Brain 3T magnetic resonance imaging in neonates: features and incidental findings from a research cohort enriched for preterm birth.

BACKGROUND AND OBJECTIVES: The survival rate and patterns of brain injury after very preterm birth are evolving with changes in clinical practices. Additionally, incidental findings can present legal, ethical and practical considerations. Here, we report MRI features and incidental findings from a large, contemporary research cohort of very preterm infants and term controls. METHODS: 288 infants had 3T MRI at term-equivalent age: 187 infants born <32 weeks without major parenchymal lesions, and 101 term-born controls. T1-weighted, T2-weighted and susceptibility-weighted imaging were used to classify white and grey matter injury according to a structured system, and incidental findings described. RESULTS: Preterm infants: 34 (18%) had white matter injury and 4 (2%) had grey matter injury. 51 (27%) infants had evidence of intracranial haemorrhage and 34 (18%) had punctate white matter lesions (PWMLs). Incidental findings were detected in 12 (6%) preterm infants. Term infants: no term infants had white or grey matter injury. Incidental findings were detected in 35 (35%); these included intracranial haemorrhage in 22 (22%), periventricular pseudocysts in 5 (5%) and PWMLs in 4 (4%) infants. From the whole cohort, 10 (3%) infants required referral to specialist services. CONCLUSIONS: One-fifth of very preterm infants without major parenchymal lesions have white or grey matter abnormalities at term-equivalent age. Incidental findings are seen in 6% of preterm and 35% of term infants. Overall, 3% of infants undergoing MRI for research require follow-up due to incidental findings. These data should help inform consent procedures for research and assist service planning for centres using 3T neonatal brain MRI for clinical purposes.

A prospective evaluation of the prostate microbiome in malignant and benign tissue using transperineal biopsy.

BACKGROUND: The link between the prostate microbiome and prostate cancer remains unclear. Few studies have analyzed the microbiota of prostate tissue, and these have been limited by potential contamination by transrectal biopsy. Transperineal prostate biopsy offers an alternative and avoids fecal cross-contamination. We aim to characterize the prostate microbiome using transperineal biopsy. METHODS: Patients with clinical suspicion for prostate cancer who were to undergo transperineal prostate biopsy with magnetic resonance imaging (MRI) fusion guidance were prospectively enrolled from 2022 to 2023. Patients were excluded if they had Prostate Imaging Reporting and Data System lesions with scores ≤ 3, a history of prostate biopsy within 1 year, a history of prostate cancer, or antibiotic use within 30 days of biopsy. Tissue was collected from the MRI target lesions and nonneoplastic transitional zone. Bacteria were identified using 16S ribosomal RNA gene sequencing. RESULTS: Across the 42 patients, 76% were found to have prostate cancer. Beta diversity indices differed significantly between the perineum, voided urine, and prostate tissue. There were no beta diversity differences between cancerous or benign tissue, or between pre- and postbiopsy urines. There appear to be unique genera more abundant in cancerous versus benign tissue. There were no differences in alpha diversity indices relative to clinical findings including cancer status, grade, and risk group. CONCLUSIONS: We demonstrate a rigorous method to better characterize the prostate microbiome using transperineal biopsy and to limit contamination. These findings provide a framework for future large-scale studies of the microbiome of prostate cancer.

Deuterium MRI of serine metabolism in mouse models of glioblastoma.

PURPOSE: Serine is a major source of one-carbon units needed for the synthesis of nucleotides and the production of intramitochondrial nicotinamide adenine dinucleotide phosphate (NADPH), and it plays an important role in cancer cell proliferation. The aim of this study was to develop a deuterium (2H) MRS imaging method for imaging tumor serine metabolism. METHODS: Sequential (2H) spectra and spectroscopic images were used to monitor the metabolism of [2,3,3-2H3]serine in patient-derived glioblastoma cells in vitro and in tumors obtained by their orthotopic implantation in mouse brain. RESULTS: [14,14-2H2] 5,10-methylene-tetrahydrofolate, [2H]glycine, [2H]formate, and labeled water were detected in cell suspensions and water labeling in spectroscopic images of tumors. Studies in cells and tumors with variable mitochondrial content and inhibitor studies in cells demonstrated that most of the labeled serine was metabolized in the mitochondria. Water labeling in the cell suspensions was correlated with formate labeling; therefore, water labeling observed in tumors could be used to provide a surrogate measure of flux in the pathway of one-carbon metabolism in vivo. CONCLUSION: The method has the potential to be used clinically to select patients for treatment with inhibitors of one-carbon metabolism and subsequently to detect their early responses to such treatment.

Draft genome assemblies of three Klebsiella grimontii strains isolated from catheterized urine samples from the same male participant over the course of 6 months.

Klebsiella grimontii is a newly identified species within the Klebsiella oxytoca complex. Here, we present the draft genome sequence of three K. grimontii strains that were isolated from catheterized urine samples collected from a participant in a longitudinal study over ~6 months.

VAMP2 regulates phase separation of α-synuclein.

α-Synuclein (αSYN), a pivotal synaptic protein implicated in synucleinopathies such as Parkinson's disease and Lewy body dementia, undergoes protein phase separation. We reveal that vesicle-associated membrane protein 2 (VAMP2) orchestrates αSYN phase separation both in vitro and in cells. Electrostatic interactions, specifically mediated by VAMP2 via its juxtamembrane domain and the αSYN C-terminal region, drive phase separation. Condensate formation is specific for R-SNARE VAMP2 and dependent on αSYN lipid membrane binding. Our results delineate a regulatory mechanism for αSYN phase separation in cells. Furthermore, we show that αSYN condensates sequester vesicles and attract complexin-1 and -2, thus supporting a role in synaptic physiology and pathophysiology.

Evidence of Lactobacillus strains shared between the female urinary and vaginal microbiota.

Lactobacillus species are common inhabitants of the 'healthy' female urinary and vaginal communities, often associated with a lack of symptoms in both anatomical sites. Given identification by prior studies of similar bacterial species in both communities, it has been hypothesized that the two microbiotas are in fact connected. Here, we carried out whole-genome sequencing of 49 Lactobacillus strains, including 16 paired urogenital samples from the same participant. These strains represent five different Lactobacillus species: L. crispatus, L. gasseri, L. iners, L. jensenii, and L. paragasseri. Average nucleotide identity (ANI), alignment, single-nucleotide polymorphism (SNP), and CRISPR comparisons between strains from the same participant were performed. We conducted simulations of genome assemblies and ANI comparisons and present a statistical method to distinguish between unrelated, related, and identical strains. We found that 50 % of the paired samples have identical strains, evidence that the urinary and vaginal communities are connected. Additionally, we found evidence of strains sharing a common ancestor. These results establish that microbial sharing between the urinary tract and vagina is not limited to uropathogens. Knowledge that these two anatomical sites can share lactobacilli in females can inform future clinical approaches.

Obesity-associated microbiomes instigate visceral adipose tissue inflammation by recruitment of distinct neutrophils.

Neutrophils are increasingly implicated in chronic inflammation and metabolic disorders. Here, we show that visceral adipose tissue (VAT) from individuals with obesity contains more neutrophils than in those without obesity and is associated with a distinct bacterial community. Exploring the mechanism, we gavaged microbiome-depleted mice with stool from patients with and without obesity during high-fat or normal diet administration. Only mice receiving high-fat diet and stool from subjects with obesity show enrichment of VAT neutrophils, suggesting donor microbiome and recipient diet determine VAT neutrophilia. A rise in pro-inflammatory CD4+ Th1 cells and a drop in immunoregulatory T cells in VAT only follows if there is a transient spike in neutrophils. Human VAT neutrophils exhibit a distinct gene expression pattern that is found in different human tissues, including tumors. VAT neutrophils and bacteria may be a novel therapeutic target for treating inflammatory-driven complications of obesity, including insulin resistance and colon cancer.

Exploring Factors Affecting Acceptance of Fecal Microbiota Transplantation for Patients with Recurrent Urinary Tract Infections: a Descriptive Qualitative Study.

Purpose: Patients with recurrent urinary tract infections face complex management challenges. Fecal microbiota transplantation is a superior treatment for chronic infectious diseases, but limited patient knowledge affects treatment decisions. This study aims to identify factors associated with hesitancy towards fecal microbiota transplantation among patients with recurrent urinary tract infections, to help physicians and nurses in providing accurate and useful information to patients. Patients and Methods: A descriptive qualitative approach was employed, utilizing semi-structured interviews conducted with patients experiencing recurrent urinary tract infections who expressed hesitancy towards fecal microbiota transplantation. The interviews took place between September 2021 and December 2022. Thematic analysis was conducted on the semi-structured interviews to identify perceived facilitators and barriers associated with fecal microbiota transplantation. Results: The analysis included interviews with thirty adult female patients with recurrent urinary tract infections. Four facilitators influencing patients' decision-making regarding fecal microbiota transplantation were identified: (1) the motivating role of hope and expectations for active patient participation; (2) the influence of healthcare providers, as well as family members and friends on patients' decisions to pursue fecal microbiota transplantation; (3) the patients' perception of fecal microbiota transplantation as a low-risk treatment option; and (4) the dedication to the advancement of medical treatments. In contrast, two primary barriers to accepting fecal microbiota transplantation were identified: (1) that conventional treatment controls disease activity, while fecal microbiota transplantation effects remain uncertain; and (2) that safety concerns surrounding fecal microbiota transplantation. Conclusion: Comprehensive information about fecal microbiota transplantation, including donor selection, sample processing, the procedure, and potential discomfort, is essential for patients and families to make informed treatment decisions. Registration: CHiCTR2100048970.

Carbonate uranium isotopes record global expansion of marine anoxia during the Toarcian Oceanic Anoxic Event.

The Toarcian Oceanic Anoxic Event (T-OAE; ~183 Mya) was a globally significant carbon-cycle perturbation linked to widespread deposition of organic-rich sediments, massive volcanic CO2 release, marine faunal extinction, sea-level rise, a crisis in carbonate production related to ocean acidification, and elevated seawater temperatures. Despite recognition of the T-OAE as a potential analog for future ocean deoxygenation, current knowledge on the severity of global ocean anoxia is limited largely to studies of the trace element and isotopic composition of black shales, which are commonly affected by local processes. Here, we present the first carbonate-based uranium isotope (δ238U) record of the T-OAE from open marine platform limestones of the southeastern Tethys Ocean as a proxy for global seawater redox conditions. A significant negative δ238U excursion (~0.4‰) is recorded just prior to the onset of the negative carbon isotope excursion comprised within the T-OAE, followed by a long-lived recovery of δ238U values, thus confirming that the T-OAE represents a global expansion of marine anoxia. Using a Bayesian inverse isotopic mass balance model, we estimate that anoxic waters covered ~6 to 8% of the global seafloor during the peak of the T-OAE, which represents 28 to 38 times the extent of anoxia in the modern ocean. These data, combined with δ238U-based estimates of seafloor anoxic area for other CO2-driven Phanerozoic OAEs, suggest a common response of ocean anoxia to carbon release, thus improving prediction of future anthropogenically induced ocean deoxygenation.

Development of a survey to support assessment of safety learning systems.

BACKGROUND: Patient safety learning systems play a critical role in supporting safety culture in healthcare organisations. A lack of explicit standards leads to inconsistent implementation across organisations, causing uncertainty about their roles and impact. Organisations can address inconsistent implementation by using a self-assessment tool based on agreed-on best practices. Therefore, we aimed to create a survey instrument to assess an organisation's approach to learning from safety events. METHODS: The foundation for this work was a recent systematic review that defined features associated with the performance of a safety learning system. We organised features into themes and rephrased them into questions (items). Face validity was checked, which included independent pre-testing to ensure comprehensibility and parsimony. It also included clinical sensibility testing in which a representative sample of leaders in quality at a large teaching hospital (The Ottawa Hospital) answered two questions to judge each item for clarity and necessity. If more than 20% of respondents judged a question unclear or unnecessary, we modified or removed that question accordingly. Finally, we checked the internal consistency of the questionnaire using Cronbach's alpha. RESULTS: We initially developed a 47-item questionnaire based on a prior systematic review. Pre-testing resulted in the modification of 15 of the questions, 2 were removed and 2 questions were added to ensure comprehensiveness and relevance. Face validity was assessed through yes/no responses, with over 80% of respondents confirming the clarity and 85% the necessity of each question, leading to the retention of all 47 questions. Data collected from the five-point responses (strongly disagree to strongly agree) for each question were used to assess the questionnaire's internal consistency. The Cronbach's alpha was 0.94, indicating a high internal consistency. CONCLUSION: This self-assessment questionnaire is evidence-based and on preliminary testing is deemed valid, comprehensible and reliable. Future work should assess the range of survey responses in a large sample of respondents from different hospitals.

A genetically inducible endothelial niche enables vascularization of human kidney organoids with multilineage maturation and emergence of renin expressing cells.

Vascularization plays a critical role in organ maturation and cell-type development. Drug discovery, organ mimicry, and ultimately transplantation hinge on achieving robust vascularization of in vitro engineered organs. Here, focusing on human kidney organoids, we overcame this hurdle by combining a human induced pluripotent stem cell (iPSC) line containing an inducible ETS translocation variant 2 (ETV2) (a transcription factor playing a role in endothelial cell development) that directs endothelial differentiation in vitro, with a non-transgenic iPSC line in suspension organoid culture. The resulting human kidney organoids show extensive endothelialization with a cellular identity most closely related to human kidney endothelia. Endothelialized kidney organoids also show increased maturation of nephron structures, an associated fenestrated endothelium with de novo formation of glomerular and venous subtypes, and the emergence of drug-responsive renin expressing cells. The creation of an engineered vascular niche capable of improving kidney organoid maturation and cell type complexity is a significant step forward in the path to clinical translation. Thus, incorporation of an engineered endothelial niche into a previously published kidney organoid protocol allowed the orthogonal differentiation of endothelial and parenchymal cell types, demonstrating the potential for applicability to other basic and translational organoid studies.

Associations between atypical intracortical myelin content and neuropsychological functions in middle to older aged adults with ASD.

INTRODUCTION: In vivo myeloarchitectonic mapping based on Magnetic Resonance Imaging (MRI) provides a unique view of gray matter myelin content and offers information complementary to other morphological indices commonly employed in studies of autism spectrum disorder (ASD). The current study sought to determine if intracortical myelin content (MC) and its age-related trajectories differ between middle aged to older adults with ASD and age-matched typical comparison participants. METHODS: Data from 30 individuals with ASD and 36 age-matched typical comparison participants aged 40-70 years were analyzed. Given substantial heterogeneity in both etiology and outcomes in ASD, we utilized both group-level and subject-level analysis approaches to test for signs of atypical intracortical MC as estimated by T1w/T2w ratio. RESULTS: Group-level analyses showed no significant differences in average T1w/T2w ratio or its associations with age between groups, but revealed significant positive main effects of age bilaterally, with T1w/T2w ratio increasing with age across much of the cortex. In subject-level analyses, participants were classified into subgroups based on presence or absence of clusters of aberrant T1w/T2w ratio, and lower neuropsychological function was observed in the ASD subgroup with atypically high T1w/T2w ratio in spatially heterogeneous cortical regions. These differences were observed across several neuropsychological domains, including overall intellectual functioning, processing speed, and aspects of executive function. CONCLUSIONS: The group-level and subject-level approaches employed here demonstrate the value of examining inter-individual variability and provide important preliminary insights into relationships between brain structure and cognition in the second half of the lifespan in ASD, suggesting shared factors contributing to atypical intracortical myelin content and poorer cognitive outcomes for a subset of middle aged to older autistic adults. These atypicalities likely reflect diverse histories of neurodevelopmental deficits, and possible compensatory changes, compounded by processes of aging, and may serve as useful markers of vulnerability to further cognitive decline in older adults with ASD.

Just a head knock? Emergency physicians need to get serious about concussion.

Attention and awareness regarding concussion injury in Australia have significantly increased in the last decade. Although most of this increase is because of discussion regarding concussions from sporting endeavours, the majority of concussions are from non-sport environments including motor vehicle crashes, workplace incidents, falls, accidents, assault and intimate partner violence. In all cases, hospital EDs are the first point of contact, yet as argued in our Opinion here, there are concerns regarding the consistency of care protocols, because of a number of reasons, as well as management and follow-up clinical practices. Our Opinion is to provide a constructive discussion as well as calling for ACEM to support research to provide evidence-based data. Finally, we provide some recommendations that could be implemented immediately to improve clinical practice for presentations of concussion injuries in EDs.

Outcomes of Patients With Mild Cognitive Impairment With Lewy Bodies or Alzheimer Disease at 3 and 5 Years After Diagnosis.

BACKGROUND AND OBJECTIVES: Retrospective studies indicate that dementia with Lewy bodies (DLB) may be preceded by a mild cognitive impairment (MCI) prodrome. Research criteria for the prospective identification of MCI with Lewy bodies (MCI-LB) have been developed. We aimed to assess the prognosis of a prospectively identified MCI-LB cohort at 2 key milestones, 3- and 5 years after diagnosis, to examine classification stability over time and rates of adverse outcomes (dementia or death). METHODS: This was a retrospective examination of data from 2 longitudinal observational cohort studies where participants with MCI were prospectively recruited from North East England and differentially classified as MCI due to Alzheimer disease (MCI-AD), possible MCI-LB, or probable MCI-LB. Adverse outcomes (DLB/other dementia or death) and stability of disease-specific classifications were examined in each group. RESULTS: Of 152 participants with baseline MCI (54 MCI-AD, 29 possible MCI-LB, and 69 probable MCI-LB), 126 were followed for up to 3 years (mean age 75.3 years; 40% female). We found that prospective probable MCI-LB classifications were both sensitive (91%) and specific (94%) to classifications either remaining as probable MCI-LB or progressing to DLB (in some cases autopsy confirmed) for 3 or more years after. Classifications were at least as stable as those in MCI-AD. In this cohort with disease-specific MCI classifications, rates of progression to dementia were high: 55% of MCI-LB had developed DLB within 3 years. Dementia occurred in 47% of MCI-AD over the same duration (odds ratio 1.68, 95% CI 0.66-4.26, p = 0.278). Premature death was a common competing risk, occurring in 9% of MCI-AD and 11% of MCI-LB within 3 years. DISCUSSION: These findings support that prospectively identified probable MCI-LB is a prodromal presentation of DLB and that disease-specific classifications of MCI may reliably identify different prodromal dementias.

A randomized multicenter trial of a chronic disease management intervention for decompensated cirrhosis. The Australian Liver Failure (ALFIE) trial.

BACKGROUND AND AIMS: Improving the care of decompensated cirrhosis is a significant clinical challenge. The primary aim of this trial was to assess the efficacy of a chronic disease management (CDM) model to reduce liver-related emergency admissions (LREA). The secondary aims were to assess model effects on quality-of-care and patient-reported outcomes. APPROACH AND RESULTS: The study design was a 2-year, multicenter, randomized controlled study with 1:1 allocation of a CDM model versus usual care. The study setting involved both tertiary and community care. Participants were randomly allocated following a decompensated cirrhosis admission. The intervention was a multifaceted CDM model coordinated by a liver nurse. A total of 147 participants (intervention=75, control=71) were recruited with a median Model for End-Stage Liver Disease score of 19. For the primary outcome, there was no difference in the overall LREA rate for the intervention group versus the control group (incident rate ratio 0.89; 95% CI: 0.53-1.50, p=0.666) or in actuarial survival (HR=1.14; 95% CI: 0.66-1.96, p=0.646). However, there was a reduced risk of LREA due to encephalopathy in the intervention versus control group (HR=1.87; 95% CI: 1.18-2.96, p=0.007). Significant improvement in quality-of-care measures was seen for the performance of bone density (p<0.001), vitamin D testing (p<0.001), and HCC surveillance adherence (p=0.050). For assessable participants (44/74 intervention, 32/71 controls) significant improvements in patient-reported outcomes at 3 months were seen in self-management ability and quality of life as assessed by visual analog scale (p=0.044). CONCLUSIONS: This CDM intervention did not reduce overall LREA events and may not be effective in decompensated cirrhosis for this end point.

Transferring Learned Behaviors between Similar and Different Radios.

Transfer learning (TL) techniques have proven useful in a wide variety of applications traditionally dominated by machine learning (ML), such as natural language processing, computer vision, and computer-aided design. Recent extrapolations of TL to the radio frequency (RF) domain are being used to increase the potential applicability of RFML algorithms, seeking to improve the portability of models for spectrum situational awareness and transmission source identification. Unlike most of the computer vision and natural language processing applications of TL, applications within the RF modality must contend with inherent hardware distortions and channel condition variations. This paper seeks to evaluate the feasibility and performance trade-offs when transferring learned behaviors from functional RFML classification algorithms, specifically those designed for automatic modulation classification (AMC) and specific emitter identification (SEI), between homogeneous radios of similar construction and quality and heterogeneous radios of different construction and quality. Results derived from both synthetic data and over-the-air experimental collection show promising performance benefits from the application of TL to the RFML algorithms of SEI and AMC.

Adverse effects of methylphenidate for apathy in patients with Alzheimer's disease (ADMET2 trial).

OBJECTIVES: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia. METHODS: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist. RESULTS: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6-month follow-up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow-up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post-baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period. CONCLUSIONS: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment.

Healthcare Resource Utilization in Medicare Beneficiaries Obtaining Medication Synchronization.

BACKGROUND: An appointment-based medication synchronization (ABMS) is a service which aligns patients' chronic medications to a predetermined routine pickup date and includes a comprehensive medication review or other clinical appointment at the pharmacy. We compared healthcare utilization outcomes (outpatient, inpatient, emergency department visits, and pharmacy utilization) of Medicare beneficiaries enrolled in a med-sync program to beneficiaries not enrolled in such a program. METHODS: This retrospective cohort study included Medicare beneficiaries obtaining medications from pharmacies providing ABMS. All Medicare inpatient, outpatient, emergency, and pharmacy claims data from 2014 to 2016 obtained from the Research Data Assistance Center (ResDAC). These pharmacy claims were used to create medication-synchronized (med-sync) (n=13,193) and non-med-sync (n=156,987) cohorts. All patients were followed longitudinally for 12 months before and after a 2015 index/enrollment date. Baseline characteristics were utilized to create a logistic regression model for propensity score matching. A 1:1 greedy nearest neighbor matching algorithm was adapted for sequentially matching both cohorts. Difference-in-differences (DID) was used to compare mean changes in healthcare utilization outcomes (outpatient, inpatient, emergency department visits, and pharmacy utilization) between cohorts. RESULTS: After matching, 13,193 beneficiaries in each cohort were used for analysis. DID for mean of healthcare utilizations were significantly lower in the med-sync cohort compared to the non-med-sync cohort for outpatient visits (DID:0.012, p=0.0073) and pharmacy utilization (DID:0.013, p<0.0001). There was no significant DID for inpatient and emergency department visits between cohorts. CONCLUSION: Outpatient and pharmacy utilization changes were significantly lower in the med-sync cohort compared to the non-med-sync cohort in the 12-months after enrollment. Lower pharmacy utilization could be due to reducing duplicate prescriptions during synchronized refills or optimization of therapy during medication reviews if patients are enrolled in ABM med-sync.