotic efficacy and inactivation rate. Together, these findings reveal that exploitation of pre-occurring antimicrobial resistance, and inter-specific competition, can have large impacts on pathogen antibiotic susceptibility, highlighting the importance of microbial ecology for designing successful antibiotic treatments for multispecies communities.

Measurement and initial characterization of leukocyte telomere length in 474,074 participants in UK Biobank.

Leukocyte telomere length (LTL) is a proposed marker of biological age. Here we report the measurement and initial characterization of LTL in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average ~7 years younger in 'biological age' than men. Compared to white Europeans, LTL is markedly longer in African and Chinese ancestries. Older paternal age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes show weaker associations. Age, ethnicity, sex and white cell count explain ~5.5% of LTL variance. Using paired samples from 1,351 participants taken ~5 years apart, we estimate the within-individual variability in LTL and provide a correction factor for this. This resource provides opportunities to investigate determinants and biomedical consequences of variation in LTL.

Gender differences in barriers to mental healthcare for UK military veterans: a preliminary investigation.

INTRODUCTION: Limited UK research focuses on female military veterans' gender-related experiences and issues when accessing civilian mental healthcare support. This study sought to illuminate a preliminary understanding of any gender differences in barriers that may discourage them accessing mental healthcare support. METHODS: A total of 100 participants completed an open online survey of UK triservice veterans who identified as having experienced postmilitary mental health problems. They completed a 30-item Barriers to Access to Care Evaluation scale and were asked to elaborate using free-text questions. Resulting quantitative data were analysed for gender-related differences, while the qualitative text was thematically explored. RESULTS: While stigma, previous poor experience of mental healthcare and a lack of trust in civilian providers were found to act as barriers to postmilitary support for both men and women, significantly more women reported that their gender had also impacted on their intention to seek help. Women also commented on the impact of gender-related discrimination during service on their help-seeking experiences. CONCLUSIONS: While efforts are being made by the UK Ministry of Defence to reduce barriers to mental healthcare for those still serving in the Armed Forces, it has been more difficult to provide a similar level of support to the veteran population. With little veteran research focusing on the specific experiences of women, this study suggests that female veterans encounter specific access barriers and issues related to their gender. Further research is therefore needed to ensure these findings are addressed.

Computational Modeling of Glycan Processing in the Golgi for Investigating Changes in the Arrangements of Biosynthetic Enzymes.

Modeling glycan biosynthesis is becoming increasingly important due to the far-reaching implications that glycosylation can exhibit, from pathologies to biopharmaceutical manufacturing. Here we describe a stochastic simulation approach, to overcome the deterministic nature of previous models, that aims to simulate the action of glycan modifying enzymes to produce a glycan profile. This is then coupled with an approximate Bayesian computation methodology to systematically fit to empirical data in order to determine which set of parameters adequately describes the organization of enzymes within the Golgi. The model is described in detail along with a proof of concept and therapeutic applications.

Early motor development in infants with moderate or severe bronchopulmonary dysplasia.

BACKGROUND: Timely development of early motor skills is essential for later skill development in multiple domains. Infants with severe bronchopulmonary dysplasia (BPD) have significant risk for developmental delays. Early motor skill development in this population has not been described. The aim of the present study was to characterize motor skill acquisition at 3 and 6 months corrected age (CA) and assess trajectories of skill development over this time period in infants with severe BPD. METHODS: We performed a single-center, retrospective descriptive study. Motor skills were categorized as present and normal, present but atypical, or absent at 3 and 6 months CA. Logistic regression was used to identify clinical characteristics associated with negative trajectories of skill acquisition. RESULTS: Data were available for 232 infants and 187 infants at 3 and 6 months CA, respectively. Ten motor skills were present and normal in 5-44%(range) of subjects at 3 months. Nineteen motor skills were present and normal in 1-63%(range) of subjects at 6 months. Significant postural asymmetry was noted throughout the study period. Loss of skills and worsening asymmetries over time were common. Exposure to sedating medications was significantly associated with poor development. CONCLUSION: We report delays in motor skill acquisition and postural asymmetries in infants with severe BPD at both 3 and 6 months CA. The association between sedating medications and poor development suggests that efforts to limit these exposures may lead to improved development. Targeted interventions to facilitate early motor development may improve outcomes of this high-risk population.

"Watch Me Grow- Electronic (WMG-E)" surveillance approach to identify and address child development, parental mental health, and psychosocial needs: study protocol.

BACKGROUND: The COVID-19 pandemic and the associated economic recession has increased parental psychosocial stress and mental health challenges. This has adversely impacted child development and wellbeing, particularly for children from priority populations (culturally and linguistically diverse (CALD) and rural/regional communities) who are at an already increased risk of health inequality. The increased mental health and psychosocial needs were compounded by the closure of in-person preventive and health promotion programs resulting in health organisations embracing technology and online services. Watch Me Grow- Electronic (WMG-E) - developmental surveillance platform- exemplifies one such service. WMG-E was developed to monitor child development and guide parents towards more detailed assessments when risk is identified. This Randomised Controlled Trial (RCT) aims to expand WMG-E as a digital navigation tool by also incorporating parents' mental health and psychosocial needs. Children and families needing additional assessments and supports will be electronically directed to relevant resources in the 'care-as-usual' group. In contrast, the intervention group will receive continuity of care, with additional in-person assessment and 'warm hand over' by a 'service navigator' to ensure their needs are met. METHODS: Using an RCT we will determine: (1) parental engagement with developmental surveillance; (2) access to services for those with mental health and social care needs; and (3) uptake of service recommendations. Three hundred parents/carers of children aged 6 months to 3 years (recruited from a culturally diverse, or rural/regional site) will be randomly allocated to the 'care-as-usual' or 'intervention' group. A mixed methods implementation evaluation will be completed, with semi-structured interviews to ascertain the acceptability, feasibility and impact of the WMG-E platform and service navigator. CONCLUSIONS: Using WMG-E is expected to: normalise and de-stigmatise mental health and psychosocial screening; increase parental engagement and service use; and result in the early identification and management of child developmental needs, parental mental health, and family psychosocial needs. If effective, digital solutions such as WMG-E to engage and empower parents alongside a service navigator for vulnerable families needing additional support, will have significant practice and policy implications in the pandemic/post pandemic period. TRIAL REGISTRATION: The trial (Protocol No. 1.0, Version 3.1) was registered with ANZCTR (registration number: ACTRN12621000766819 ) on July 21st, 2021 and reporting of the trial results will be according to recommendations in the CONSORT Statement.