Combining Automated Organoid Workflows with Artificial Intelligence-Based Analyses: Opportunities to Build a New Generation of Interdisciplinary High-Throughput Screens for Parkinson's Disease and Beyond

Parkinson's disease (PD) is the second most common neurodegenerative disease and primarily characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Despite decades of research and the development of various disease model systems, there is no curative treatment. This could be due to current model systems, including cell culture and animal models, not adequately recapitulating human PD etiology. More complex human disease models, including human midbrain organoids, are maturing technologies that increasingly enable the strategic incorporation of the missing components needed to model PD in vitro. The resulting organoid-based biological complexity provides new opportunities and challenges in data analysis of rich multimodal data sets. Emerging artificial intelligence (AI) capabilities can take advantage of large, broad data sets and even correlate results across disciplines. Current organoid technologies no longer lack the prerequisites for large-scale high-throughput screening (HTS) and can generate complex yet reproducible data suitable for AI-based data mining. We have recently developed a fully scalable and HTS-compatible workflow for the generation, maintenance, and analysis of three-dimensional (3D) microtissues mimicking key characteristics of the human midbrain (called “automated midbrain organoids,” AMOs). AMOs build a reproducible, scalable foundation for creating next-generation 3D models of human neural disease that can fuel mechanism-agnostic phenotypic drug discovery in human in vitro PD models and beyond. Here, we explore the opportunities and challenges resulting from the convergence of organoid HTS and AI-driven data analytics and outline potential future avenues toward the discovery of novel mechanisms and drugs in PD research. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society     

Australian parents’ work–family conflict: accumulated effects on children’s family environment and mental health

Purpose

Many parents struggle to balance their work and family responsibilities. Yet, little research in the field of social psychiatry has explored the emergence of work–family conflict (WFC) as an important social determinant of mental health, particularly for children. The current study used longitudinal Australian population-based data to investigate the impact of parents’ accumulated experiences of work–family conflict on children’s mental health. Levels of parent psychological distress, marital satisfaction and parenting irritability were examined as potential explanatory factors within the family environment.

Methods

The study used five waves of data from the Australian Longitudinal Study of Australian Children (LSAC), a representative community sample of Australian children and their parents. Analyses were restricted to coupled, employed mothers (1903) and fathers (1584) who reported their WFC levels in all five waves. Structural Equation Modelling (SEM) was used to examine the association between accumulated experiences of work–family conflict across all time-points (AWFC) and children’s mental health at wave 5. Family environment factors were assessed as possible explanatory mediators.

Results

There was a significant association between AWFC and children’s mental health at wave 5. Parent psychological distress, marital satisfaction and parenting irritability were all found to significantly explain this association (accounting for 66% of the total effect).

Conclusions

Children whose parents have ongoing or accumulated difficulties managing their work and family responsibilities are more likely to have poorer mental health. This has important implications for family-friendly work arrangements and demonstrates the need to further understand the intergenerational impacts of parents’ jobs on their children’s psychological wellbeing.

     

Neuromodulatory pathways in learning and memory: Lessons from invertebrates

In an ever‐changing environment, animals have to continuously adapt their behaviour. The ability to learn from experience is crucial for animals to increase their chances of survival. It is therefore not surprising that learning and memory evolved early in evolution and are mediated by conserved molecular mechanisms. A broad range of neuromodulators, in particular monoamines and neuropeptides, have been found to influence learning and memory, although our knowledge on their modulatory functions in learning circuits remains fragmentary. Many neuromodulatory systems are evolutionarily ancient and well‐conserved between vertebrates and invertebrates. Here, we highlight general principles and mechanistic insights concerning the actions of monoamines and neuropeptides in learning circuits that have emerged from invertebrate studies. Diverse neuromodulators have been shown to influence learning and memory in invertebrates, which can have divergent or convergent actions at different spatiotemporal scales. In addition, neuromodulators can regulate learning dependent on internal and external states, such as food and social context. The strong conservation of neuromodulatory systems, the extensive toolkit and the compact learning circuits in invertebrate models make these powerful systems to further deepen our understanding of neuromodulatory pathways involved in learning and memory.     

Effect of shared care on blood pressure in patients with chronic kidney disease: a cluster randomised controlled trial

Background

Chronic kidney disease (CKD) is highly prevalent in patients with diabetes or hypertension in primary care. A shared care model could improve quality of care in these patients

Aim

To assess the effect of a shared care model in managing patients with CKD who also have diabetes or hypertension.

Design and setting

A cluster randomised controlled trial in nine general practices in The Netherlands.

Method

Five practices were allocated to the shared care model and four practices to usual care for 1 year. Primary outcome was the achievement of blood pressure targets (130/80 mmHg) and lowering of blood pressure in patients with diabetes mellitus or hypertension and an estimated glomerular filtration rate (eGFR)<60ml/min/1.73m².

Results

Data of 90 intervention and 74 control patients could be analysed. Blood pressure in the intervention group decreased with 8.1 (95% CI = 4.8 to 11.3)/1.1 (95% CI = −1.0 to 3.2) compared to −0.2 (95% CI = −3.8 to 3.3)/−0.5 (95% CI = −2.9 to 1.8) in the control group. Use of lipid-lowering drugs, angiotensin-system inhibitors and vitamin D was higher in the intervention group than in the control group (73% versus 51%, 81% versus 64%, and 15% versus 1%, respectively, [P = 0.004, P = 0.01, and P = 0.002]).

Conclusion

A shared care model between GP, nurse practitioner and nephrologist is beneficial in reducing systolic blood pressure in patients with CKD in primary care.     

Impact of the mandibular divergence on the position of the inferior alveolar nerve and mylohyoid nerve: a computed tomography study and its relevance to bilateral sagittal split osteotomy

Purpose

Bilateral sagittal split osteotomy (BSSO) is the most common procedure used to treat mandibular deformities. BSSO procedures include the Epker technique and the Dal Pont technique which are the most frequently used. Because of the intramandibular pathway of the inferior alveolar nerve (IAN), neurosensory disturbance of the lower lip and chin is the most common complication of BSSO. This study performed quantitative measurements from computed tomographic (CT) data obtained on dry human mandibles. The main aim of the study was to evaluate if mandibular divergence can predict the position of the IAN and the mylohyoid nerve (MHN) to prevent nerve injury.

Methods

After CT and 3D reconstruction of 65 dry mandibles, 30 measurements were made on 3 planes for each hemi-mandible. This allowed analysis of the IAN and MHN pathways. Three groups of hemi-mandibles were created depending on their divergence, and a statistical analysis was performed.

Results

Eight out of the 30 measurements showed a significant difference among the 3 groups. There was no significant difference for the remaining 22 measurements.

Conclusions

The IAN seems to have a more superior position in the groups of mandibular hypo- and hyper-divergence. Orthognathic surgeons should use a more superficial retromolar bone incision in these cases. Finally, the Epker technique would be safer for preserving the MHN in normo- and hypo-divergent patients.     

Acute gastroenteritis outbreaks in closed and semi-closed facilities during 2017 in Catalonia,Spain

Acute gastroenteritis (AGE) is a leading cause of disease worldwide. The aim of this prospective observational study is to describe the epidemiology of AGE in closed and semi-closed institutions in Catalonia. In 2017, 151 outbreaks were reported; 30.5% occurred in closed and semi-closed institutions; 71.7% caused by norovirus (NoV) (1532) cases. Person-to-person transmission accounted for 75.8% of NoV outbreaks vs 46.1% in non-NoV outbreaks (p?<?0.001). Attack rate for NoV outbreaks was 33.1% vs 14.3% for non-NoV outbreaks (RR?=?2.3; 95%CI: 2.0–2.7). The high number of affected underscores prompt and intense preventive measures to avoid the extension and perpetuation of outbreaks in these settings.

     

Long-term serological follow-up after primary Coxiella burnetii infection in patients with vascular risk factors for chronic Q fever

We evaluated the long-term serological follow-up of patients with vascular risk factors for chronic Q fever that were previously Coxiella burnetii seropositive. C. burnetii phase I IgG titers were reevaluated in patients that gave informed consent or retrospectively collected in patients already deceased or lost to follow-up. Of 107 patients, 25 (23.4%) became seronegative, 77 (72.0%) retained a profile of past resolved Q fever infection, and five (4.7%) developed chronic Q fever. We urge clinicians to stay vigilant for chronic Q fever beyond two years after primary infection and perform serological testing based on clinical presentation.