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There is little information available about the characteristics of patients admitted to geriatric units with high and low turnover rates of patients. It is often suggested that high turnover units do not admit the more physically disabled person. This study set out to investigate whether this view is true. Six geriatric units with different patient discharge rates were investigated. Those units with a high turnover of patients tend to admit more severely immobile people per bed, when compared to those units with below average throughput. Although these immobile people admitted to high turnover units suffered a higher mortality rate, a significantly greater proportion regained the ability to transfer themselves independently from bed to chair and to the toilet. [ABSTRACT FROM PUBLISHER]

Macrophages are specialized phagocytes that play central roles in immunity and tissue repair. Their diverse functionalities have led to an evolution of new allogenic and autologous macrophage products. However, realizing the full therapeutic potential of these cell-based therapies requires development of imaging technologies that can track immune cell migration within tissues in real-time. Such innovations will not only inform treatment regimens and empower interpretation of therapeutic outcomes but also enable prediction and early intervention during adverse events. Here, phase-changing nanoemulsion contrast agents are reported that permit real-time, continuous, and high-fidelity ultrasound imaging of macrophages in situ. Using a de novo designed peptide emulsifier, liquid perfluorocarbon nanoemulsions are prepared and show that rational control over interfacial peptide assembly affords formulations with tunable acoustic sensitivity, macrophage internalization, and in cellulo stability. Imaging experiments demonstrate that emulsion-loaded macrophages can be readily visualized using standard diagnostic B-mode and Doppler ultrasound modalities. This allows on-demand and long-term tracking of macrophages within porcine coronary arteries, as an exemplary model. The results demonstrate that this platform is poised to open new opportunities for non-invasive, contrast-enhanced imaging of cell-based immunotherapies in tissues, while leveraging the low-cost, portable, and safe nature of diagnostic ultrasound., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

Numerical skills are part of cognitive and formal education development, and low performance in math has been associated with adverse features such as low income and unemployment. The studies of functional magnetic resonance imaging (fMRI) activation in numerical Stroop interference had been accomplished to evidence neural correlates of numerical, automatic, and controlled processes. The aim of this research was to summarize the results of the neural correlates of a number-size congruity task through meta-analysis of fMRI, behavioral evidence, and connectometry. Our study includes 15 fMRI papers (total number of subjects n=155-302, the total number of foci=81-233). Meta-analyses used an activation likelihood estimation (ALE) logarithm. For connectometry, it was used the diffusion tensor image. We found that, for the attentional control numerical Stroop effect, the activated areas were the dorsolateral prefrontal cortex, the anterior cingulate gyrus, and the intraparietal sulcus. Consistent activation over both paradigms was found in five clusters, two in the frontal and three in the parietal lobe. The matrix of connectivity showed connections between insula and inferior parietal right with 587 fibers, cingulate gyrus, and inferior parietal right with 843 fibers. Both paradigms activate parietal areas but differ in the activation of regions correlated to attentional control. The results of these meta-analyses summarized results from fMRI studies that may contribute to current theories. The results of connectometry could be interpreted regarding the fibers connection between the clusters right inferior parietal with insula and cingulate gyrus that suggests the integration of information., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Family health history (FHH) is a data type serving risk assessment, diagnosis, research, and preventive health. Despite technological leaps in genomic variant detection, FHH remains the most accessible, least expensive, and most practical assessment tool for assessing risks attributable to genetic inheritance. The purpose of this manuscript is to outline a process to assist primary care professionals in choosing FHH digital tools for patient care based on the new ISO/TS 82304-2 Technical Specification (TS), which is a recently developed method to determine eHealth app quality. With a focus on eHealth in primary care, we applied the quality label concept to FHH, and how a primary care physician can quickly review the quality and reliability of an FHH app. Based on our review of the ISO TS's 81 questions, we compiled a list of 25 questions that are recommended to be more succinct as an initial review. We call this process the FHH Quick App Review. Our 'informative-only' 25 questions do not produce a quality score, but a guide to complete an initial review of FHH apps. Most of the questions are straight from the ISO TS, some are modified or de novo. We believe the 25 questions are not only relevant to FHH app reviews but could also serve to aid app development and clinical implementation.

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits.

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage 1-7 . The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis 8 . Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1 D325A mutant mouse strain. Whereas Ripk1 -/- mice died postnatally from systemic inflammation, Ripk1 D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1 D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1 D325A/D325A and Ripk1 D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1 D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.

In this study we developed a Fast Healthcare Interoperability Resources (FHIR) profile to support exchanging a full pedigree based family health history (FHH) information across multiple systems and applications used by clinicians, patients, and researchers. We used previously developed clinical element models (CEMs) that are capable of representing the FHH information, and derived essential data elements including attributes, constraints, and value sets. We analyzed gaps between the FHH CEM elements and existing FHIR resources. Based on the analysis, we developed a profile that consists of 1) FHIR resources for essential FHH data elements, 2) extensions for additional elements that were not covered by the resources, and 3) a structured definition to integrate patient and family member information in a FHIR message. We implemented the profile using an open-source based FHIR framework and validated it using patient-entered FHH data that was captured through a locally developed FHH tool.

Objective: To identify the cause of disease in an adult patient presenting with recent-onset fevers, chills, urticaria, fatigue, and profound myalgia, who was found to be negative for cryopyrin-associated periodic syndrome (CAPS) NLRP3 mutations by conventional Sanger DNA sequencing., Methods: We performed whole-exome sequencing and targeted deep sequencing using DNA from the patient's whole blood to identify a possible NLRP3 somatic mutation. We then screened for this mutation in subcloned NLRP3 amplicons from fibroblasts, buccal cells, granulocytes, negatively selected monocytes, and T and B lymphocytes and further confirmed the somatic mutation by targeted sequencing of exon 3., Results: We identified a previously reported CAPS-associated mutation, p.Tyr570Cys, with a mutant allele frequency of 15% based on exome data. Targeted sequencing and subcloning of NLRP3 amplicons confirmed the presence of the somatic mutation in whole blood at a ratio similar to the exome data. The mutant allele frequency was in the range of 13.3-16.8% in monocytes and 15.2-18% in granulocytes. Notably, this mutation was either absent or present at a very low frequency in B and T lymphocytes, in buccal cells, and in the patient's cultured fibroblasts., Conclusion: Our findings indicate the possibility of myeloid-restricted somatic mosaicism in the pathogenesis of CAPS, underscoring the emerging role of massively parallel sequencing in clinical diagnosis., (Published 2015. This article is a U.S. Government work and is in the public domain in the USA.)

Background: We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood., Methods: We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells., Results: All nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia - phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers., Conclusions: Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.).

Community-acquired Staphylococcus aureus infections are a public health concern, yet little is known about infections that do not present to hospital. We identified community-onset S. aureus infections via specimens submitted to a community-based pathology service. Referring doctors confirmed eligibility and described infection site, severity and treatment. Isolates were characterized on antibiotic resistance, PFGE, MLST/SCCmec, and Panton-Valentine leukocidin (PVL), representing 106 community-onset infections; 34 non-multiresistant methicillin-resistant S. aureus (nmMRSA) (resistant to <3 non-β-lactam antibiotics), 15 multiply antibiotic-resistant MRSA (mMRSA) and 57 methicillin-sensitive S. aureus (MSSA). Most (93%) were skin and soft tissue infections. PVL genes were carried by 42% of nmMRSA isolates [95% confidence interval (CI) 26-61] and 15% of MSSA (95% CI 8-28). PVL was associated with infections of the trunk, head or neck (56·4% vs. 24·3%, P=0·005) in younger patients (23 vs. 52 years, P<0·001), and with boils or abscesses (OR 8·67, 95% CI 2·9-26·2), suggesting underlying differences in exposure and/or pathogenesis.

Health care has become increasingly information intensive. The advent of genomic data, integrated into patient care, significantly accelerates the complexity and amount of clinical data. Translational research in the present day increasingly embraces new biomedical discovery in this data-intensive world, thus entering the domain of "big data." The Electronic Medical Records and Genomics consortium has taught us many lessons, while simultaneously advances in commodity computing methods enable the academic community to affordably manage and process big data. Although great promise can emerge from the adoption of big data methods and philosophy, the heterogeneity and complexity of clinical data, in particular, pose additional challenges for big data inferencing and clinical application. However, the ultimate comparability and consistency of heterogeneous clinical information sources can be enhanced by existing and emerging data standards, which promise to bring order to clinical data chaos. Meaningful Use data standards in particular have already simplified the task of identifying clinical phenotyping patterns in electronic health records.

Individuals with Behçet's disease suffer from episodic inflammation often affecting the orogenital mucosa, skin and eyes. To discover new susceptibility loci for Behçet's disease, we performed a genome-wide association study (GWAS) of 779,465 SNPs with imputed genotypes in 1,209 Turkish individuals with Behçet's disease and 1,278 controls. We identified new associations at CCR1, STAT4 and KLRC4. Additionally, two SNPs in ERAP1, encoding ERAP1 p.Asp575Asn and p.Arg725Gln alterations, recessively conferred disease risk. These findings were replicated in 1,468 independent Turkish and/or 1,352 Japanese samples (combined meta-analysis P < 2 × 10(-9)). We also found evidence for interaction between HLA-B*51 and ERAP1 (P = 9 × 10(-4)). The CCR1 and STAT4 variants were associated with gene expression differences. Three risk loci shared with ankylosing spondylitis and psoriasis (the MHC class I region, ERAP1 and IL23R and the MHC class I-ERAP1 interaction), as well as two loci shared with inflammatory bowel disease (IL23R and IL10) implicate shared pathogenic pathways in the spondyloarthritides and Behçet's disease.

Aims: Inducible resistance to clindamycin in Staphylococcus aureus is common but not easily identified by routine testing, and can result in treatment failure if not detected. The gold standard method is the D-test described by the Clinical and Laboratory Standards Institute (CLSI). The Vitek-2 AST-P612 card contains an 'inducible clindamycin resistance' (ICR) test. We aimed to determine the accuracy of the Vitek-2 ICR test compared to the D-test., Methods: Isolates of erythromycin non-susceptible, clindamycin susceptible Staphylococcus aureus were identified. Routine antimicrobial susceptibility testing was performed using the Vitek-2 AST-P612 card, including the ICR test, and compared against the D-test., Results: 217 isolates were obtained. All of the 191 isolates that were ICR positive were D-test positive. Of the 27 ICR negative isolates, 10 (37%) were D-test positive [9 methicillin-sensitive S. aureus (MSSA), 1 methicillin-resistant S. aureus (MRSA)]. This correlates with a specificity of 100%, sensitivity of 95%, positive predictive value of 100%, and negative predictive value of 72%., Conclusions: The ICR test is reliable in the presence of a positive result; however there is a false negative rate of approximately one in four. This will lead to susceptibility reporting errors, with potentially serious clinical implications. A negative ICR should be confirmed by CLSI D-test before reporting clindamycin as susceptible where the organism is not susceptible to erythromycin.

Objective: To determine if atopic disease is associated with infantile hemangioma., Study Design: Case control study., Setting: State of Utah inpatient and outpatient records obtained from the Department of Health, Intermountain Healthcare medical records, and the University of Utah Health Care medical records using the Utah Population Database., Subjects: Patients given an International Classification of Diseases, Ninth Revision diagnosis of hemangioma prior to age 5 years, from 1991 to 2009., Methods: Allergy, asthma, and eczema rates in the hemangioma cohort compared to randomly matched controls using logistic regression analysis., Results: The authors identified 2063 patients in the hemangioma group. The overall odds ratio of atopic disease in patients diagnosed with hemangioma was 1.67 compared to the control group (P < .0001). In the hemangioma cohort, the authors found a 36% increased risk of allergies (P < .0001), 67% increased risk of asthma (P < 4e-12), and 82% increased risk of eczema (P < 2e-16)., Conclusion: This study indicates that allergy, asthma, and eczema are positively associated with hemangioma. Eczema was most strongly associated with hemangioma, with a nearly 2-fold increased risk. Understanding the relationship between atopic disease and infantile hemangioma may elucidate the pathophysiology of each and ultimately lead to better treatment options.

Objectives: To assess the degree of relationship among individuals with hemangiomas and to evaluate the relative risk (RR) for family members of individuals with hemangiomas., Design: Retrospective case-control study., Setting: Utah Population Database., Participants: Data sets of individuals of different ages with International Classification of Diseases, Ninth Revision (ICD-9) codes for hemangiomas were created from sources having medical records linked to the Utah Population Database. Controls were selected who matched cases for sex, birth year, and birthplace inside vs outside of Utah. Ten controls were selected per case, and sampling was performed without replacement. Kinship analysis tools were used to identify pedigrees having excess individuals with hemangiomas., Main Outcome Measure: Using conditional logistic regression analysis, RR for hemangiomas among several kinship classes was determined., Results: Identified were 2514 distinct cases 12 years or younger with ICD-9 code 228.01, and the RR for sibs in this group was significantly increased (RR, 2.52; P < .001). Seventy-three founder families had 5 or more affected descendants with cluster P values ≤ .01; familial standardized incidence ratios ranged from 1.64 to 9.50. Family sizes ranged from 546 to 22 291 descendants., Conclusions: Sibs have increased RR for infantile hemangiomas, suggesting a potential genetic contribution to this likely multifactorial disease. Identification of large families with distantly related individuals will be helpful for future shared segment identification analyses.

The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4(+)/CD25(+) T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4(+)/HLA-DR(+) T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker.

Personalized medicine will require detailed clinical patient profiles, and a particular focus on capturing data that is useful in forecasting risk. A detailed family health history is considered a critical component of these profiles, insomuch that it has been coined as 'the best genetic test available'. Despite this, tools aimed at capturing this information for use in electronic health records have been characterized as inadequate. In this manuscript we detail the creation of a patient-facing family health history tool known as OurFamilyHealth, whose long-term emphasis is to facilitate risk assessment and clinical decision support. We present the rationale for such a tool, describe its development and release as a component of Intermountain Healthcare's patient portal, and detail early usage statistics surrounding the application. Data derived from the tool since its release are also compared against family history charting patterns in Intermountain's electronic health records, revealing differences in data availability.

The family health history has long been recognized as an effective way of understanding individuals' susceptibility to familial disease; yet electronic tools to support the capture and use of these data have been characterized as inadequate. As part of an ongoing effort to build patient-facing tools for entering detailed family health histories, we have compiled a set of concepts specific to familial disease using multi-source sampling. These concepts were abstracted by analyzing family health history data patterns in our enterprise data warehouse, collection patterns of consumer personal health records, analyses from the local state health department, a healthcare data dictionary, and concepts derived from genetic-oriented consumer education materials. Collectively, these sources yielded a set of more than 500 unique disease concepts, represented by more than 2500 synonyms for supporting patients in entering coded family health histories. We expect that these concepts will be useful in providing meaningful data and education resources for patients and providers alike.

Interactions among insect pests, crops and weeds are well recognised. In fact, the elimination of weed hosts outside of the crop is a common practice to control many insect-vectored viruses. However, little is known about interactions among insect pests, crops and native vegetation, and whether native plants may be used to revegetate areas where weed hosts have been eliminated as part of horticultural management regimes. We used the Northern Adelaide Plains horticultural region (South Australia, Australia) as a model system to study the potential of various plant taxa in hosting four pest thrips (three exotic, one native; Frankliniella occidentalis, F. schultzei, Thrips tabaci and T. imaginis) when located adjacent to, and distant from, horticultural crops. Flower funnels were used for standardised sampling of thrips on flowers from 19 exotic weed and 12 native plant species, representing 13 and three families, respectively. Flowers were sampled monthly over a year, and statistical analyses were performed to identify significant determinants of probability of thrips occurrence and density. Plant family was found to significantly influence both measures for each thrips species. In addition, crop proximity influenced the probability of occurrence for the two Frankliniella species (but only influenced density of the key pest F. occidentalis), and season influenced density of all four pest thrips. All native plant species tested had a low likelihood of hosting the three exotic thrips species. Overall, results suggest that judicious choice of surrounding vegetation has potential to be an important component of integrated pest management (IPM) while increasing biodiversity conservation.

Family history (FH) is an important risk factor for many diseases and its assessment can be a powerful tool for identifying and stratifying patients at risk. As part of an initiative to improve FH collection and decision support at Intermountain Healthcare we conducted a literature review on FH data collection and reviewed a number of current Web-based tools. An ideal list of features was produced to help implement goals of the initiative.

The German yellowjacket, Vespula germanica (F.) (Hymenoptera: Vespidae), was introduced into Australia in 1959 and has established throughout southern Australia. In urban environments, V. germanica is frequently a nuisance pest at public gatherings and to homeowners. In native environments, it has the potential to pose a threat to native invertebrates. The current practice for controlling the wasps is nest destruction with pesticide. However, locating the nest(s) is not always practical or possible. Meat baits impregnated with an insecticide that foraging wasps cut and carry back to the nest offer a means of suppressing wasps where the nest sites are unknown. The success of meat baits depends on the attractiveness and acceptance of the meat to the wasp and the mode of action of the insecticide. Our objective was to determine wasp preference and acceptance of five processed meats: canned chicken or fish and freeze-dried chicken, fish, or kangaroo. We found that more wasps visited and took freeze-dried kangaroo and canned chicken than the other baits. Canned and freeze-dried fish were similarly preferred, and freeze-dried chicken was the least attractive and accepted by foraging wasps. Our findings demonstrate that wasps prefer some processed meats and hence take more loads back to the nest. By combining a suitable insecticide with a meat bait preferred by wasps, the likelihood of effective suppression of nuisance wasp populations should be increased.

As the knowledge about the genetic factors associated with clinical conditions increases, access to information that can help practicing clinicians better understand these factors becomes essential for optimal care and communication with patients. We describe the implementation of 'infobuttons' from the problem list module of an electronic health record (EHR) to on-line genetic resources.

The objectives of this study were to estimate heritability of acetone concentration in milk, based on monthly samples of milk obtained as part of a routine milk testing program, and to evaluate the feasibility of using such data in a genetic evaluation program for selection against ketosis incidence. Milk samples were collected from January to December of 1999 in herds enrolled in the Ontario Dairy Herd Improvement Association, and acetone concentration was measured using an inline chemical procedure. The original data included more than 50,000 records. Because ketosis is generally a problem during early lactation, only the single test with the fewest days in milk was retained. In addition, data were retained only for cows with pedigree information. The final data set included 10,375 records. Among these data, only 6.56% had detectable levels of acetone. Acetone data were log-transformed prior to statistical analysis. Simple ANOVA indicated that herd, parity number, days in milk, and month of test had significant effects on acetone concentration. Acetone levels increased with lactation number and were higher in early lactation. Three approaches were applied for genetic analysis. First, REML was used with a simple linear animal model. Then, a separate procedure used data augmentation and Gibbs Sampling to obtain continuously distributed underlying values for records with zero acetone concentration, and these data were analyzed with both an animal and sire model. Heritability of acetone concentration was less than 1% for all 3 analyses. Herd effects accounted for about 5% of the phenotypic variance. Low estimates of heritability were due either to low actual levels of genetic variance or inability to detect all of the genetic variance present, due to infrequent recording during the early part of the lactation. Genetic evaluation based on recording of acetone concentration on a monthly basis seems of little use as a selection tool to decrease incidence of ketosis.

The objective of this study was to use field data collected by dairy herd improvement programs to estimate genetic parameters for concentrations of milk urea nitrogen (MUN). Edited data were 36,074 test-day records of MUN and yields of milk, fat, and protein obtained from 6102 cows in Holstein herds in Ontario, Canada. Data were divided into three sets, for the first three lactations. Two analyses were performed on data from each lactation. The first procedure used ANOVA to estimate the significance of the effects of several environmental factors on MUN. Herd-test-day effects had the most significant impact on MUN. Effects of stage of lactation were also important, and MUN levels tended to increase from the time of peak yield until the end of lactation. The second analysis used a random regression model to estimate heritabilities and genetic correlations of MUN and the yield traits. Heritability estimates for MUN in lactations one, two, and three were 0.44, 0.59, and 0.48, respectively. Heritabilities for the yield traits were of a similar magnitude. Little relationship was observed between MUN and yield. Raw phenotypic correlations were all <0.10 (absolute value). Genetic correlations with production traits were close to zero in lactations one and three and only slightly positive in lactation two. The results indicate that selection on MUN is possible, but relationships between MUN and other economically important traits such as metabolic disease and fertility are needed.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory syndrome that results from mutations in TNFRSF1A, the gene that encodes the 55-kd tumor necrosis factor receptor. Clinically, patients present with recurrent episodes of fever in conjunction with localized inflammation at various sites. Myalgia is one of the most characteristic features of this syndrome and is frequently associated with an overlying erythematous, macular rash that, together with the myalgia, displays centrifugal migration. This has previously been believed to occur as a result of myositis. We describe herein the case of a 60-year-old man with TRAPS, in whom magnetic resonance imaging of the left thigh demonstrated edematous changes in the muscle compartments and surrounding soft tissues. A full-thickness wedge biopsy was performed, and hematoxylin and eosin staining and immunohistochemistry analysis of the specimen demonstrated normal myofibrils but a severely destructive monocytic fasciitis. These results suggest that the myalgia experienced by individuals with TRAPS is due to a monocytic fasciitis and not to myositis.

Background & Aims: Celiac disease and hereditary hemochromatosis are common HLA-defined conditions in northwestern Europe. We sought to determine whether there is a genetic relationship between the 2 diseases and if hemochromatosis susceptibility gene (HFE) mutations are protective against iron deficiency in celiac disease., Methods: Polymerase chain reaction amplification using sequence-specific primers capable of identifying the 2 HFE gene mutations (H63D and C282Y) and the HLA class I and II alleles was used to type 145 white patients with celiac disease and 187 matched controls. Hemoglobin and fasting serum iron levels in celiac patients were measured at diagnosis., Results: HFE gene mutations, H63D or C282Y, were identified in 70 celiac patients (48.3%) and 61 controls (32.6%) (P = 0.004). The C282Y mutation was associated with HLA-A*03 and B*07 alleles in controls and with A*01, A*03, B*08, and DRB1*0301 alleles in celiac patients; the H63D mutation was associated with HLA-A*25 and DRB1*03 alleles in controls and A*29 and DRB1*03 alleles in celiac patients. At diagnosis, celiac patients with the C282Y mutation had higher mean hemoglobin and fasting serum iron levels compared with the HFE wild type (P = 0.0002 and 0.006, respectively). This was not observed with the H63D mutation., Conclusions: In celiac disease, HFE gene mutations are common and are in linkage disequilibrium with different HLA alleles compared with controls. A disease-specific haplotype that carries C282Y and DQB1*02 is suggested. We propose that HFE gene mutations provide a survival advantage by ameliorating the iron deficiency seen in celiac patients.

In the last five years, the Web has changed the way information is disseminated, knowledge is gained, and health care is provided. Even though the health care industry has yet to fully realize the potential of the Internet, the Web is only the beginning. Several emerging technologies will be changing the rules again. With new forms of network connectivity and faster, new wireless technologies, the adoption rate of mobile, handheld computers in health care will grow feverishly. Intelligent, autonomous software agents that guide the patient through the continuum of care will extend the reach of health care providers to all places at all times. The author discusses these new concepts, how they might be applied in health care, and the doctor-patient health care transaction.

Information is the lifeblood of the health care organization. In the past, chief information officers were responsible for nothing else but assuring a constant flow of information. Today, they are being asked to do a great deal more. From E-business to E-health strategy, the chief information officer is the focal point of an organization's ability to leverage new technology.

Case reports of transdiaphragmatic fistulas connecting subphrenic collections and empyemas are uncommon. We report the rare complication of a fistulous connection between a subphrenic collection and the bronchial tree.

The location of the active site of membrane-bound activated protein C (APC) relative to the phospholipid surface was determined both in the presence and absence of its cofactor, protein S, using fluorescence resonance energy transfer (FRET). APC was chemically modified to create the FRET donor species, Fl-FPR-APC, with a fluorescein dye (Fl) covalently attached to the active site via a D-Phe-Pro-Arg (FPR) tether and located in the active site near S4. FRET was observed when Fl-FPR-APC was titrated in the presence of Ca2+ ions with phosphatidylcholine/phosphatidylserine (4:1) vesicles containing the FRET acceptor, octadecylrhodamine (OR). Assuming a random orientation of transition dipoles (kappa2 = 2/3), the average distance of closest approach between the fluorescein in the active site of the membrane-bound APC and the OR at the membrane surface is 94 A. The same calcium-dependent distance was obtained for both small and large unilamellar vesicles and for vesicles that contained phosphatidylethanolamine. The active site of membrane-bound APC is therefore located far above the phospholipid surface. Upon addition of protein S, the efficiency of Fl-FPR-APC to OR energy transfer increased due to a protein S-dependent rotational and/or translational movement of the APC protease domain relative to the surface. If this movement were solely translational, then the average height of the fluorescein in the membrane-bound APC.protein S complex would be 84 A above the surface. The extent of Fl-FPR-APC to OR energy transfer was unaltered by the addition of thrombin-inactivated protein S. The protein S effect was also specific for APC, since the addition of protein S to similarly-labeled derivatives of factor Xa, factor IXa, or factor VIIa did not alter the locations of their active sites. This direct measurement demonstrates that the binding of the protein S cofactor to its cognate enzyme elicits a relocation of the active site of APC relative to the membrane surface and thereby provides a structural explanation for the recently observed protein S-dependent change in the site of factor Va cleavage by APC.

The preparation of two wheat reference materials and the certification of their ochratoxin A content is described. The materials were prepared and certified within the European Commission. Measurements and Testing Programme (M&T). The first and second phases of this project, two intercomparisons of procedures for the determination of ochratoxin A in wheat, at levels of approximately 13 micrograms/kg, and 7 micrograms/kg, respectively have already been reported. This paper describes the work carried out in certification of the ochratoxin A content (mass fraction) of two wheat reference materials: a blank wheat CRM 471, and a contaminated wheat, CRM 472. These materials were prepared for use in the second intercomparison referred to above and reported previously. Reference material CRM 472 was prepared from naturally-contaminated wheat blended with the blank wheat (CRM 471). Details are given of the milling, blending and packaging procedure, and the checks to ensure homogeneity and stability of the material. The certification exercise was carried out by 15 laboratories using a variety of extraction and clean-up procedures, and the certified ochratoxin A content (mass fraction) of CRM 471 was < 0.6 microgram/kg. The value for CRM 472 was 8.2 micrograms/kg with an uncertainty of 1.0 microgram/kg.

The European Commission, Measurements and Testing Programme (BCR) has undertaken a project to improve methodology and to prepare certified reference materials for ochratoxin A determination. The first phase of this project, an intercomparison of procedures for the determination of ochratoxin A in wheat, at a content of approximately 13 micrograms/kg, has already been reported. The second intercomparison study, described in this paper, involved 26 European laboratories, from 11 countries, which analysed wheat naturally contaminated at a level of approximately 7 micrograms/kg, and a 'blank' wheat sample (ochratoxin A content < 0.2 microgram/kg). The participants used a variety of procedures which involved different extraction solvents and clean-up procedures. All laboratories used HPLC as the determinative step. Some laboratories also used immunoaffinity column clean-up in comparison with their normal method. Recoveries of the normal methods used by laboratories ranged from 58 to 114%; only three laboratories obtained recoveries outside the accepted range of 70 to 110%. Recoveries of the immunoaffinity column methods, using two sources of column, ranged from 58 to 114% for one and from 4 to 86% for the other. The between-laboratory reproducibility coefficient of variation for all results was 34% for the normal methods, and 34 and 42% for the two types of immunoaffinity columns. It was noted that, after the results were corrected for spike recovery, some laboratories became outliers owing to low spike recoveries. Further investigations of the spiking protocols used by each laboratory showed that the time left for evaporation of the spiking solvent was crucial to the recovery obtained.

We prospectively studied the pathogenic significance of Moraxella (Branhamella) catarrhalis isolated from 212 patients of community practitioners in Australia. This organism was most commonly isolated during winter and early spring, and 92% of isolates were beta-lactamase producers. On the basis of predetermined clinical and microbiological criteria, 42% of the isolates were definitely pathogenic, 7% were probably pathogenic, 21% were of indeterminate pathogenicity, and 30% were nonpathogenic. Factors associated with pathogenic significance included pneumonia or bronchitis (87% of patients), predisposing respiratory or systemic conditions (62%), isolation from sputum, and pure isolation. Thirty-six percent of patients were < 5 years old, but only 9% of isolates from these patients were pathogenic or probably pathogenic, a finding that reflects the fact that nasal-swab and nasopharyngeal-aspirate sampling is a common practice. Isolates from older patients were more likely to be pathogenically significant. An assessment of the pathogenic significance of M. catarrhalis isolated from a patient in a community practice should take into consideration factors such as the patient's age, clinical illness, and underlying conditions; the presence of other organisms; and the source of the isolate.

Reliable analytical procedures and certified reference materials are essential for the establishment and enforcement of tolerance levels for ochratoxin A in foods. The inadequacy of analytical procedures, together with the need for certified reference materials, led the Commission of the European Communities Community Bureau of Reference (BCR) to undertake a project to prepare suitable reference materials for ochratoxin A in wheat, in order to improve methodology and to harmonise agreement of results between member states. The first intercomparison study indicated problems in the analysis due to the influence of co-extractives in the matrix, and demonstrated that further work was necessary to improve recovery, clean-up and reproducibility. The second intercomparison study, in the EC Measurements and Testing Programme, correlated the performance of the different methods for ochratoxin A measurement in a separate batch of contaminated wheat, and compared novel immunoaffinity column methods with the standard laboratory methods. Results were obtained from 26 laboratories within 11 European countries, which therefore gives a good representation of the scope of methods currently used in Europe. Considerable improvements in the determination of ochratoxin A were noted compared with the first intercomparison study.

This report describes T cell lines derived from a patient with subacute cutaneous lupus after treatment with intravenous pulse cyclophosphamide. We selected for mitotically active, hypoxanthine-guanine phosphoribosyltransferase-deficient (HPRT-) T cells, by culture in a selective medium containing 6-thioguanine. When HPRT- cell lines were derived 6 days after pulse cyclophosphamide (CYC) treatment, they were predominantly CD8+ and T cell receptor (TCR) gamma/delta+, producing interferon-gamma (IFN gamma). Cell lines derived 21 days after CYC treatment were CD4+, TCR alpha/beta+ and produced both IFN gamma and interleukin-4. These results support a possible role for gamma/delta+ T cells in subacute cutaneous lupus and suggest a mechanism for the therapeutic effect of CYC.

The Commission of the European Communities' Community Bureau of Reference (BCR) has undertaken a project to improve methodology and to prepare suitable certified reference materials in order to provide a basis for analytical quality control for the determination of ochratoxin A. The first phase of the project, an intercomparison of procedures for the determination of ochratoxin A in wheat at a level of approximately 13 micrograms/kg, is described. The study involved 24 European laboratories which analysed a naturally contaminated wheat and a 'blank' wheat sample (ochratoxin A content < 1 microgram/kg). The participants used a variety of procedures, including chloroform, methanol, toluene and ethyl acetate for extraction, and silica-, reversed phase- and immunoaffinity columns for clean-up. HPLC (one laboratory used TLC) was applied as the determinative step. Several performance characteristics were checked and the ochratoxin A content was determined. Recoveries were found to range from 25 to 100%. The coefficient of variation from all the results calculated on the basis of peak height was 23%. The study showed that the variation of results was influenced more by the clean-up step than by the extraction solvent. Some laboratories suffered significant day-to-day effects while others found difficulties with interfering peaks in the 'blank' material. It is planned for the next study to improve the recovery range, the clean-up step and the reproducibility (within-laboratory, between-days) and to check the influence of co-extractives from the matrix.

We report on 17 Australian cases of human infection or colonization with Scedosporium inflatum. The spectrum of clinical manifestations was similar to that in infection caused by Scedosporium apiospermum. The patients were classified into three groups. Four immunocompetent patients who presented with localized infections of a joint, nail bed, eye, or sphenoidal sinus made up the first group. Our first case, in a boy with posttraumatic septic arthritis, responded to surgical drainage with amphotericin B followed by treatment with itraconazole. The other three cases were cured by surgery alone. The second group consisted of five immunocompromised patients who presented with disseminated infections in a variety of sites. Four of these patients did not respond to antifungal therapy and died. The fifth apparently responded to antifungal drugs after correction of his neutropenia. The third group included eight patients with asymptomatic colonization in the external ear (five cases) or respiratory secretions (three cases). The nine isolates of S. inflatum tested by both disk and agar dilution methods were resistant to antifungal drugs. In our first case, which responded clinically to itraconazole, the MIC of this drug for the fungal isolate was 25 micrograms/mL. Thus S. inflatum can cause a broad spectrum of human infections whose severity and prognosis depend largely on the host's immune status.

Previous studies have demonstrated that NZB marrow can transfer features of autoimmunity. Therefore, we undertook a study of NZB marrow to determine whether it demonstrated any phenotypic abnormalities. In Whitlock-Witte cultures, NZB marrow cells generated nonadherent cells at low seeding densities, densities at which marrow from other strains did not generate nonadherent cells. In contrast, NZB marrow grew less well than controls in Dexter cultures. Inasmuch as the latter favor growth of granulocyte-macrophage precursors and the former B cells, these results suggest a possible skewing of NZB marrow cells toward lymphocyte production. Unfractionated marrow cells from NZB mice were found to produce 10-fold more splenic colonies in lethally irradiated recipients than marrow cells from control mice. This result was independent of the genotype of the recipient. When the progenitor Thy-1lo, Lin- marrow subpopulation was studied, NZB mice did not differ substantially from controls regarding splenic CFU. Therefore, Thy-1-, Lin- marrow cells were studied as a possible source of the excess splenic CFU in NZB mice. Indeed, the NZB Thy-1-, Lin- population contained 30-fold more splenic CFU than did the Thy-1-, Lin- population from control mice. These results suggest that NZB mice have unusual marrow progenitor cells; such cells may play a role in their autoimmune disease.

The finding of a positive hepatitis B core antibody (anti-HBc) in the absence of hepatitis B surface antigen (HBsAg) or hepatitis B surface antibody (anti-HBs) is relatively uncommon. This finding is known to occur during the 'window period' of acute hepatitis B between loss of HBsAg and the appearance of anti-HBs. It may also occur with active infection or following resolution. The aim of this study was to determine if response to hepatitis B vaccination would allow the separation of these subgroups of patients with isolated anti-HBc. Seventeen patients with persistent isolated core antibody were vaccinated and serum obtained at 2, 4 and 8 weeks. Results were compared with a seronegative control group. Six subjects (35%) but no control patients (p = 0.016) responded with a titre of greater than 50mIU/mL at two weeks, suggesting an anamnestic response due to prior infection and immunity. A further seven subjects (41%) finally seroconverted (anti-HBs titre greater than 10mIU/mL) thus excluding chronic infection and suggesting initial false positive results. Only two subjects did not respond to a full course of vaccination, but neither they nor any other subjects were positive for HBV DNA. These results indicate that hepatitis B vaccination and subsequent measurement of anti-HBs will identify evidence of past infection in the form of an anamnestic response in up to one third of the patients and will also exclude chronic infection on the grounds of a normal vaccine response in a majority of the remainder.

It has been shown that partial amino acid sequence homology between alpha gliadin and an early region protein (E1B-58 kDa) of adenovirus 12 results in immunological cross reaction. This led to the proposal that prior infection by adenovirus 12 could be associated with the development of coeliac disease. To examine this hypothesis, evidence was sought of persistent adenovirus 12 infection in the small intestinal mucosa of patients with coeliac disease. DNA isolated from biopsy samples from 24 control and 18 coeliac disease patients was analysed by the polymerase chain reaction for adenovirus 12 DNA encoding the E1B-58 kDa protein. Four of 18 coeliac disease and two of 24 control patients were positive. There is thus a low prevalence of this infection on both groups of patients but certainly no significantly increased incidence in coeliac disease. These results suggest that persistent adenovirus 12 infection is not a major element in the pathogenesis of coeliac disease.

The preparation of two peanut butter reference materials and the certification of their aflatoxins B1, B2, G1, G2 and total aflatoxin contents is described. The materials were prepared and certified within the BCR Programme of the Commission of the European Community as part of a broad activity to improve accuracy and agreement of measurements of importance in food and agriculture (Wagstaffe and Belliardo 1990). Reference material RM 385 was prepared from naturally contaminated peanuts, roasted and ground into a paste and then blended with uncontaminated peanut butter to achieve the desired aflatoxin concentrations. Details are given of the blending and canning procedure, and the checks to ensure homogeneity and stability of the material. Reference material RM 401 was similarly prepared but from an uncontaminated peanut butter. The certification exercise was carried out by nine laboratories using a variety of extraction and clean-up procedures, but all using high performance liquid chromatography (HPLC) as the determinative stage although operating under a variety of chromatographic conditions. RM 385 was certified as containing aflatoxins B1, B2, G1 and G2 at levels of 7.0 +/- 0.8 micrograms/kg, 1.1 +/- 0.2 micrograms/kg, 1.7 +/- 0.3 micrograms/kg and 0.3 +/- 0.2 micrograms/kg respectively (total aflatoxin content of 10.1 +/- 1.5 micrograms/kg) and RM 401 as containing aflatoxin B1, B2 and G2 at less than 0.2 micrograms/kg and aflatoxin G1 at less than 0.3 micrograms/kg (total aflatoxin content less than 0.9 micrograms/kg). The materials are intended for the verification of methods used to determine aflatoxins in nuts and nut products.

Distal duodenal biopsy specimens taken from 30 white, 35 Indian, and 20 Afro-Caribbean residents of West Birmingham during routine endoscopy for dyspepsia, were assessed by dissecting microscopy and morphometry. Finger-shaped villi were significantly less frequent in the Indian and Afro-Caribbean subjects than in the white subjects when assessed by dissecting microscopy (p less than 0.005), and both immigrant groups had decreased mucosal thickness (p less than 0.01), villous height (p less than 0.001), villous:crypt ratios (p less than 0.01) and enterocyte height (p less than 0.05) compared with the white group. In the Indian subjects, villous height and villous:crypt ratios correlated significantly with the time since the last visit to the Indian subcontinent (p less than 0.005). Serum alkaline phosphatase values were significantly higher in the Indian subjects compared with the whites (p less than 0.02), and serum globulins were increased in both the Afro-Caribbean and Indian subjects (p less than 0.01). There were no correlations between morphometric indices and body habitus or biochemical or haematological indices and the long term effect of the morphological changes is not clear.

While monitoring the occurrence of toxigenic moulds in foods, using a bioassay screen, it was shown that an isolate of Wallemia sebi produced toxic effects in several of the bioassays. The toxic metabolite was isolated and purified using solvent extraction, TLC and HPLC coupled with the brine shrimp assay to monitor the toxic fractions. The purified toxin, which we propose to call walleminol A, has been partially characterized by mass spectroscopy, nuclear magnetic resonance, ultraviolet and infrared spectroscopy. It can be provisionally interpreted as a tricyclic dihydroxy compound, C15H24O2, with structural features characteristic of a sesquiterpene with an isolated double bond, but further work is required to characterize this compound unequivocally. The minimum inhibitory dose of walleminol A in the bioassays is approximately 50 micrograms/ml, which is comparable with a number of mycotoxins such as citrinin and penicillic acid.

A case of myxoedema coma is reported where the administration of chlorpromazine resulted in a prolonged dystonic reaction. A similar challenge with a butyrophenone when the patient was on thyroxine caused a similar but much abbreviated response.