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PubMed2025

Estimating the association of antimicrobial resistance genes with minimum inhibitory concentration in Escherichia coli: an observational study.

BACKGROUND: Surveillance and prediction of antibiotic resistance in Escherichia coli relies on curated databases of genes and mutations. We aimed to quantify the effect of acquiring specific genetic elements on minimum inhibitory concentrations (MICs) for particular antibiotic-species combinations, addressing the current scarcity of such data in existing databases. METHODS: For this observational study, we evaluated a collection of E coli isolates with linked whole-genome sequencing and MIC data, originating from human urinary or bloodstream infections obtained from the Oxford University Hospitals National Health Service Foundation Trust in Oxfordshire, UK. We used multivariable interval regression models to estimate the change in MIC (with 95% CIs) for specific antibiotics associated with the acquisition of antibiotic resistance genes and associated mutations in the National Center for Biotechnology Information AMRFinder database, with and without an adjustment for population structure. We then tested the ability of these models to predict MIC and binary resistance or susceptibility using leave-one-out cross-validation. FINDINGS: We evaluated 2875 E coli isolates obtained during 2013-2018 and 2020. Although most ARGs and resistance mutations (89 [80%] of 111) were associated with an increased MIC, a much smaller number (27 [24%] of 111) was found to be putatively independently resistance-conferring (ie, associated with an MIC above the European Committee on Antimicrobial Susceptibility Testing breakpoint) when acquired in isolation. We found evidence of differential effects of acquired ARGs and resistance mutations between different generations of cephalosporin antibiotics and showed that sub-breakpoint variation in MIC can be linked to genetic mechanisms of resistance. 20 697 (83·3%; range 52·9-97·7 across all antibiotics) of 24 858 MICs were correctly exactly predicted and 23 677 (95·2%; 87·3-97·7) of 24 858 MICs were predicted to within one doubling dilution. INTERPRETATION: Quantitative estimates of the independent effect of the acquisition of ARGs on MIC add to the interpretability and utility of existing databases. Compared with approaches using machine learning models, the use of these estimates yields similar or better performance in the prediction of antibiotic resistance phenotype with more readily interpretable results. The methods outlined here could be readily applied to other antibiotic-pathogen combinations. FUNDING: The National Institute for Health and Care Research (NIHR) and the Medical Research Council (MRC).

Escherichia coli↗
PubMed2005

Evolutionary dynamics of genes controlling floral development.

Advances in the understanding of floral developmental genetics in model species such as Arabidopsis continue to provide an important foundation for comparative studies in other flowering plants. In particular, floral organ identity genes are the focus of many projects that are addressing both ancient and recent evolutionary questions. Expanded analyses of the evolution of these gene lineages have highlighted the dynamic nature of the gene birth-and-death process, and may have significant implications for the evolution of genetic pathways. Crucial functional studies of floral organ identity genes in diverse taxa are allowing the first real insight into the conservation of gene function, while findings on the genetic control of organ elaboration offer to open up new avenues for investigation. Taken together, these trends show that the field of floral developmental evolution continues to make significant progress towards elucidating the processes that have shaped the evolution of flower development and morphology.

Evolution, Molecular↗
PubMed2005

Regulation of proliferation during central nervous system development.

The retina is one of the best-characterized regions of the central nervous system (CNS) and has served as a model for many of the principles that now form the foundation for CNS development. In the past several years, a number of advances have been made in our understanding of the coordination of proliferation and cell fate specification during retinal development. In this review, we will draw on findings from studies of the retina and highlight similarities and differences in other regions in the CNS, namely the cerebellum and cortex. We will present a framework in which to pose challenges and outstanding questions for future studies on the coordination of proliferation and cell fate specification in the developing CNS.

Cell Differentiation↗
PubMedDate not supplied

What causes birth order-intelligence patterns? The admixture hypothesis, revived.

Recent evidence shows that the relation between birth order and intelligence is not the same in cross-sectional and within-family data. This simple empirical observation invalidates the conclusions from hundreds of previous birth order studies that relied on cross-sectional data. Simultaneously, the empirical foundation disappears from underneath theories like dilution and the confluence model that use explanatory processes occurring within the family. A theory proposed almost 25 years ago--the admixture hypothesis--effectively accounts for these empirical patterns. In this article, the author describes why birth order is of such intense interest to both parents and researchers (the birth order trap), discusses past birth order-intelligence patterns, shows that the admixture hypothesis accounts for those patterns, and reframes the original argument to support future productive research efforts.

Birth Order↗
PubMed2005

Externalizing psychopathology in adulthood: a dimensional-spectrum conceptualization and its implications for DSM-V.

Mental disorders involving antisocial behavior and substance use are genetically linked and vary continuously. The authors present a review and integrative conceptualization of these observations in terms of a dimensional and hierarchically organized externalizing spectrum. As a foundation for this conceptualization, the authors introduce a quantitative, model-based approach to comparing categorical and continuous conceptions of psychopathology and apply this approach in an empirical study of patterns of comorbidity among externalizing disorders as defined in the Diagnostic and Statistical Manual of Mental Disorders. The authors present evidence that comorbidity among externalizing disorders is best modeled by an underlying normally distributed continuum of risk for multiple disorders within the externalizing spectrum. The authors conclude by discussing implications of the externalizing spectrum conceptualization for classification of disorders in the upcoming 5th edition of the Diagnostic and Statistical Manual of Mental Disorders.

Adult↗
PubMed2002

Human monoclonal natural autoantibodies against the T-cell receptor inhibit interleukin-2 production in murine T cells.

Natural autoantibodies (NAAbs) specific for the T-cell receptor (TCR) are present in all human sera, but individuals with rheumatoid arthritis (RA) generally produce higher titres of immunoglobulin M (IgM) isotype autoantibodies (AAbs) against Vbeta TCR epitopes. To investigate possible correlations between the specificity of such AAbs and their role in immunomodulation, we generated seven B-cell hetero-hybridomas, secreting monoclonal IgM NAAbs, from the synovial tissue and peripheral blood of patients with RA. Here we report three anti-TCR monoclonal autoantibodies (mAAbs)--OR2, OR5 and Syn 2H-11--with the ability to bind subsets of murine T cells, including the ovalbumin-specific DO-11.10 clone. These antibodies did not induce apoptosis in vitro, but prevented interleukin-2 (IL-2) production by antigen-specific T cells. These findings suggest an immunomodulatory function for NAAbs to TCR V-region epitopes and serve as the foundation for testing human anti-TCR mAAbs in animal models with the eventual goal of using them as therapeutic agents in human disease.

Animals↗
PubMed2006

Occupational therapists' reflection on practice within psychiatric care: a Delphi study.

AIM: The aim of this study was to describe the reflections on practice in a group of Swedish occupational therapists in psychiatric care in order to illuminate the present practice and ideas about the future using a Delphi survey of three rounds. MATERIAL AND METHOD: The sample consisted of 14 occupational therapists in psychiatric care. The answers from the first and second rounds illustrate the wide variation in their practice. The third round points out consensus and disagreements in the domains: professional role, theories in practice, domain of concern, occupational therapy assessment, goal setting/treatment, outcome/evaluation and thoughts about the future. A consensus was reached in all domains, but not regarding competence to treat functional reduction and symptoms, or on the importance of theories for documentation, the choice of a theoretical foundation, and the importance of an evidence-based treatment model, although the theories were seen as supporting practice. Disagreements were found as to the effectiveness of repeated assessments as a means of evaluation. The future for OTs within psychiatric care was looked upon as positive. DISCUSSION: The results developed from providing a relatively unclear and shallow perspective on OT practice to indicating a depth that shows what occupational therapy within psychiatry can be. During the process it became more and more clear how OTs think and act.

Adult↗
PubMedDate not supplied

The sudden infant death syndrome and infant botulism.

Fecal and serum specimens taken from 30 cases of sudden infant death and from eight cases of nonsudden infant death that were diagnosed at a single facility in King County, Wash., were examined for the presence of Clostridium botulinum organisms and toxin. Organisms, but not toxin, were recovered from a fecal specimen in one case of sudden infant death, results that parallel those from studies previously reported by investigators in California. Studies made in our laboratory of a nonfatal case of infant botulism revealed that an estimated 366,000 mouse minimal lethal doses of toxin were excreted in feces collected by purging the infant. Organisms and toxin were excreted for at least 15 days after the infant was hospitalized. Observations made in our laboratory of atypical responses in mice to both fecal and serum extracts, coupled with recently described experiments in which mice were used as an animal model for infant botulism in humans, provide a biologically plausible foundation for the hypothesis that C. botulinum may be implicated etiologically in some sudden infant deaths. Additional microbiologic, physiologic, and toxicologic data are needed to adequately test this hypothesis.

Botulinum Toxins↗
PubMed2004

[New forms of management and their impact on health inequalities].

In recent years in Spain the system of health foundations has been favoured among the so-called new ways of management, as a mechanism to increase the efficiency of public health centers. The purpose of our research is to compare the running of health foundations with hospitals managed in the traditional way who attend a population with similar characteristics. From the comparison between the two types of centers it has been deduced that foundations have less staff in all the categories (doctors, nurses, etc.), and offer fewer beds and operating theatres/1000 inhabitants. The numbers of admissions, surgical operations, emergencies services, and medical consultations/1000 inhabitants are all lower in the foundations, although only the latter case has statistical significance. Also, waiting lists for surgery are longer, and expenditure/1000 inhabitants per year is lower, in both cases statistically significant. From all this it has been deduced that the foundations spend less per inhabitant because they offer fewer health services to the reference population, something which creates access problems and is a source of inequality. The foundations exhibit a notable lack of transparency, which has limited the variables available for study and has made it difficult to carry out an investigation of quality between the two models.

Female↗
PubMed2001

Surgery for pediatric subglottic stenosis: disease-specific outcomes.

To set the foundation to develop a disease-based, operation-specific model to predict the outcome of pediatric airway reconstruction surgery, we performed a retrospective database review of children operated on at a single, tertiary-care children's hospital. Over the 12-year period 1988 to 2000, a total of 1,296 airway reconstruction procedures were performed. Out of these, charts were identified for 199 children who underwent laryngotracheal reconstruction for a sole diagnosis of subglottic stenosis. Children were excluded from the study if their disorder included supraglottic, glottic, or upper tracheal disease. The main outcome measures were Myer-Cotton grade-specific decannulation and extubation rates, including both operation-specific and overall results. There were 101 children who underwent double-stage laryngotracheal reconstruction. The operation-specific decannulation rates for Myer-Cotton grades 2, 3, and 4 were 85% (18/21), 37% (23/61), and 50% (7/14) (chi2 analysis, p = .0007). The overall decannulation rates were 95% (20/21), 74% (45/61), and 86% (12/14) (chi2 analysis, p = .04). There were 98 children who underwent single-stage laryngotracheal reconstruction. The operation-specific extubation rates for Myer-Cotton grades 2, 3, and 4 were 82% (37/45), 79% (34/43), and 67% (2/3) (chi2 analysis, p = .63). The overall extubation rates were 100% (45/45), 86% (37/43), and 100% (3/3) (chi2 analysis, p = .03). Logistic regression analysis showed no effect of age (less than or greater than 2 years of age) on operation-specific or overall outcome parameters. We conclude that laryngotracheal reconstruction for pediatric subglottic stenosis remains a challenging set of procedures in which multiple operations may be required to achieve eventual extubation or decannulation. Children with Myer-Cotton grade 3 or 4 disease continue to represent a significant challenge, and refinements of techniques are being examined to address this subset of children. Disease-based, operation-specific outcome statistics are the first step in the development of a meaningful predictive model.

Adolescent↗
PubMed2006

Transforming the curriculum through the intergenerational lens.

Our society is aging at a rapid rate and with this trend comes many of the social and economic demands that the profession of Social Work addresses. Akey dilemma of the profession is how to interest and educate undergraduate social work students in aging and gerontology so that the needs of elderly can be supported. Social Work students notoriously are primarily interested in working with children and adolescents. With the support of the John A. Hartford Foundation's Geriatric Enrichment in Social Work Education grant, the authors developed a Spiral Perspective to infuse intergenerational content into the curriculum of their department and to give students exposure to geriatric content throughout their educational experience.

Aged↗
PubMed2003

Natural killer T cells as targets for therapeutic intervention in autoimmune diseases.

Natural killer T (NKT) cells are a subset of lymphocytes that express receptors characteristic of conventional T cells together with receptors typically found on natural killer cells. A key feature of NKT cells is the expression of a semi-invariant T cell receptor that is specific for glycolipid antigens presented by the unusual major histocompatibility complex class I-like molecule CD1d. While their precise immunological functions remain unknown, NKT cells have been implicated in the regulation of adaptive immune responses, including those directed against autoantigens. These findings raise the possibility that specific stimulation of NKT cells may be exploited for therapeutic purposes. A number of laboratories have tested this hypothesis, utilizing the sea sponge-derived agent alpha-galactosylceramide (alpha-GalCer), a specific agonist of NKT cells. Administration of alpha-GalCer to mice results in potent activation of NKT cells, rapid and robust cytokine production, and activation of a variety of cells of the innate and adaptive immune systems. Most notably, repeated administration of alpha-GalCer to mice favors the generation of conventional T lymphocytes producing T helper (Th) type 2 cytokines such as IL-4 and IL-10. These findings suggest that alpha-GalCer can modulate inflammatory conditions that are mediated by pathogenic Th1 cells. Indeed, recent studies have demonstrated that alpha-GalCer prevents the development of Type 1 diabetes in non-obese diabetic mice and central nervous system inflammation in mouse models of multiple sclerosis. Collectively, these studies provide a solid foundation for the development of NKT cell ligands as pharmacological agents for treatment of autoimmune diseases.

Animals↗
PubMed1995

Genetics of the interval from weaning to estrus in first-litter sows: distribution of data, direct response of selection, and heritability.

A selection experiment with a selection and a control line maintained for eight generations was set up to study efficacy of selection for a short interval from weaning to estrus after weaning the first litter and to estimate genetic variation in the Dutch Landrace population. Intervals were recorded without truncation (i.e., intervals up to 234 d were observed). A mating scheme with 10 mating groups was used to avoid inbreeding. Distribution of intervals from weaning to estrus was described by a mixture of a normal and an exponential distribution. Between lines, both underlying distributions were similar, but the contribution to the total distribution was different. From generation 4 onward, intervals were significantly shorter in the selection line than in the control line. Variances within lines, generations, and mating groups varied to a large extent. Response per unit selection differential was calculated for original data and three sets of transformed data, both with and without correction for unequal subclass numbers. Standardized responses were more precise and linear, when data were log-transformed, and when corrected for unequal subclass numbers. The assumed best estimate of the realized heritability was .17. The heritability in the foundation population was estimated at .36 +/- .05, using an animal model including all genetic relationships in the data. It was concluded that genetic selection decreases the average interval from weaning to estrus by reducing the number of sows with a record in the exponential part of the distribution.

Algorithms↗
PubMed2026

Prophage landscapes in clinical MRSA: safety profiling and discovery of Lys81, a broad-spectrum bacteriolytic enzyme.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat to global healthcare, requiring novel therapeutic strategies. Prophages, latent phage genomes integrated into bacterial chromosomes, are important resources for antimicrobial development due to their genomic stability and genetic engineering potential. METHODS: In this study, we performed genomewide sequencing on 329 MRSA isolates to predict prophage sequences, followed by analyses of these prophages-including examinations of virulence genes, antibiotic resistance genes, homologous proteins of pathogenic MRSA phages, and functional predictions of these homologous proteins-to evaluate their safety and value as genetic engineering scaffolds and to screen for novel broadspectrum bacteriolytic enzymes. RESULTS: Our data indicate that 85.7% (282/329) of strains carried complete prophage sequences; 64 strains lacked virulence factors or genes, meeting the core criteria for safe vectors. Resistance screening found only 6 prophages carried msrA, confirming the biosafety of the remaining strains. A significant correlation existed between prophage virulence gene capacity and genomic structure (R2 = 0.99986684, p = 3.64e-69). High-virulence clusters (>10 factors) showed high structural similarity; 10 characteristic sequences linked to S. aureus phages and their prevalence patterns were identified via conserved motif analysis. Collinearity analysis with reference to virulent MRSA phages and 3D structural predictions of orthologous proteins identified two lysozymes and a host-recognition device. Notably, Lys81, an N-acetylmuramoyl-L-alanine amidase ortholog, was prioritized and characterized as a broad-spectrum lytic enzyme. Our data show Lys81 has key properties: (1) Broad-spectrum antibacterial activity, lysing 52.3% (23/44) of clinical S. aureus strains and cross-acting against Gram-positive bacteria such as Pseudomonas aeruginosa and Listeria; (2) Excellent environmental adaptability, maintaining activity at pH 5.0 and 0°C, with 25 mM Na+ and Ca2 + enhancing function; (3) Potent biofilm clearance, achieving 83% MRSA biofilm reduction at 50 μg/mL; and (4) Favorable in vivo safety/efficacy, eradicating MRSA infections in lung organoid models with minimal cytotoxicity. DISCUSSION: This study establishes a theoretical foundation for the clinical translation of MRSA prophages, positioning Lys81 as a novel candidate for treating drug-resistant bacterial infections.

Lys81↗
PubMed1999

Heritability of recurrent exertional rhabdomyolysis in Thoroughbred racehorses.

OBJECTIVE: To determine the likely mode of inheritance and identify probable foundation horses for recurrent exertional rhabdomyolysis (RER) in Thoroughbred (TB) racehorses. ANIMALS: 4 families of TB racehorses with a high prevalence of RER, consisting of 3 to 53 horses/family, were used to determine mode of inheritance. Sixty-two TB horses with RER and 34 control TB racehorses without RER were used to identify probable foundation horses for the RER trait. PROCEDURE: RER was diagnosed by a veterinarian and verified by detecting high serum creatine kinase activity. Pedigrees dating from 1930 for all horses were entered into a database. Pedigrees of horses in 4 families were visually inspected for a pattern of inheritance and used for calculation of foundation horse contributions and inbreeding coefficients. The Markov chain Monte Carlo technique was used to analyze pedigrees of the 62 affected and 34 control horses for the conditional probability of foundation genotypes. A dominant mode of inheritance with variable expression model was used. RESULTS: Pedigree analysis supported an autosomal dominant mode of inheritance with variable expression. All affected horses from the 4 families shared a common ancestor. This ancestor and 5 other stallions had a conditional probability of 1.00 for being affected. All 6 stallions shared a common male ancestor within 3 to 5 generations. CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of this study, the RER trait has been in TB racehorses for more than 70 years and may be inherited as an autosomal dominant trait with variable expression.

Alleles↗
PubMed1990

Influencing decision-making of referring physicians.

As marketing budgets for physician liaison departments increase, health care marketers are being held more accountable for their efforts by managers. Market researchers at The Cleveland Clinic Foundation (CCF) have developed a health care organizational information dissemination model that provides an understanding of how referring physicians choose a referral center for their patients. Interviews with 89 new referring physicians show patient influence and interpersonal media to be the two most influential channels of information. Financial analysis of referrals shows that a true physician referral generates significantly more revenue than a patient-influenced referral. CCF managers and marketers have used the data to understand better the effectiveness of their current programs targeted at physicians.

Decision Making↗
PubMed1985

An analysis of proposed nonprofit to for-profit conversion sales.

Not-for-profit hospitals are increasingly considering the sale or long-term lease of assets to for-profit chains as a proactive response to anticipated future operating conditions. Analyzed here are two simplified examples, one a proposed sale and the other a lease option. They provide the basis for determining whether the hospital's current commitment to charity and community service will be met in the future

Charities↗