The Significance of Intracellular versus Extracellular Calcium Pyrophosphate Crystals in Diagnosing Calcium Pyrophosphate Crystal Arthritis.

OBJECTIVE: Acute and chronic calcium pyrophosphate (CPP) crystal arthritis is characterised by the presence of synovial CPP crystals within a clinically inflamed joint. CPP crystals may be situated intracellularly or extracellularly, however the clinical significance of their location remains under studied. The objective of this retrospective cohort study was to assess the relevance of the CPP crystal location in diagnosing acute/chronic CPP crystal arthritis. METHODS: Data was collected from Waikato District Health Board to identify a study population with synovial fluid samples positive for CPP crystals. The cohort was stratified into two groups based on crystal location: intracellular and extracellular. The proportion of acute/chronic CPP crystal arthritis cases were compared between these groups. Acute/chronic CPP crystal arthritis was diagnosed when synovial CPP crystals were present, with objective evidence of joint inflammation and no other alternative diagnosis. Further analysis was made with respect to demographics, other laboratory results and cartilage calcification. RESULTS: This study included 134 patients, 108 with intracellular CPP crystals and 26 with extracellular CPP crystals. Acute/chronic CPP crystal arthritis was diagnosed in 85% of the intracellular and 50% of the extracellular group (p<0.001). Following exclusion of the septic arthritis cases, acute/chronic CPP crystal arthritis was diagnosed in 97% of the intracellular and 62% of the extracellular group (p<0.001). CONCLUSION: The presence of intracellular CPP crystals is more strongly associated with acute/chronic CPP crystal arthritis, whereas an extracellular CPP crystal location appears less specific.

Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease.

Caloric restriction (CR) is a widely recognized geroprotective intervention that slows or prevents Alzheimer's disease (AD) in animal models. CR is typically implemented via feeding mice a single meal per day; as CR mice rapidly consume their food, they are subject to a prolonged fast between meals. While CR has been shown to improve metabolic and cognitive functions and suppress pathological markers in AD mouse models, the specific contributions of fasting versus calorie reduction remains unclear. Here, we investigated the contribution of fasting and energy restriction to the beneficial effects of CR on AD progression. To test this, we placed 6-month-old 3xTg mice on one of several diet regimens, allowing us to dissect the effects of calories and fasting on metabolism, AD pathology, and cognition. We find that energy restriction alone, without fasting, was sufficient to improve glucose tolerance and reduce adiposity in both sexes, and to reduce Aß plaques and improve aspects of cognitive performance in females. However, we find that a prolonged fast between meals is necessary for many of the benefits of CR, including improved insulin sensitivity, reduced phosphorylation of tau, decreased neuroinflammation, inhibition of mTORC1 signaling, and activation of autophagy, as well as for the full cognitive benefits of CR. Finally, we find that fasting is essential for the benefits of CR on survival in male 3xTg mice. Overall, our results demonstrate that fasting is required for the full benefits of a CR diet on the development and progression of AD in 3xTg mice, and suggest that both when and how much we eat influences the development and progress of AD.

Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease.

Genetic prion diseases are caused by mutations in PRNP, which encodes the prion protein (PrPC). Why these mutations are pathogenic, and how they alter the properties of PrPC are poorly understood. We have consented and accessed 22 individuals of a multi-generational Israeli family harboring the highly penetrant E200K PRNP mutation and generated a library of induced pluripotent stem cells (iPSCs) representing nine carriers and four non-carriers. iPSC-derived neurons from E200K carriers display abnormal synaptic architecture characterized by misalignment of postsynaptic NMDA receptors with the cytoplasmic scaffolding protein PSD95. Differentiated neurons from mutation carriers do not produce PrPSc, the aggregated and infectious conformer of PrP, suggesting that loss of a physiological function of PrPC may contribute to the disease phenotype. Our study shows that iPSC-derived neurons can provide important mechanistic insights into the pathogenesis of genetic prion diseases and can offer a powerful platform for testing candidate therapeutics.

Multicenter, multivendor validation of liver quantitative susceptibility mapping in patients with iron overload at 1.5 T and 3 T.

PURPOSE: To evaluate the repeatability and reproducibility of QSM of the liver via single breath-hold chemical shift-encoded MRI at both 1.5 T and 3 T in a multicenter, multivendor study in subjects with iron overload. METHODS: This prospective study included four academic medical centers with three different MRI vendors at 1.5 T and 3 T. Subjects with known or suspected liver iron overload underwent multi-echo spoiled gradient-recalled-echo scans at each field strength. A subset received repeatability testing at either 1.5 T or 3 T. Susceptibility and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ maps were reconstructed from the multi-echo images and analyzed at a single center. QSM-measured susceptibility was compared with R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and a commercial R2-based liver iron concentration method across centers and field strengths using linear regression and F-tests on the intercept and slope. Field-strength reproducibility and test/retest repeatability were evaluated using Bland-Altman analysis. RESULTS: A total of 155/80 data sets (test/retest) were available at 1.5 T, and 159/70 data sets (test/retest) were available at 3 T. Calibrations across sites were reproducible, with some variability (e.g., susceptibility slope with liver iron concentration ranged from 0.102 to 0.123 g/[mg · $$ \cdotp $$ ppm] across centers at 1.5 T). Field strength reproducibility was good (concordance correlation coefficient = 0.862), and test/retest repeatability was excellent (intraclass correlation coefficient = 0.951). CONCLUSION: QSM as an imaging biomarker of liver iron overload is feasible and repeatable across centers and MR vendors. It may be complementary with R 2 * $$ {\mathrm{R}}_2^{\ast } $$ as they are obtained from the same acquisition. Although good reproducibility was observed, liver QSM may benefit from standardization of acquisition parameters. Overall, QSM is a promising method for liver iron quantification.

Current state of nanomedicine drug products: An industry perspective.

Nanomedicine drug products have reached an unprecedented high in terms of global commercial acceptance and media exposure with the approvals of the mRNA COVID-19 vaccines in 2021. In this paper, we examine the current state of the art for nanomedicine technologies as applied for pharmaceutical products and compare those trends with results from a recent IQ Consortium industry survey on nanomedicine drug products. We find that 1) industry companies continue to push the envelope in terms of new technologies for characterizing their specific drug products, 2) new analytical technologies continue to be utilized by industry to characterize the increasingly complex nanomedicine drug products and 3) alignment and communication are key between industry and regulatory authorities to better understand the regulatory filings that are being submitted. There are many CMC challenges that a company must overcome to successfully file a nanomedicine drug product. In 2022, the FDA Guidance on Drug Products containing Nanomaterials was published, and it provides a roadmap for submission of a nanomedicine drug product. We propose that our paper serves as a complimentary guide providing knowledge on specific CMC issues such as quality attributes, physicochemical characterization methods, excipients, and stability.

Investigation of ComBat Harmonization on Radiomic and Deep Features from Multi-Center Abdominal MRI Data.

ComBat harmonization has been developed to remove non-biological variations for data in multi-center research applying artificial intelligence (AI). We investigated the effectiveness of ComBat harmonization on radiomic and deep features extracted from large, multi-center abdominal MRI data. A retrospective study was conducted on T2-weighted (T2W) abdominal MRI data retrieved from individual patients with suspected or known chronic liver disease at three study sites. MRI data were acquired using systems from three manufacturers and two field strengths. Radiomic features and deep features were extracted using the PyRadiomics pipeline and a Swin Transformer. ComBat was used to harmonize radiomic and deep features across different manufacturers and field strengths. Student's t-test, ANOVA test, and Cohen's F score were applied to assess the difference in individual features before and after ComBat harmonization. Between two field strengths, 76.7%, 52.9%, and 26.7% of radiomic features, and 89.0%, 56.5%, and 0.1% of deep features from three manufacturers were significantly different. Among the three manufacturers, 90.1% and 75.0% of radiomic features and 89.3% and 84.1% of deep features from two field strengths were significantly different. After ComBat harmonization, there were no significant differences in radiomic and deep features among manufacturers or field strengths based on t-tests or ANOVA tests. Reduced Cohen's F scores were consistently observed after ComBat harmonization. ComBat harmonization effectively harmonizes radiomic and deep features by removing the non-biological variations due to system manufacturers and/or field strengths in large multi-center clinical abdominal MRI datasets.

Bringing Back the Core Concepts of Physiology in an Advanced Medical School Senior Elective.

Integrating physiology core concepts into the clinical years of medical education has been challenging despite efforts. This paper describes a fourth-year medical school elective, Advanced Physiology in Critical Care Medicine, that focused on integrating physiology core concepts in a case-based learning approach. The elective used interdisciplinary faculty in a virtual forum. Senior students were asked to generate mechanism of disease (MOD) maps, highlight the physiology core concepts associated with paper cases of critically ill patients, and discuss with faculty the relevance of the underlying basic science. The weekly footprint consisted of a student led session presenting MOD maps for three cases which examined aspects of core physiology concepts, and later in the same week, student presentation of order sets for the management of the cases. Students ended the 4-week elective with a mini-grand rounds presentation on a topic of their choice incorporating the core concept paradigm. Student perception data and faculty reflections of the elective course are included. Student data and faculty observations suggest they appreciate and can apply physiological core concepts to patient care. Faculty experience in the course suggests that this senior elective helped them better approach all pre-clinical teaching with the Core Concepts framework in mind.

Long-term effect of increasing water intake on repeated self-assessed health-related quality of life (HRQoL) in autosomal dominant polycystic kidney disease.

Background: The aim of this study was to determine the long-term effect of increasing water intake in patients with autosomal dominant polycystic kidney disease (ADPKD) on longitudinal changes in health-related quality of life (HRQoL) in the setting of a clinical trial. Methods: Self-completed HRQoL (using the KDQoL-SF, v.1.3 questionnaire) was assessed annually in participants of a 3-year randomized controlled clinical trial (n = 187), allocated (1:1) either to increase water intake to reduce urine osmolality to ≤270 mosmol/kg (implemented by dietetic coaching, self-monitoring tools, text messaging) or continue usual water intake. Results: Overall, 96% and 81.8% of participants (n = 187) completed the questionnaire at the baseline and final study visits, respectively. At baseline, the physical component summary score (PCS) and mental component summary score (MCS) were similar in the two groups (P > 0.05) and the five dimensions with the lowest scores in both groups were: energy and fatigue; general and overall health; sleep; emotional well-being; and pain. Within each group, there were no longitudinal changes over time. At the final visit, the PCS was higher in the increased water intake group (51.3 ± 7.6, mean ± standard deviation) compared to the usual water intake group 48.8 ± 9.3; P = 0.037) whereas the MCS was numerically similar. The improvement in the PCS was due to higher sub-scale values for physical functioning and pain (both P < 0.05). By multivariate analysis, only baseline PCS and height-corrected total kidney volume were associated with the final PCS (P < 0.05). Conclusion: HRQoL scores remained stable over a 3 year period, and were not adversely affected by the intervention to increase water intake. Future studies should evaluate the clinical significance of the higher PCS in the increased water intake group.

Mandatum.

In this poem, a patient refuses curative treatment. It explores ideas of consent, understanding, and the spirit.

Surface hydrophilicity promotes bacterial twitching motility.

Twitching motility is a form of bacterial surface translocation powered by the type IV pilus (T4P). It is frequently analyzed by interstitial colony expansion between agar and the polystyrene surfaces of petri dishes. In such assays, the twitching motility of Acinetobacter nosocomialis was observed with MacConkey but not Luria-Bertani (LB) agar media. One difference between these two media is the presence of bile salts as a selective agent in MacConkey but not in LB. Here, we demonstrate that the addition of bile salts to LB allowed A. nosocomialis to display twitching. Similarly, bile salts enhanced the twitching of Acinetobacter baumannii and Pseudomonas aeruginosa in LB. These observations suggest that there is a common mechanism, whereby bile salts enhance bacterial twitching and promote interstitial colony expansion. Bile salts disrupt lipid membranes and apply envelope stress as detergents. Surprisingly, their stimulatory effect on twitching appears not to be related to a bacterial physiological response to stressors. Rather, it is due to their ability to alter the physicochemical properties of a twitching surface. We observed that while other detergents promoted twitching like bile salts, stresses applied by antibiotics, including the outer membrane-targeting polymyxin B, did not enhance twitching motility. More importantly, bacteria displayed increased twitching on hydrophilic surfaces such as those of glass and tissue culture-treated polystyrene plastics, and bile salts no longer stimulated twitching on these surfaces. Together, our results show that altering the hydrophilicity of a twitching surface significantly impacts T4P functionality. IMPORTANCE: The bacterial type IV pilus (T4P) is a critical virulence factor for many medically important pathogens, some of which are prioritized by the World Health Organization for their high levels of antibiotic resistance. The T4P is known to propel bacterial twitching motility, the analysis of which provides a convenient assay for T4P functionality. Here, we show that bile salts and other detergents augment the twitching of multiple bacterial pathogens. We identified the underlying mechanism as the alteration of surface hydrophilicity by detergents. Consequently, hydrophilic surfaces like those of glass or plasma-treated polystyrene promote bacterial twitching, bypassing the requirement for detergents. The implication is that surface properties, such as those of tissues and medical implants, significantly impact the functionality of bacterial T4P as a virulence determinant. This offers valuable insights for developing countermeasures against the colonization and infection by bacterial pathogens of critical importance to human health on a global scale.

Stem Cell-Based Acellular Therapy: Insight into Biogenesis, Bioengineering and Therapeutic Applications of Exosomes.

The vast regenerative potential of stem cells has laid the foundation for stem cell-based therapies. However, certain challenges limit the application of cell-based therapies. The therapeutic use of cell-free therapy can avoid limitations associated with cell-based therapies. Acellular stem cell-based therapies rely on the use of biological factors released by stem cells, including growth factors and extracellular vesicles such as exosomes. Due to their comparable regenerative potential, acellular therapies may provide a feasible and scalable alternative to stem cell-based therapies. Exosomes are small vesicles secreted by various types of cells, including stem cells. Exosomes contain parent cell-derived nucleic acids, proteins, lipids, and other bioactive molecules. They play an important role in intra-cellular communication and influence the biological characteristics of cells. Exosomes inherit the properties of their parent cells; therefore, stem cell-derived exosomes are of particular interest for applications of regenerative medicine. In comparison to stem cell-based therapy, exosome therapy offers several benefits, such as easy transport and storage, no risk of immunological rejection, and few ethical dilemmas. Unlike stem cells, exosomes can be lyophilized and stored off-the-shelf, making acellular therapies standardized and more accessible while reducing overall treatment costs. Exosome-based acellular treatments are therefore readily available for applications in patients at the time of care. The current review discusses the use of exosomes as an acellular therapy. The review explores the molecular mechanism of exosome biogenesis, various methods for exosome isolation, and characterization. In addition, the latest advancements in bioengineering techniques to enhance exosome potential for acellular therapies have been discussed. The challenges in the use of exosomes as well as their diverse applications for the diagnosis and treatment of diseases have been reviewed in detail.

Directed assembly of small binary clusters of magnetizable ellipsoids.

We report the effect of shape anisotropy and material properties on the directed assembly of binary suspensions composed of magnetizable ellipsoids. In a Monte Carlo simulation, we implement the ellipsoid-dipole model to calculate the pairwise dipolar interaction energy as a function of position and orientation. The analysis explores dilute suspensions of paramagnetic and diamagnetic ellipsoids with different aspect ratios in a superparamagnetic medium. We analyze the local order of binary structures as a function of particle aspect ratio, medium permeability, and dipolar interaction strength. Our results show that local order and symmetry are tunable under the influence of a uniform magnetic field when one component of the structure is dilute with respect to the other. The simulation results match previously reported experiments on the directed assembly of binary suspension of spheres. Additionally, we report the conditions on particle aspect ratios and medium properties for various structures with rotational symmetries, as well as open and enclosed structures under the influence of a uniform magnetic field.

A small intestinal bile acid modulates the gut microbiome to improve host metabolic phenotypes following bariatric surgery.

Bariatric surgical procedures such as sleeve gastrectomy (SG) provide effective type 2 diabetes (T2D) remission in human patients. Previous work demonstrated that gastrointestinal levels of the bacterial metabolite lithocholic acid (LCA) are decreased after SG in mice and humans. Here, we show that LCA worsens glucose tolerance and impairs whole-body metabolism. We also show that taurodeoxycholic acid (TDCA), which is the only bile acid whose concentration increases in the murine small intestine post-SG, suppresses the bacterial bile acid-inducible (bai) operon and production of LCA both in vitro and in vivo. Treatment of diet-induced obese mice with TDCA reduces LCA levels and leads to microbiome-dependent improvements in glucose handling. Moreover, TDCA abundance is decreased in small intestinal tissue from T2D patients. This work reveals that TDCA is an endogenous inhibitor of LCA production and suggests that TDCA may contribute to the glucoregulatory effects of bariatric surgery.

Butyrate and tributyrin reduce LPS-induced inflammatory cytokine production from human visceral fat.

INTRODUCTION: The current obesity crisis has resulted in many people with excess adipose tissue suffering from chronic inflammation. This inflammation is largely due to the release of cytokines and chemokines from visceral fat. The aim of this study was to identify potential anti-inflammatory agents that might alleviate obesity-induced chronic inflammation. METHODS: To identify agents that might alleviate this obesity-induced chronic inflammation we have developed a simple protocol for incubating intact pieces of human visceral adipose tissue in 35 mm tissue culture plates, in the presence of low-dose lipopolysaccharide (LPS) and co-incubating these samples with potential anti-inflammatory agents. RNA-Seq analysis was performed to identify enriched gene expression signatures among the most significantly differentially expressed genes. RESULTS: From this screen, we have identified the short-chain fatty acid (SCFA) sodium butyrate and its triacylglyceride form, tributyrin, as effective agents, significantly reducing the production of LPS-induced inflammatory cytokines and chemokines from all adipose tissue samples tested. As well, these agents appear to be non-toxic at the concentrations tested. RNA-Seq analysis has revealed that IL36γ is one of the most upregulated genes in response to LPS and one of the most downregulated when sodium butyrate is added to human fat samples stimulated with LPS. IL-36γ ELISAs confirmed this holds true at the protein level as well. CONCLUSIONS: These studies suggest that the short-chain fatty acid, sodium butyrate, and its triacylglyceride form, tributyrin, might alleviate the chronic inflammation that is associated with many individuals with obesity.

Impact of medicine shortages on hospital practice: role of a multidisciplinary medicine shortages team.

Medicine shortages are an increasing issue, with broad public health implications for patients, health professionals and institutions. Despite national notification mechanisms involving sponsors and national regulators (e.g. Australian Therapeutic Goods Administration), shortages continue to be a significant workload in hospitals, particularly for pharmacy staff. In this article, we describe the implications of medicine shortages and a team approach to their management in an Australian public hospital. The medicine shortages team comprises senior pharmacists, a pharmacy technician, and a purchasing officer, in consultation with medical staff. A 10 week audit recorded 34 medicine shortages and/or discontinuations, comprising 49 usually stocked products. Shortages were more quickly identified by the purchasing officer using established relationships with suppliers, rather than relying on sponsor or government communication. Having a team systematically dealing with these shortages enables expertise in supply chains, finances, therapeutics, and medicine safety to be shared, to identify optimal interventions to mitigate patient risk.

Evaluating the impact of virtual reality game training on upper limb motor performance in children and adolescents with developmental coordination disorder: a scoping review using the ICF framework.

OBJECTIVE: This scoping review aims to explore published literature testing Virtual Reality (VR) interventions for improving upper limb motor performance in children and adolescents with Developmental Coordination Disorder (DCD). Our primary focus was on the types of VR systems used and the measurement tools employed within the International Classification of Functioning, Disability and Health Children and Youth Version (ICF-CY) domains in these studies. METHODS: A comprehensive search of six electronic databases up to 11th January 2024 was conducted using predefined terms. Inclusion and exclusion criteria were applied to determine study eligibility, with two authors independently assessing titles, abstracts, and full-text articles. RESULTS: Out of 788 potential studies, 14 met the eligibility criteria. Studies predominantly utilized non-immersive VR (nVR) systems, for example, commercial platforms such as Nintendo Wii. Most interventions targeted general motor coordination or balance, with only four studies specifically focusing on upper limb motor performance. The Movement Assessment Battery for Children-2 was the predominant assessment tool. However, the use of game scores and trial durations raised concerns about the accuracy of assessments. The majority of studies reported no significant improvement in upper limb motor performance following VR interventions, though some noted improvements in specific tasks or overall outcomes. CONCLUSION: The findings suggest that, while nVR interventions are being explored for paediatric motor rehabilitation, their impact on enhancing upper limb motor performance in children with DCD is unclear. The variability in intervention designs, outcome measures, and the predominant focus on general motor skills rather than specific upper limb improvements highlight the need for more targeted research in this area. IMPACT: This review underscores the importance of developing precise and clinically relevant measurement tools in a broader range of VR technologies to optimize the use of VR in therapy for children with DCD. Future research should aim for more rigorous study designs and emerging immersive technologies to maximize therapeutic benefits.

Beyond Rubik: The Embodiment-Presence-Interactivity Cube applied to exercise.

Evidence-based interventions are needed to promote engagement in physical activity. Audio-visual stimuli are frequently employed to enhance the exercise experience. Nonetheless, there is a paucity of research that examines the qualities of technological devices that are employed. Using the Embodiment-Presence-Interactivity Cube (Flavián et al., 2019) as a guiding conceptual framework, the aim of this registered report was to examine how each dimension of the cube (i.e., embodiment, presence and interactivity) influenced a range of exercise-related affective and perceptual variables. A counterbalanced within-subjects design was employed (N = 24). Participants completed 20-min exercise bouts on a cycle ergometer under four conditions: Television, augmented reality, 360° video and virtual reality. A repeated-measures ANOVA indicated a significant Condition × Timepoint interaction for affective valence (p = 0.046), with greater embodiment offered by technological devices leading to more positive responses. Analyses also indicated main effects of condition for exercise enjoyment, remembered pleasure and forecasted pleasure, with greater presence of technological devices leading to more positive responses. Technologies that combine high levels of embodiment, presence and interactivity (e.g., virtual reality) appear to yield several benefits in terms of in-task (e.g., affective valence) and post-task (e.g., remembered pleasure) responses for exercise conducted at ventilatory threshold.

Can perpetrators discern survivors from voice?

Background: Research has shown that potential perpetrators and individuals high in psychopathic traits tend to body language cues to target a potential new victim. However, whether targeting occurs also by tending to vocal cues has not been examined. Thus, the role of voice in interpersonal violence merits investigation.Objective: In two studies, we examined whether perpetrators could differentiate female speakers with and without sexual and physical assault histories (presented as rating the degree of 'vulnerability' to victimization).Methods: Two samples of male listeners (sample one N = 105, sample two, N = 109) participated. Each sample rated 18 voices (9 survivors and 9 controls). Listener sample one heard spontaneous speech, and listener sample two heard the second sentence of a standardized passage. Listeners' self-reported psychopathic traits and history of previous perpetration were measured.Results: Across both samples, history of perpetration (but not psychopathy) predicted accuracy in distinguishing survivors of assault.Conclusions: These findings highlight the potential role of voice in prevention and intervention. Gaining a further understanding of what voice cues are associated with accuracy in discerning survivors can also help us understand whether or not specialized voice training could have a role in self-defense practices.

We examined whether listeners with history of perpetration could differentiate female speakers with and without assault histories (presented as rating the degree of 'vulnerability' to victimization).Listeners' higher history of perpetration was associated with higher accuracy in differentiating survivors of assault from non-survivors.These findings highlight that voice could have a crucial role in prevention and intervention.