Dynamic ventral disc contraction is necessary for Giardia attachment and host pathology.

Giardia lamblia is a common parasitic protist that infects the small intestine and causes giardiasis, resulting in diarrhea, vomiting, weight loss, and malabsorption. Giardiasis leads to cellular damage, including loss of microvilli, disruption of tight junctions, impaired barrier function, enzyme inhibition, malabsorption, and apoptosis. In the host, motile Giardia trophozoites attach to the duodenal microvilli using a unique microtubule organelle called the ventral disc. Despite early observations of disc-shaped depressions in microvilli after parasite detachment, little is known about disc-mediated attachment mechanisms and there little direct evidence showing that parasite attachment causes cellular damage. However, advancements in in vitro organoid models of infection and genetic tools have opened new possibilities for studying molecular mechanisms of attachment and the impact of attachment on the host. Through high-resolution live imaging and a novel disc mutant, we provide direct evidence for disc contraction during attachment, resolving the long-standing controversy of its existence. Specifically, we identify three types of disc movements that characterize contraction, which in combination result in a decrease in disc diameter and volume. Additionally, we investigate the consequences of attachment and disc contractility using an attachment mutant that has abnormal disc architecture. In a human organoid model, we demonstrate that this mutant has a limited ability to break down the epithelial barrier as compared to wild type. Based on this direct evidence, we propose a model of attachment that incorporates disc contraction to generates the forces required for the observed "grasping" of trophozoites on the host epithelium. Overall, this work highlights the importance of disc contractility in establishing and maintaining parasite attachment, leading to intestinal barrier breakdown.

A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia.

The emerging understanding of gut microbiota as 'metabolic machinery' influencing many aspects of physiology has gained substantial attention in the field of psychiatry. This is largely due to the many overlapping pathophysiological mechanisms associated with both the potential functionality of the gut microbiota and the biological mechanisms thought to be underpinning mental disorders. In this systematic review, we synthesised the current literature investigating differences in gut microbiota composition in people with the major psychiatric disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), compared to 'healthy' controls. We also explored gut microbiota composition across disorders in an attempt to elucidate potential commonalities in the microbial signatures associated with these mental disorders. Following the PRISMA guidelines, databases were searched from inception through to December 2021. We identified 44 studies (including a total of 2510 psychiatric cases and 2407 controls) that met inclusion criteria, of which 24 investigated gut microbiota composition in MDD, seven investigated gut microbiota composition in BD, and 15 investigated gut microbiota composition in SZ. Our syntheses provide no strong evidence for a difference in the number or distribution (α-diversity) of bacteria in those with a mental disorder compared to controls. However, studies were relatively consistent in reporting differences in overall community composition (ß-diversity) in people with and without mental disorders. Our syntheses also identified specific bacterial taxa commonly associated with mental disorders, including lower levels of bacterial genera that produce short-chain fatty acids (e.g. butyrate), higher levels of lactic acid-producing bacteria, and higher levels of bacteria associated with glutamate and GABA metabolism. We also observed substantial heterogeneity across studies with regards to methodologies and reporting. Further prospective and experimental research using new tools and robust guidelines hold promise for improving our understanding of the role of the gut microbiota in mental and brain health and the development of interventions based on modification of gut microbiota.

A machine-learning assisted review of the use of habit formation in medication adherence interventions for long-term conditions.

Adherence to medication in long-term conditions is around 50%. The key components of successful interventions to improve medication adherence remain unclear, particularly when examined over prolonged follow-up periods. Behaviour change theories are increasingly interested in the utility of habit formation for the maintenance of health behaviour change, but there is no documentation on how habit has been conceptualised in the medication adherence intervention literature, or what effect the key technique identified in habit formation theory (context dependent repetition) has in these studies. To examine this, a machine-learning assisted review was conducted. Searches of MEDLINE, EMBASE and PSYCInfo and the reference list of a comprehensive systematic review of medication adherence interventions yielded 5973 articles. Machine learning-assisted title and abstract screening identified 15 independent RCTs published between 1976 and 2021, including 18 intervention comparisons of interest. Key findings indicate that conceptualisations of habit in the medication adherence literature are varied and behaviour change technique coding identified only six studies which explicitly described using habit formation. Future work should aim to develop this evidence base, drawing on contemporary habit theory and with explicit demonstration of what techniques have been used to promote habit formation.

Denosumab and invasive cervical root resorption: a case report.

This case report describes an adverse side effect from long-term denosumab therapy in a patient with metastatic breast cancer. The patient presented with extensive invasive cervical root resorption affecting most of her dentition. There were no other identified risk factors. As the treatment of breast cancer evolves leading to improved survival, and the number of cancer survivors increases, it is expected that dental practitioners will see a growing number of patients who are on long-term denosumab. Comprehensive dental examinations including radiographs are warranted to identify unusual or unexpected findings such as invasive cervical root resorption. © 2022 Australian Dental Association.

Development of a model of medication review for use in clinical practice: Bristol medication review model.

BACKGROUND: Medication review is a core aspect of medicine optimisation, yet existing models of review vary substantially in structure and content and are not necessarily easy to implement in clinical practice. This study aimed to use evidence from the existing literature to identify key medication review components and use this to inform the design of an improved review model. METHODS: A systematic review was conducted (PROSPERO: CRD42018109788) to identify randomised control trials of stand-alone medication review in adults (18+ years). The review updated that by Huiskes et al. (BMC Fam Pract. 18:5, 2017), using the same search strategy implemented in MEDLINE and Embase. Studies were assessed using the Cochrane risk of bias tool. Key review components were identified, alongside relevant clinical and health service outcomes. A working group (patients, doctors and pharmacists) developed the model through an iterative consensus process (appraisal of documents plus group discussions), working from the systematic review findings, brief evidence summaries for core review components and examples of previous models, to agree on the main purpose of the review model, overarching model structure, review components and supporting material. RESULTS: We identified 28 unique studies, with moderate bias overall. Consistent medication review components included reconciliation (26 studies), safety assessment (22), suboptimal treatment (19), patient knowledge/preferences (18), adherence (14), over-the-counter therapy (13) and drug monitoring (10). There was limited evidence from studies for improvement in key clinical outcomes. The review structure was underpinned by patient values and preferences, with parallel information gathering and evaluation stages, feeding into the final decision-making and implementation. Most key components identified in the literature were included. The final model was considered to benefit from a patient-centred, holistic approach, which captured both patient-orientated and medication-focused problems, and aligned with traditional consultation methods thus facilitating implementation in practice. CONCLUSIONS: The Bristol Medication Review Model provides a framework for standardised delivery of structured reviews. The model has the potential for use by all healthcare professionals with relevant clinical experience and is designed to offer flexibility of implementation not limited to a particular healthcare setting.

Custom workflows to improve joint variant calling from multiple related tumour samples: FreeBayesSomatic and Strelka2Pass.

SUMMARY: This work describes two novel workflows for variant calling that extend the widely used algorithms of Strelka2 and FreeBayes to call somatic mutations from multiple related tumour samples and one matched normal sample. We show that these workflows offer higher precision and recall than their single tumour-normal pair equivalents in both simulated and clinical sequencing data. AVAILABILITY AND IMPLEMENTATION: Source code freely available at the following link: https://atlassian.petermac.org.au/bitbucket/projects/DAW/repos/multisamplevariantcalling and executable through Janis (https://github.com/PMCC-BioinformaticsCore/janis) under the GPLv3 licence. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A controlled trial to investigate whether the orientation of the bevel and angle of approach determine the side of endobronchial intubation in an adult manikin.

One of the commonest complications of endotracheal intubation occurs when the tip of the endotracheal tube passes distal to the carina and enters one of the main bronchi. The perioperative practitioner may observe high airway pressures, hypoxia or even pneumothorax. The most common reason given for the high incidence of right endobronchial intubation is that the right main bronchus comes off the trachea at a more acute angle from the midline. We sought, however, to explore two other factors which may explain this phenomenon ­ the angle of the tube's bevel and its trajectory of approach. We conducted a prospective controlled trial in which doctors from our department intubated the trachea of an adult manikin in three distinct sets using standard tube, reversed tubes and reversed laryngoscope blades. We found that the angle of the bevel and trajectory of approach determines the side of endobronchial intubation in an adult manikin.

Temporal variation in the vocal behaviour of southern right whales in the Auckland Islands, New Zealand.

Autonomous recorders are frequently used for examining vocal behaviour of animals, and are particularly effective in remote habitats. Southern right whales are known to have an extensive acoustic repertoire. A recorder was moored at the isolated sub-Antarctic Auckland Islands for a year to examine whether the acoustic behaviour of southern right whales differed seasonally and throughout the day at their main calving ground in New Zealand. Recordings were made in each month except June, and vocalizations were audible in all months with recordings except January. A total of 35 487 calls were detected, of which upcalls were the most common (11 623). Call rate peaked in August (288 ± 5.9 [s.e.] calls/hour) and July (194 ± 8.3). Vocal behaviour varied diurnally with highest call rates detected at dusk and night, consistent with the concept that upcalls function primarily as contact calls. Zero-inflated model results confirmed that seasonal variation was the most important factor for explaining differences in vocal behaviour. An automated detector designed to expedite the analysis process for North Atlantic right whales correctly identified 80% of upcalls, although false detections were frequent, particularly when call rates were low. This study is the first to attempt year-round monitoring of southern right whale presence in New Zealand.

Deterministic Limit of Intracellular Calcium Spikes.

In nonexcitable cells, global Ca^{2+} spikes emerge from the collective dynamics of clusters of Ca^{2+} channels that are coupled by diffusion. Current modeling approaches have opposed stochastic descriptions of these systems to purely deterministic models, while both paradoxically appear compatible with experimental data. Combining fully stochastic simulations and mean-field analyses, we demonstrate that these two approaches can be reconciled. Our fully stochastic model generates spike sequences that can be seen as noise-perturbed oscillations of deterministic origin, while displaying statistical properties in agreement with experimental data. These underlying deterministic oscillations arise from a phenomenological spike nucleation mechanism.