Vitamin B12 status and hyperhomocysteinemia in patients with Rheumatoid arthritis treated with methotrexate and folic acid.

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory arthritis in which the immune system targets synovial joints. Methotrexate serves as the mainstay of treatment for RA due to its efficacy. However, patients treated with methotrexate are uniquely at risk for vitamin B12 deficiency and hyperhomocysteinemia due to coincident disease risk factors and the fact that methotrexate use is associated with malabsorption. The objective of this study was to assess for vitamin B12 deficiency among patients with RA treated with methotrexate and folic acid. METHODS: This cross-sectional study included 50 patients with RA treated with methotrexate and folic acid and 49 patients with RA treated with other therapies. Patients were matched by age, sex, race, renal function, and disease activity. We compared plasma vitamin B12, methylmalonic acid, and homocysteine levels between these two groups utilizing quantitative and categorical analyses. RESULTS: Thirty-seven (74 %) RA patients on methotrexate and folic acid had elevated plasma homocysteine levels compared with only 27 (55 %) RA patients receiving other therapies (P < 0.05). The proportion of patients with low vitamin B12 and high methylmalonic acid levels did not differ between the two groups. CONCLUSIONS: Our data show high plasma homocysteine levels among RA patients treated with methotrexate and folic acid. While plasma vitamin B12 levels were similar between the two groups, high plasma homocysteine is also a sensitive marker of vitamin B12 deficiency. Additional studies should evaluate for the presence of clinical features of vitamin B12 deficiency and hyperhomocysteinemia among RA patients treated with methotrexate and folic acid.

Tailoring follow-up endoscopy in patients with severe oesophagitis.

Objective: We aimed to investigate the clinical utility of follow-up oesophagogastroduodenoscopy (OGD2) in patients with severe oesophagitis (Los Angeles grades C or D) through evaluating the yield of Barrett's oesophagus (BO), cancer, dysplasia and strictures. Second, we aimed to determine if the Clinical Frailty Scale (CFS) may be used to identify patients to undergo OGD2s. Design/method: Patients in NHS Lothian with an index OGD (OGD1) diagnosis of severe oesophagitis between 1 January 2014 and 31 December 2015 were identified. Univariate analysis identified factors associated with grade. Patients were stratified by frailty and a diagnosis of stricture, cancer, dysplasia and BO. Results: In total 964 patients were diagnosed with severe oesophagitis, 61.7% grade C and 38.3% grade D. The diagnostic yield of new pathology at OGD2 was 13.2% (n=51), new strictures (2.3%), dysplasia (0.5%), cancer (0.3%) and BO (10.1%). A total of 140 patients had clinical frailty (CFS score ≥5), 88.6% of which were deceased at review (median of 76 months). In total 16.4% of frail patients underwent OGD2s and five new pathologies were diagnosed, none of which were significantly associated with grade. Among non-frail patients at OGD2, BO was the only pathology more common (p=0.010) in patients with grade D. Rates of cancer, dysplasia and strictures did not vary significantly between grades. Conclusion: Our data demonstrate that OGD2s in patients with severe oesophagitis may be tailored according to clinical frailty and only be offered to non-frail patients. In non-frail patients OGD2s have similar pick-up rates of sinister pathology in both grades of severe oesophagitis.

Towards a scalable approach to assess speech organization across the psychosis-spectrum -online assessment in conjunction with automated transcription and extraction of speech measures.

Automatically extracted measures of speech constitute a promising marker of psychosis as disorganized speech is associated with psychotic symptoms and predictive of psychosis-onset. The potential of speech markers is, however, hampered by (i) lengthy assessments in laboratory settings and (ii) manual transcriptions. We investigated whether a short, scalable data collection (online) and processing (automated transcription) procedure would provide data of sufficient quality to extract previously validated speech measures. To evaluate the fit of our approach for purpose, we assessed speech in relation to psychotic-like experiences in the general population. Participants completed an 8-minute-long speech task online. Sample 1 included measures of psychometric schizotypy and delusional ideation (N = 446). Sample 2 included a low and high psychometric schizotypy group (N = 144). Recordings were transcribed both automatically and manually, and connectivity, semantic, and syntactic speech measures were extracted for both types of transcripts. 73%/86% participants in sample 1/2 completed the experiment. Nineteen out of 25 speech measures were strongly (r > 0.7) and significantly correlated between automated and manual transcripts in both samples. Amongst the 14 connectivity measures, 11 showed a significant relationship with delusional ideation. For the semantic and syntactic measures, On Topic score and the Frequency of personal pronouns were negatively correlated with both schizotypy and delusional ideation. Combined with demographic information, the speech markers could explain 11-14% of the variation of delusional ideation and schizotypy in Sample 1 and could discriminate between high-low schizotypy with high accuracy (0.72-0.70, AUC = 0.78-0.79) in Sample 2. The moderate to high retention rate, strong correlation of speech measures across manual and automated transcripts and sensitivity to psychotic-like experiences provides initial evidence that online collected speech in combination with automatic transcription is a feasible approach to increase accessibility and scalability of speech-based assessment of psychosis.

Association of Calcium and Vitamin D Supplements with Fractures in Persons with a Traumatic SCI.

Background: Osteoporotic fractures occur in almost half of patients with a spinal cord injury (SCI) and are associated with significant morbidity and excess mortality. Paralyzed Veterans Administration (PVA) guidelines suggest that adequate calcium and vitamin D intake is important for skeletal health, however, the association of these supplements with osteoporotic fracture risk is unclear. Objectives: To determine the association of filled prescriptions for calcium and vitamin D with fracture risk in Veterans with an SCI. Methods: The 5897 persons with a traumatic SCI of at least 2 years' duration (96% male; 4% female) included in the VSSC SCI/D Registry in FY2014 were followed from FY2014 to FY2020 for incident upper and lower extremity fractures. Filled daily prescriptions for calcium or vitamin D supplements for ≥6 months with an adherence ≥80% were examined. Results: Filled prescriptions for calcium (hazard ratio [HR] 0.65; 95% CI, 0.54-0.78) and vitamin D (HR 0.33; 95% CI, 0.29-0.38) supplements were associated with a significantly decreased risk for incident fractures. Conclusion: Calcium and vitamin D supplements are associated with decreased risk of fracture, supporting PVA guidelines that calcium and vitamin D intake are important for skeletal health in persons with an SCI.

Control of ZIF-62 and ag ZIF-62 Film Thickness within Asymmetric Tubular Supports through Pressure and Dose Time Variation of Atomic Layer Deposition.

Thin-films of metal-organic frameworks (MOFs) have widespread potential applications, especially with the emergence of glass-forming MOFs, which remove the inherent issue of grain boundaries and allow coherent amorphous films to be produced. Herein, it is established that atomic layer deposition (ALD) of zinc oxide lends excellent control over the thickness and localization of resultant polycrystalline and glass zeolitic imidazole framework-62 (ZIF-62) thin-films within tubular α-alumina supports. Through the reduction of the chamber pressure and dose times during zinc oxide deposition, the resultant ZIF-62 films are reduced from 38 µm to 16 µm, while the presence of sporadic ZIF-62 (previously forming as far as 280 µm into the support) is prevented. Furthermore, the glass transformation shows a secondary reduction in film thickness from 16 to 2 µm.

Curricular Reform in Serious Illness Communication and Palliative Care: Using Medical Students' Voices to Guide Change.

PURPOSE: To gather and leverage the voices of students to drive creation of required, integrated palliative care curricula within undergraduate medical education in Massachusetts, which is lacking in a majority of U.S. medical schools. METHOD: The study was conducted by the Massachusetts Medical Schools' Collaborative, a working group committed to ensuring all medical students in Massachusetts receive foundational training in serious illness communication (SIC) and palliative care. Eight focus groups (2 per participating medical school) were conducted during January-May 2021 and included a total of 50 students from Boston University Chobanian & Avedisian School of Medicine, Harvard Medical School, Tufts University School of Medicine, and the UMass Chan Medical School. Data collected from focus groups were discussed and coded. Themes were identified using the immersion/crystallization qualitative data analysis approach. RESULTS: Six key themes emerged. Students viewed SIC as essential to high-quality medical practice regardless of specialty, and believed training in SIC skills and palliative care should be required in medical school curricula. Students preferred to learn and practice these skills using frameworks, particularly in real-world situations. Students recognized the expertise of palliative care specialists and described them as a scarce, often misunderstood resource in health care. Students reported it was mostly "luck" if they were included in family meetings and observed good role models. Finally, students desired practice in debriefing after difficult and emotional situations. CONCLUSIONS: This study confirms long-standing themes on students' experiences with SIC and palliative care topics, including feeling inadequately prepared to care for seriously ill patients as future physicians. Our study collected students' perspectives as actionable data to develop recommendations for curricular change. Collaborative faculty also created recommendations based on the focus group data for immediate and ongoing SIC and palliative care curricular change in Massachusetts, which can apply to medical schools nationwide.

Combating ageism in medical education with narrative medicine.

Ageism is common in medical trainees and difficult to overcome. The My Life, My Story program has been shown to be an effective tool for increasing empathy. We explored its use as an instrument for combating ageism by implementing it in a Geriatrics clerkship for fourth year medical students. During our evaluation, 151 students interviewed patients about their lives using a semi-structured question guide. Students completed the UCLA Geriatrics Attitudes Scale and the Expectations Regarding Aging Survey pre-and post-clerkship. We also facilitated 9 student debriefs and 5 faculty interviews. After completing My Life, My Story, students were more likely to disagree with "I would rather see younger patients than elderly ones" and "it's normal to be depressed when you are old". In qualitative analysis of the debriefs, we identified a key summative theme: "impact of the intervention on care teams". Within that, we describe three subthemes: an awareness of richness of the lives led by older people, their current value to society, and the social determinants of health they have faced. After participating in My Life, My Story, students' attitudes toward aging changed. A narrative medicine program using life stories can be a practical tool for addressing ageist stereotypes.

Clinical Use of Trabecular Bone Score: The 2023 ISCD Official Positions.

Osteoporosis can currently be diagnosed by applying the WHO classification to bone mineral density (BMD) assessed by dual-energy x-ray absorptiometry (DXA). However, skeletal factors other than BMD contribute to bone strength and fracture risk. Lumbar spine TBS, a grey-level texture measure which is derived from DXA images has been extensively studied, enhances fracture prediction independent of BMD and can be used to adjust fracture probability from FRAX® to improve risk stratification. The purpose of this International Society for Clinical Densitometry task force was to review the existing evidence and develop recommendations to assist clinicians regarding when and how to perform, report and utilize TBS. Our review concluded that TBS is most likely to alter clinical management in patients aged ≥ 40 years who are close to the pharmacologic intervention threshold by FRAX. The TBS value from L1-L4 vertebral levels, without vertebral exclusions, should be used to calculate adjusted FRAX probabilities. L1-L4 vertebral levels can be used in the presence of degenerative changes and lumbar compression fractures. It is recommended not to report TBS if extreme structural or pathological artifacts are present. Monitoring and reporting TBS change is unlikely to be helpful with the current version of the TBS algorithm. The next version of TBS software will include an adjustment based upon directly measured tissue thickness. This is expected to improve performance and address some of the technical factors that affect the current algorithm which may require modifications to these Official Positions as experience is acquired with this new algorithm.

PanomiR: a systems biology framework for analysis of multi-pathway targeting by miRNAs.

Charting microRNA (miRNA) regulation across pathways is key to characterizing their function. Yet, no method currently exists that can quantify how miRNAs regulate multiple interconnected pathways or prioritize them for their ability to regulate coordinate transcriptional programs. Existing methods primarily infer one-to-one relationships between miRNAs and pathways using differentially expressed genes. We introduce PanomiR, an in silico framework for studying the interplay of miRNAs and disease functions. PanomiR integrates gene expression, mRNA-miRNA interactions and known biological pathways to reveal coordinated multi-pathway targeting by miRNAs. PanomiR utilizes pathway-activity profiling approaches, a pathway co-expression network and network clustering algorithms to prioritize miRNAs that target broad-scale transcriptional disease phenotypes. It directly resolves differential regulation of pathways, irrespective of their differential gene expression, and captures co-activity to establish functional pathway groupings and the miRNAs that may regulate them. PanomiR uses a systems biology approach to provide broad but precise insights into miRNA-regulated functional programs. It is available at https://bioconductor.org/packages/PanomiR.

Quality standards for the management of alcohol-related liver disease: consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology ARLD special interest group.

OBJECTIVE: Alcohol-related liver disease (ALD) is the most common cause of liver-related ill health and liver-related deaths in the UK, and deaths from ALD have doubled in the last decade. The management of ALD requires treatment of both liver disease and alcohol use; this necessitates effective and constructive multidisciplinary working. To support this, we have developed quality standard recommendations for the management of ALD, based on evidence and consensus expert opinion, with the aim of improving patient care. DESIGN: A multidisciplinary group of experts from the British Association for the Study of the Liver and British Society of Gastroenterology ALD Special Interest Group developed the quality standards, with input from the British Liver Trust and patient representatives. RESULTS: The standards cover three broad themes: the recognition and diagnosis of people with ALD in primary care and the liver outpatient clinic; the management of acutely decompensated ALD including acute alcohol-related hepatitis and the posthospital care of people with advanced liver disease due to ALD. Draft quality standards were initially developed by smaller working groups and then an anonymous modified Delphi voting process was conducted by the entire group to assess the level of agreement with each statement. Statements were included when agreement was 85% or greater. Twenty-four quality standards were produced from this process which support best practice. From the final list of statements, a smaller number of auditable key performance indicators were selected to allow services to benchmark their practice and an audit tool provided. CONCLUSION: It is hoped that services will review their practice against these recommendations and key performance indicators and institute service development where needed to improve the care of patients with ALD.

Grazing livestock move by Lévy walks: Implications for soil health and environment.

Grazing livestock plays an important role in the context of food security, agricultural sustainability and climate change. Understanding how livestock move and interact with their environment may offer new insights on how grazing practices impact soil and ecosystem functions at spatial and temporal scales where knowledge is currently limited. We characterized daily and seasonal grazing patterns using Global Positioning System (GPS) data from two grazing strategies: conventionally- and rotationally-grazed pastures. Livestock movement was consistent with the so-called Lévy walks, and could thus be simulated with Lévy-walk based probability density functions. Our newly introduced "Moovement model" links grazing patterns with soil structure and related functions by coupling animal movement and soil structure dynamics models, allowing to predict spatially-explicit changes in key soil properties. Predicted post-grazing management-specific bulk densities were consistent with field measurements and confirmed that rotational grazing produced similar disturbance as conventional grazing despite hosting higher stock densities. Harnessing information on livestock movement and its impacts in soil structure within a modelling framework can help testing and optimizing grazing strategies for ameliorating their impact on soil health and environment.

Robust estimation of cortical similarity networks from brain MRI.

Structural similarity is a growing focus for magnetic resonance imaging (MRI) of connectomes. Here we propose Morphometric INverse Divergence (MIND), a new method to estimate within-subject similarity between cortical areas based on the divergence between their multivariate distributions of multiple MRI features. Compared to the prior approach of morphometric similarity networks (MSNs) on n > 11,000 scans spanning three human datasets and one macaque dataset, MIND networks were more reliable, more consistent with cortical cytoarchitectonics and symmetry and more correlated with tract-tracing measures of axonal connectivity. MIND networks derived from human T1-weighted MRI were more sensitive to age-related changes than MSNs or networks derived by tractography of diffusion-weighted MRI. Gene co-expression between cortical areas was more strongly coupled to MIND networks than to MSNs or tractography. MIND network phenotypes were also more heritable, especially edges between structurally differentiated areas. MIND network analysis provides a biologically validated lens for cortical connectomics using readily available MRI data.

Sugar distributions on gangliosides guide the formation and stability of amyloid-ß oligomers.

Aggregation of Aß peptides is a key contributor to the etiology of Alzheimer's disease. Being intrinsically disordered, monomeric Aß is susceptible to conformational excursions, especially in the presence of important interacting partners such as membrane lipids, to adopt specific aggregation pathways. Furthermore, components such as gangliosides in membranes and lipid rafts are known to play important roles in the adoption of pathways and the generation of discrete neurotoxic oligomers. Yet, what roles do carbohydrates on gangliosides play in this process remains unknown. Here, using GM1, GM3, and GD3 ganglioside micelles as models, we show that the sugar distributions and cationic amino acids within Aß N-terminal region modulate oligomerization of Aß temporally, and dictate the stability and maturation of oligomers. These results demonstrate the selectivity of sugar distributions on the membrane surface toward oligomerization of Aß and thus implicate cell-selective enrichment of oligomers.

De novo amyloid peptides with subtle sequence variations differ in their self-assembly and nanomechanical properties.

Proteinaceous amyloids are well known for their widespread pathological roles but lately have emerged also as key components in several biological functions. The remarkable ability of amyloid fibers to form tightly packed conformations in a cross ß-sheet arrangement manifests in their robust enzymatic and structural stabilities. These characteristics of amyloids make them attractive for designing proteinaceous biomaterials for various biomedical and pharmaceutical applications. In order to design customizable and tunable amyloid nanomaterials, it is imperative to understand the sensitivity of the peptide sequence for subtle changes based on amino acid position and chemistry. Here we report our results from four rationally-designed amyloidogenic decapeptides that subtly differ in hydrophobicity and polarity at positions 5 and 6. We show that making the two positions hydrophobic renders the peptide with enhanced aggregation and material properties while introducing polar residues in position 5 dramatically changes the structure and nanomechanical properties of the fibrils formed. A charged residue at position 6, however, abrogates amyloid formation. In sum, we show that subtle changes in the sequence do not make the peptide innocuous but rather sensitive to aggregation, reflected in the biophysical and nanomechanical properties of the fibrils. We conclude that tolerance of peptide amyloid for changes in the sequence, however small they may be, should not be neglected for the effective design of customizable amyloid nanomaterials.

Perspectives on residential involvement and engagement in everyday life-a qualitative study.

Background: Worldwide, the population is ageing, and the need for nursing homes is increasing. institutionalization and a culture change from task-orientated care delivery towards increased involvement and engagement in a meaningful everyday life are evolving and, thus, contributing to nursing home residents' quality of life and well-being.Aims/Objectives: To explore nursing home staff's and local managers' perspectives on everyday life with a specific focus on involvement and engagement.Material and Methods: Positioned within interpretivism and hermeneutics, a qualitative exploratory design was applied using individual and group interviews for data generation and abductive thematic analysis as the analytical method.Results: Through the analyses, three main themes appeared-A good day-Everyday life in a nursing home, Doing together-involvement in Everyday life and Involvement in Everyday life-difficult to practice-together with four subthemes-Home and people within, Knowing and relating to the person, If they can - they must and Service and Habits.Conclusions: Fulfilling the needs of both residents and the institution was found to be challenging by nursing home staff and local managers.Significance: A different approach to care, facilitated by, for example, occupational therapists, might be required to enable increased involvement and engagement in everyday life.

Enabling quantitative analysis of complex polymer blends by infrared nanospectroscopy and isotopic deuteration.

Atomic-force microscopy coupled with infrared spectroscopy (AFM-IR) deciphers surface morphology of thin-film polymer blends and composites by simultaneously mapping physical topography and chemical composition. However, acquiring quantitative phase and composition information from multi-component blends can be challenging using AFM-IR due to the possible overlapping infrared absorption bands between different species. Isotope labeling one of the blend components introduces a new type of bond (carbon-deuterium vibration) that can be targeted using AFM-IR and responds at wavelengths sufficiently shifted toward unoccupied regions (around 2200 cm-1). In this project, AFM-IR was used to probe the surface morphology and chemical composition of three polymer blends containing deuterated polystyrene; each blend is expected to exhibit various degrees of miscibility. AFM-IR results successfully demonstrated that deuterium labeling prevents infrared spectral overlap and enables the visualization of blend phases that could not normally be distinguished by other scanning probe techniques. The nanoscale domain composition was resolved by fast infrared spectrum analysis. Overall, we presented isotope labeling as a robust approach for circumventing obstacles preventing the quantitative analysis of multiphase systems by AFM-IR.

Flagellar Genes Are Associated with the Colonization Persistence Phenotype of the Drosophila melanogaster Microbiota.

In this work, we use Drosophila melanogaster as a model to identify bacterial genes necessary for bacteria to colonize their hosts independent of the bulk flow of diet. Early work on this model system established that dietary replenishment drives the composition of the D. melanogaster gut microbiota, and subsequent research has shown that some bacterial strains can stably colonize, or persist within, the fly independent of dietary replenishment. Here, we reveal transposon insertions in specific bacterial genes that influence the bacterial colonization persistence phenotype by using a gene association approach. We initially established that different bacterial strains persist at various levels, independent of dietary replenishment. We then repeated the analysis with an expanded panel of bacterial strains and performed a metagenome-wide association (MGWA) study to identify distinct bacterial genes that are significantly correlated with the level of colonization by persistent bacterial strains. Based on the MGWA study, we tested if 44 bacterial transposon insertion mutants from 6 gene categories affect bacterial persistence within the flies. We identified that transposon insertions in four flagellar genes, one urea carboxylase gene, one phosphatidylinositol gene, one bacterial secretion gene, and one antimicrobial peptide (AMP) resistance gene each significantly influenced the colonization of D. melanogaster by an Acetobacter fabarum strain. Follow-up experiments revealed that each flagellar mutant was nonmotile, even though the wild-type strain was motile. Taken together, these results reveal that transposon insertions in specific bacterial genes, including motility genes, are necessary for at least one member of the fly microbiota to persistently colonize the fly. IMPORTANCE Despite the growing body of research on the microbiota, the mechanisms by which the microbiota colonizes a host can still be further elucidated. This study identifies bacterial genes that are associated with the colonization persistence phenotype of the microbiota in Drosophila melanogaster, which reveals specific bacterial factors that influence the establishment of the microbiota within its host. The identification of specific genes that affect persistence can help inform how the microbiota colonizes a host. Furthermore, a deeper understanding of the genetic mechanisms of the establishment of the microbiota could aid in the further development of the Drosophila microbiota as a model for microbiome research.

Semantic Speech Networks Linked to Formal Thought Disorder in Early Psychosis.

BACKGROUND AND HYPOTHESIS: Mapping a patient's speech as a network has proved to be a useful way of understanding formal thought disorder in psychosis. However, to date, graph theory tools have not explicitly modelled the semantic content of speech, which is altered in psychosis. STUDY DESIGN: We developed an algorithm, "netts," to map the semantic content of speech as a network, then applied netts to construct semantic speech networks for a general population sample (N = 436), and a clinical sample comprising patients with first episode psychosis (FEP), people at clinical high risk of psychosis (CHR-P), and healthy controls (total N = 53). STUDY RESULTS: Semantic speech networks from the general population were more connected than size-matched randomized networks, with fewer and larger connected components, reflecting the nonrandom nature of speech. Networks from FEP patients were smaller than from healthy participants, for a picture description task but not a story recall task. For the former task, FEP networks were also more fragmented than those from controls; showing more connected components, which tended to include fewer nodes on average. CHR-P networks showed fragmentation values in-between FEP patients and controls. A clustering analysis suggested that semantic speech networks captured novel signals not already described by existing NLP measures. Network features were also related to negative symptom scores and scores on the Thought and Language Index, although these relationships did not survive correcting for multiple comparisons. CONCLUSIONS: Overall, these data suggest that semantic networks can enable deeper phenotyping of formal thought disorder in psychosis. Whilst here we focus on network fragmentation, the semantic speech networks created by Netts also contain other, rich information which could be extracted to shed further light on formal thought disorder. We are releasing Netts as an open Python package alongside this manuscript.

Correction: Ten simple rules for leveraging virtual interaction to build higher-level learning into bioinformatics short courses.

[This corrects the article DOI: 10.1371/journal.pcbi.1010220.].