Process evaluation of two large randomized controlled trials to understand factors influencing family physicians' use of antibiotic audit and feedback reports.

BACKGROUND: Unnecessary antibiotic prescriptions in primary care are common and contribute to antimicrobial resistance in the population. Audit and feedback (A&F) on antibiotic prescribing to primary care can improve the appropriateness of antibiotic prescribing, but the optimal approach is uncertain. We performed two pragmatic randomized controlled trials of different approaches to audit and feedback. The trial results showed that A&F was associated with significantly reducing antibiotic prescribing. Still, the effect size was small, and the modifications to the A&F interventions tested in the trials were not associated with any change. Herein, we report a theory-informed qualitative process evaluation to explore potential mechanisms underlying the observed effects. METHODS: Ontario family physicians in the intervention arms of both trials who were sent A&F letters were invited for one-on-one interviews. Purposive sampling was used to seek variation across interested participants in personal and practice characteristics. Qualitative analysis utilized inductive and deductive techniques informed by the Clinical Performance Feedback Intervention Theory. RESULTS: Modifications to the intervention design tested in the trial did not alter prescribing patterns beyond the changes made in response to the A&F overall for various reasons. Change in antibiotic prescribing in response to A&F depended on whether it led to the formation of specific intentions and whether those intentions translated to particular behaviours. Those without intentions to change tended to feel that their unique clinical context was not represented in the A&F. Those with intentions but without specific actions taken tended to express a lack of self-efficacy for avoiding a prescription in contexts with time constraints and/or without an ongoing patient relationship. Many participants noted that compared to overall prescribing, A&F on antibiotic prescription duration was perceived as new information and easily actionable. CONCLUSION: Our findings indicate that contextual factors, including the types of patients and the setting where they are seen, affect how clinicians react to audit and feedback. These results suggest a need to test tailored feedback reports that reflect the context of how, where, and why physicians prescribe antibiotics so that they might be perceived as more personal and more actionable. TRIAL REGISTRATION: Clinical Trial registration IDs: NCT04594200, NCT05044052.

Neutrophil extracellular traps protect the kidney from ascending infection and are required for a positive leukocyte dipstick test.

Lower urinary tract infection (UTI) is common but only rarely complicated by pyelonephritis. However, the mechanisms preventing extension to the kidney are unclear. Here, we identified neutrophil extracellular traps (NETs) in healthy human urine that provide an antibacterial defense strategy within the urinary tract. In both in vivo murine models of UTI where uropathogenic E. coli are inoculated into the bladder and ex vivo human urine models, NETs interacted with uromodulin to form large webs that entrapped the bacteria. Peptidyl arginine deiminase 4 (PADI4) inhibition in mice blocked NETosis and resulted in progression of cystitis into pyelonephritis, suggesting that NETosis of urinary neutrophils acts to prevent bacterial ascent into the kidney. Analysis of UK Biobank data revealed that genetic variants in PADI4 that associated with increased risk of rheumatoid arthritis in multiple genome-wide association studies were consistently associated with reduced susceptibility to UTI. Last, we showed that urine dipstick testing for leukocyte esterase was negative in the presence of intact blood neutrophils but became positive when neutrophils were stimulated to NET, and this could be prevented by selective PADI4 inhibition, demonstrating that this test does not detect absolute neutrophil count, as has long been assumed, but specifically detects neutrophils that have undergone NETosis. These findings highlight the role of NETosis in preventing ascending infections in the urinary tract and improve our understanding of one of the most common clinical tests in medicine.

Metastable layered lithium-rich niobium and tantalum oxides via nearly instantaneous cation exchange.

Lithium-rich early transition metal oxides are the source of excess removeable lithium that affords high energy density to lithium-rich battery cathodes. They are also candidates for solid electrolytes in all-solid-state batteries. These highly ionic compounds are sparse on phase diagrams of thermodynamically stable oxides, but soft chemical routes offer an alternative to explore new alkali-rich crystal chemistries. In this work, a new layered polymorph of Li3NbO4 with coplanar [Nb4O16]12- clusters is discovered through ion exchange chemistry. A more detailed study of the ion exchange reaction reveals that it takes place almost instantaneously, changing the crystal volume by more than 22% within seconds. The transformation of coplanar [Nb4O16]12- in L-Li3NbO4 into the supertetrahedral [Nb4O16]12- clusters found in the stable cubic c-Li3NbO4 is also explored. Furthermore, this synthetic pathway is extended to access a new layered polymorph of Li3TaO4. NMR crystallography with 6,7Li, 23Na, and 93Nb NMR, X-ray diffraction, neutron diffraction, and first-principles calculations is applied to A3MO4 (A = Li, Na; M = Nb, Ta) to identify local and long-range atomic structure, to monitor the unusually rapid reaction progression, and to track the phase transitions from the metastable layered phases to the known compounds found using high-temperature synthesis. A mechanism is proposed whereby some sodium is retained at short reaction times, which then undergoes proton exchange during water washing, forming a phase with hydrogen bonds bridging the coplanar [Nb4O16]12- clusters. This study has implications for lithium-rich transition metal oxides and associated battery materials and for ion exchange chemistry in non-framework structures. The role of techniques that can detect light elements, local structure, and subtle structural changes in soft-chemical synthesis is emphasized.

The unique metabolic and lipid profiles of patients with severe COVID-19 compared to severe community-acquired pneumonia: a potential prognostic and therapeutic target.

BACKGROUND: Compare the changes and differences in metabolome and lipidome profiles among severe COVID-19 and CAP patients with ARF to identify biomarkers that could be used for personalized diagnosis, prognosis, and treatment. RESEARCH DESIGN AND METHODS: Plasma samples were taken at hospital admission (baseline) and on the 5th day of hospitalization (follow-up) and examined by RP-LC-QTOF-MS and HILIC-LC-QTOF-MS. RESULTS: 127 patients, 17 with CAP and 110 with COVID-19, were included. The analysis revealed 87 altered metabolites, suggesting changes in the metabolism of arachidonic acid, glycerolipids, glycerophospholipids, linoleic acid, pyruvate, glycolysis, among others. Most of these metabolites are involved in inflammatory, hypoxic, and thrombotic processes. At baseline, the greatest differences were found in phosphatidylcholine (PC) 31:4 (p < 0.001), phosphoserine (PS) 34:3 (p < 0.001), and phosphatidylcholine (PC) 36:5 (p < 0.001), all of which were notably decreased in COVID-19 patients. At follow-up, the most dysregulated metabolites were monomethyl-phosphatidylethanolamine (PE-Nme) 40:5 (p < 0.001) and phosphatidylcholine (PC) 38:4 (p < 0.001). CONCLUSIONS: Metabolic and lipidic alterations suggest inhibition of innate anti-inflammatory and anti-thrombotic mechanisms in COVID-19 patients, which might lead to increased viral proliferation, uncontrolled inflammation, and thrombi formation. Results provide novel targets for predictive biomarkers against CAP and COVID-19. TRIAL REGISTRATION: Not applicable.

Changes in the Firmicutes to Bacteriodetes ratio in the gut microbiome in individuals with anorexia nervosa following inpatient treatment: A systematic review and a case series.

OBJECTIVE: Anorexia nervosa has the highest mortality rate among psychiatric illnesses. Current treatments remain ineffective for a large fraction of patients. This may be due to unclear mechanisms behind its development and maintenance. Studies exploring the role of the gut microbiome have revealed inconsistent evidence of dysbiosis. This article aims to investigate changes in the gut microbiome, particularly, mean differences in the Firmicutes to Bacteroidetes ratio, in adolescent and adult individuals with anorexia nervosa following inpatient treatment. METHODS: Longitudinal studies investigating gut microbiome composition in inpatient populations of anorexia nervosa before and after treatment were systematically reviewed. Additionally, gut microbiome compositions were characterized in three acute anorexia nervosa inpatients early after admission and after 4-12 weeks of treatment. RESULTS: Review results indicated an increase in the Firmicutes to Bacteroidetes ratio in individuals with anorexia nervosa after treatment. These however did not match values of their healthy counterparts. In the case-series samples, the reverse occurred with samples taken 4 weeks after treatment. In the patient who provided an extra sample 12 weeks after treatment, similar results to the studies included in the review were observed. Furthermore, Firmicutes to Bacteroidetes ratio values in the case-series samples were notably higher in the two patients who had chronic anorexia nervosa. DISCUSSION: Differences in methodologies, small sample sizes, and insufficient data limited the generalizability of the outcomes of the reviewed studies. Results suggest a potentially unique microbiome signature in individuals with chronic anorexia nervosa, which may explain different outcomes in this group of patients.

Developments and applications of the OPTIMADE API for materials discovery, design, and data exchange.

The Open Databases Integration for Materials Design (OPTIMADE) application programming interface (API) empowers users with holistic access to a growing federation of databases, enhancing the accessibility and discoverability of materials and chemical data. Since the first release of the OPTIMADE specification (v1.0), the API has undergone significant development, leading to the v1.2 release, and has underpinned multiple scientific studies. In this work, we highlight the latest features of the API format, accompanying software tools, and provide an update on the implementation of OPTIMADE in contributing materials databases. We end by providing several use cases that demonstrate the utility of the OPTIMADE API in materials research that continue to drive its ongoing development.

Validating self-reported driving behaviours as determinants of real-world driving speeds.

Self-reported driver behaviour has long been a tool used by road safety researchers to classify drivers and to evaluate the impact of interventions yet the relationship with real-world driving is challenging to validate due to the need for extensive, detailed observations of normal driving. This study examines this association by applying the large UDRIVE naturalistic driving study data involving 96 car drivers, comprising 131,462 trips and 1,459,110 km travelled over a duration of 32,096 hours, to compare individual questions and composite indicators based on the Driver Behaviour Questionnaire with real world driving. Self-reported speed behaviour was compared to the measured values under urban and highway conditions. Generalised Linear Mixed Models were developed to examine the relationships between the observed speed behaviours with DBQ errors and violations scores in conjunction with traffic and environmental factors. Drivers' self-reported data on speed selection seldom aligned with their real-world behaviour and there were no meaningful differences between many of the response categories. The DBQ violations and errors scales showed a highly significant correlation with driving speed indicators however they had a low explanatory power compared to other traffic situational and driving factors. Overall, the study highlights the need to validate self-reported driving data against the accuracy and relevance to real-world driving.

Self-reports of driving behaviour have long been a tool in road safety research and evaluation yet responses on speed selection are commonly inaccurate and may have little relation with real-world driving.

Controlling Noncollinear Ferromagnetism in van der Waals Metal-Organic Magnets.

Van der Waals (vdW) magnets both allow exploration of fundamental 2D physics and offer a route toward exploiting magnetism in next generation information technology, but vdW magnets with complex, noncollinear spin textures are currently rare. We report here the syntheses, crystal structures, magnetic properties and magnetic ground states of four bulk vdW metal-organic magnets (MOMs): FeCl2(pym), FeCl2(btd), NiCl2(pym), and NiCl2(btd), pym = pyrimidine and btd = 2,1,3-benzothiadiazole. Using a combination of neutron diffraction and bulk magnetometry we show that these materials are noncollinear magnets. Although only NiCl2(btd) has a ferromagnetic ground state, we demonstrate that low-field hysteretic metamagnetic transitions produce states with net magnetization in zero-field and high coercivities for FeCl2(pym) and NiCl2(pym). By combining our bulk magnetic data with diffuse scattering analysis and broken-symmetry density-functional calculations, we probe the magnetic superexchange interactions, which when combined with symmetry analysis allow us to suggest design principles for future noncollinear vdW MOMs. These materials, if delaminated, would prove an interesting new family of 2D magnets.

Integration of genetic and clinical risk factors improves the risk classification of uveitis in patients with juvenile idiopathic arthritis.

OBJECTIVES: Juvenile idiopathic arthritis (JIA)-associated uveitis (JIAU) is a serious JIA comorbidity that can result in vision impairment. This study aimed to identify genetic risk factors, within the major histocompatibility complex , for JIAU and evaluate their contribution for improving risk classification when combined with clinical risk factors. METHODS: Data on single nucleotide polymorphisms, amino acids and classical human leukocyte antigen (HLA) alleles were available for 2,497 JIA patients without uveitis and 579 JIAU patients (female=2060, male=1015). Analysis was restricted to patients with inferred European ancestry. Forward conditional logistic regression identified genetic markers exceeding a Bonferroni corrected significance (6x10-6). Multivariable logistic regression estimated the effects of clinical and genetic risk factors and a likelihood ratio test calculated the improvement in model fit when adding genetic factors. Uveitis risk classification performance of a model integrating genetic and clinical risk factors was estimated using area under the receiver operator characteristic curve and compared to a model of clinical risk factors alone. RESULTS: Three genetic risk factors were identified mapping to HLA-DRB1, HLA-DPB1 and HLA-A. These markers were statistically independent from clinical risk factors and significantly improved the fit of a model when included with clinical risk factors (P = 3.3x10-23). The addition of genetic markers improved the classification of JIAU compared to a model of clinical risk factors alone (AUC 0.75 vs. 0.71). CONCLUSIONS: Integration of a genetic and clinical risk prediction model outperforms a model based solely on clinical risk factors. Future JIAU risk prediction models should include genetic risk factors.

Fine mapping of candidate effector genes for heart rate.

An elevated resting heart rate (RHR) is associated with increased cardiovascular mortality. Genome-wide association studies (GWAS) have identified > 350 loci. Uniquely, in this study we applied genetic fine-mapping leveraging tissue specific chromatin segmentation and colocalization analyses to identify causal variants and candidate effector genes for RHR. We used RHR GWAS summary statistics from 388,237 individuals of European ancestry from UK Biobank and performed fine mapping using publicly available genomic annotation datasets. High-confidence causal variants (accounting for > 75% posterior probability) were identified, and we collated candidate effector genes using a multi-omics approach that combined evidence from colocalisation with molecular quantitative trait loci (QTLs), and long-range chromatin interaction analyses. Finally, we performed druggability analyses to investigate drug repurposing opportunities. The fine mapping pipeline indicated 442 distinct RHR signals. For 90 signals, a single variant was identified as a high-confidence causal variant, of which 22 were annotated as missense. In trait-relevant tissues, 39 signals colocalised with cis-expression QTLs (eQTLs), 3 with cis-protein QTLs (pQTLs), and 75 had promoter interactions via Hi-C. In total, 262 candidate genes were highlighted (79% had promoter interactions, 15% had a colocalised eQTL, 8% had a missense variant and 1% had a colocalised pQTL), and, for the first time, enrichment in nervous system pathways. Druggability analyses highlighted ACHE, CALCRL, MYT1 and TDP1 as potential targets. Our genetic fine-mapping pipeline prioritised 262 candidate genes for RHR that warrant further investigation in functional studies, and we provide potential therapeutic targets to reduce RHR and cardiovascular mortality.

Biomarkers in pulmonary infections: a clinical approach.

Severe acute respiratory infections, such as community-acquired pneumonia, hospital-acquired pneumonia, and ventilator-associated pneumonia, constitute frequent and lethal pulmonary infections in the intensive care unit (ICU). Despite optimal management with early appropriate empiric antimicrobial therapy and adequate supportive care, mortality remains high, in part attributable to the aging, growing number of comorbidities, and rising rates of multidrug resistance pathogens. Biomarkers have the potential to offer additional information that may further improve the management and outcome of pulmonary infections. Available pathogen-specific biomarkers, for example, Streptococcus pneumoniae urinary antigen test and galactomannan, can be helpful in the microbiologic diagnosis of pulmonary infection in ICU patients, improving the timing and appropriateness of empiric antimicrobial therapy since these tests have a short turnaround time in comparison to classic microbiology. On the other hand, host-response biomarkers, for example, C-reactive protein and procalcitonin, used in conjunction with the clinical data, may be useful in the diagnosis and prediction of pulmonary infections, monitoring the response to treatment, and guiding duration of antimicrobial therapy. The assessment of serial measurements overtime, kinetics of biomarkers, is more informative than a single value. The appropriate utilization of accurate pathogen-specific and host-response biomarkers may benefit clinical decision-making at the bedside and optimize antimicrobial stewardship.

Long-term use of investigational ß-Hydroxybutyrate salts in children with multiple acyl-CoA dehydrogenase or pyruvate dehydrogenase deficiency.

Several disorders of energy metabolism have been treated with exogenous ketone bodies. The benefit of this treatment is best documented in multiple acyl-CoA dehydrogenase deficiency (MADD) (MIM#231680). One might also expect ketone bodies to help in other disorders with impaired ketogenesis or in conditions that profit from a ketogenic diet. Here, we report the use of a novel preparation of dextro-ß-hydroxybutyrate (D-ßHB) salts in two cases of MADD and one case of pyruvate dehydrogenase (PDH) deficiency (MIM#312170). The two patients with MADD had previously been on a racemic mixture of D- and L­sodium hydroxybutyrate. Patient #1 found D-ßHB more palatable, and the change in formulation corrected hypernatraemia in patient #2. The patient with PDH deficiency was on a ketogenic diet but had not previously been given hydroxybutyrate. In this case, the addition of D-ßHB improved ketosis. We conclude that NHS101 is a good candidate for further clinical studies in this group of diseases of inborn errors of metabolism.

Developing improved crash prevention approaches through in-depth investigation of motorcycle crash causation patterns.

Despite advancements in road safety, Powered Two-Wheelers (PTWs) remain a vulnerable group with disproportionately high crash rates. This paper presents an in-depth analysis of PTW crashes in six European countries, with a case study of Loss of Control in Curves (LoCC), to address the gap between crash causation and prevention. By examining crash causation factors and their linkage to prevention strategies, the study illustrates various approaches for connecting causes and countermeasures. These approaches, which are applicable to different crash scenarios, include looking forward in the crash causation chains, looking backward, looking at only the last cause (critical events), or the first cause, or following a systemic approach. The research introduces a set of guidelines following the safe system approach, aiming to enhance the understanding of crash prevention among policymakers. The systemic approach to countermeasures, bridges the shortcomings of traditional crash causation studies that may exhibit bias or a narrow focus on "root causes". The proposed approach emphasizes the need for a comprehensive view of crash scenarios (i.e., considering the entire crash causation chain or multiple causation chains) and ensuring that preventive measures address the full spectrum of the system. It also takes in to account external factors such as cost, benefits, and politics, leading to improved road safety outcomes. The study findings are significant for researchers, since it is a step forward in in-depth crash causation studies, as well as road practitioners and policymakers, in providing a strategic framework for more effective and efficient road safety interventions.

Methods for multiancestry genome-wide association study meta-analysis.

Genome-wide association studies (GWAS) have significantly enhanced our understanding of the genetic basis of complex diseases. Despite the technological advancements, gaps in our understanding remain, partly due to small effect sizes and inadequate coverage of genetic variation. Multiancestry GWAS meta-analysis (MAGMA) addresses these challenges by integrating genetic data from diverse populations, thereby increasing power to detect loci and improving fine-mapping resolution to identify causal variants across different ancestry groups. This review provides an overview of the protocols, statistical methods, and software of MAGMA, as well as highlighting some challenges associated with this approach.

Multi-omics characterization of type 2 diabetes associated genetic variation.

Discerning the mechanisms driving type 2 diabetes (T2D) pathophysiology from genome-wide association studies (GWAS) remains a challenge. To this end, we integrated omics information from 16 multi-tissue and multi-ancestry expression, protein, and metabolite quantitative trait loci (QTL) studies and 46 multi-ancestry GWAS for T2D-related traits with the largest, most ancestrally diverse T2D GWAS to date. Of the 1,289 T2D GWAS index variants, 716 (56%) demonstrated strong evidence of colocalization with a molecular or T2D-related trait, implicating 657 cis-effector genes, 1,691 distal-effector genes, 731 metabolites, and 43 T2D-related traits. We identified 773 of these cis- and distal-effector genes using either expression QTL data from understudied ancestry groups or inclusion of T2D index variants enriched in underrepresented populations, emphasizing the value of increasing population diversity in functional mapping. Linking these variants, genes, metabolites, and traits into a network, we elucidated mechanisms through which T2D-associated variation may impact disease risk. Finally, we showed that drugs targeting effector proteins were enriched in those approved to treat T2D, highlighting the potential of these results to prioritize drug targets for T2D. These results represent a leap in the molecular characterization of T2D-associated genetic variation and will aid in translating genetic findings into novel therapeutic strategies.

Potassium Food Additives and Dietary Management of Serum Potassium: Proposed Best-Practice Recommendations.

The contribution of potassium food additives to total dietary potassium intake is unknown. This poses challenges for individuals living with kidney disease who may need to monitor their potassium intake. Additionally, different countries have varying regulations regarding the reporting of dietary potassium content in foods. This article examines the potential of published food databases to assist clinicians in helping individuals with kidney disease manage their serum potassium levels. It uses the United States Department of Agriculture's Branded Food Products Database as an example. Evidence for potassium additive content in database entries, along with their bioavailability, is discussed, and best-practice recommendations are made based on current evidence. Clinical practice and future research priorities are suggested.

Glucocorticoid resistance remodels liver lipids and prompts lipogenesis, eicosanoid, and inflammatory pathways.

We have previously demonstrated that the glucocorticoid receptor ß (GRß) isoform induces hepatic steatosis in mice fed a normal chow diet. The GRß isoform inhibits the glucocorticoid-binding isoform GRα, reducing responsiveness and inducing glucocorticoid resistance. We hypothesized that GRß regulates lipids that cause metabolic dysfunction. To determine the effect of GRß on hepatic lipid classes and molecular species, we overexpressed GRß (GRß-Ad) and vector (Vec-Ad) using adenovirus delivery, as we previously described. We fed the mice a normal chow diet for 5 days and harvested the livers. We utilized liquid chromatography-mass spectrometry (LC-MS) analyses of the livers to determine the lipid species driven by GRß. The most significant changes in the lipidome were monoacylglycerides and cholesterol esters. There was also increased gene expression in the GRß-Ad mice for lipogenesis, eicosanoid synthesis, and inflammatory pathways. These indicate that GRß-induced glucocorticoid resistance may drive hepatic fat accumulation, providing new therapeutic advantages.

PITPß promotes COPI vesicle fission through lipid transfer and membrane contact formation.

Intracellular transport among organellar compartments occurs in two general ways, by membrane-bound carriers or membrane contacts. Specific circumstances that involve the coordination of these two modes of transport remain to be defined. Studying Coat Protein I (COPI) transport, we find that phosphatidylcholine with short acyl chains (sPC) is delivered through membrane contact from the endoplasmic reticulum (ER) to sites of COPI vesicle formation at the Golgi to support the fission stage. Phosphatidylinositol transfer protein beta (PITPß) plays a key role in this process, with the elucidation of this role advancing a new understanding of how PITPß acts, providing a mechanistic understanding of a specific circumstance when vesicular transport requires membrane contact, and contributing to a basic understanding of how transport carriers in a model intracellular pathway are formed.

Genetic association and transferability for urinary albumin-creatinine ratio as a marker of kidney disease in four Sub-Saharan African populations and non-continental individuals of African ancestry.

Background: Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors influencing kidney disease in Sub-Saharan African (SSA) populations. This study presents the largest GWAS for urinary albumin-to-creatinine ratio (UACR) in SSA individuals, including 8,970 participants living in different African regions and an additional 9,705 non-resident individuals of African ancestry from the UK Biobank and African American cohorts. Methods: Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations. Results: Two genome-wide significant (P < 5 × 10-8) UACR-associated loci were identified, one in the BMP6 region on chromosome 6, in the meta-analysis of resident African individuals, and another in the HBB region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including THB53, GATM, and ARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained. Conclusion: This study contributes novel insights into the genetic architecture of kidney disease in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations Additionally, there is a need to develop integrated scores using multi-omics data and risk factors specific to the African context to improve the accuracy of predicting disease outcomes.