Respiratory virus infections in decedents in a large, urban medical examiner's office.

OBJECTIVE: Most respiratory virus surveillance relies on medically attended respiratory illness, but an understanding of the true patterns of infection independent of care-seeking behaviour would enhance clinical and public health responses to respiratory virus outbreaks. We evaluated the potential of decedent surveillance by estimating the burden of respiratory virus infection in decedents in a large, urban medical examiner's office. STUDY DESIGN: Observational. METHODS: In 2020-2022, we tested nasopharyngeal swabs from 4121 decedents in Detroit, Michigan for 15 respiratory viruses, including SARS-CoV-2, respiratory syncytial virus, and influenza virus A and B. We analysed infection prevalence over time and by age, sex, race/ethnicity, and manner of death. RESULTS: Of 4113 valid tests, 30.2% were positive for at least one virus, and 6.1% were positive for multiple viruses. All viruses were detected except for influenza A/H1N1 and influenza B. The most prevalent viruses were SARS-CoV-2 (15.7%), rhinovirus (11.2%), and adenovirus (4.9%), which were detected in all months. Most viruses exhibited decreasing prevalence with age, higher prevalence among Black and Hispanic than among White decedents and lower prevalence among deaths from natural causes; SARS-CoV-2 was a notable exception to the patterns by age and manner of death, instead reflecting community trends in catchment counties. CONCLUSIONS: There was high prevalence and diversity of respiratory viruses in decedents entering a large, urban medical examiner's office. Decedent surveillance could offer a clearer picture of the true underlying burden of infection, motivating public health priorities for intervention and vaccine development, and augmenting data for real-time response to respiratory virus outbreaks.

FAANG, establishing metadata standards, validation and best practices for the farmed and companion animal community.

The Functional Annotation of ANimal Genomes (FAANG) project aims, through a coordinated international effort, to provide high quality functional annotation of animal genomes with an initial focus on farmed and companion animals. A key goal of the initiative is to ensure high quality and rich supporting metadata to describe the project's animals, specimens, cell cultures and experimental assays. By defining rich sample and experimental metadata standards and promoting best practices in data descriptions, deposition and openness, FAANG champions higher quality and reusability of published datasets. FAANG has established a Data Coordination Centre, which sits at the heart of the Metadata and Data Sharing Committee. It continues to evolve the metadata standards, support submissions and, crucially, create powerful and accessible tools to support deposition and validation of metadata. FAANG conforms to the findable, accessible, interoperable, and reusable (FAIR) data principles, with high quality, open access and functionally interlinked data. In addition to data generated by FAANG members and specific FAANG projects, existing datasets that meet the main-or more permissive legacy-standards are incorporated into a central, focused, functional data resource portal for the entire farmed and companion animal community. Through clear and effective metadata standards, validation and conversion software, combined with promotion of best practices in metadata implementation, FAANG aims to maximise effectiveness and inter-comparability of assay data. This supports the community to create a rich genome-to-phenotype resource and promotes continuing improvements in animal data standards as a whole.

Single nucleotide variant discovery of highly inbred Leghorn and Fayoumi chicken breeds using pooled whole genome resequencing data reveals insights into phenotype differences.

BACKGROUND: Analyses of sequence variants of two distinct and highly inbred chicken lines allowed characterization of genomic variation that may be associated with phenotypic differences between breeds. These lines were the Leghorn, the major contributing breed to commercial white-egg production lines, and the Fayoumi, representative of an outbred indigenous and robust breed. Unique within- and between-line genetic diversity was used to define the genetic differences of the two breeds through the use of variant discovery and functional annotation. RESULTS: Downstream fixation test (F ST ) analysis and subsequent gene ontology (GO) enrichment analysis elucidated major differences between the two lines. The genes with high F ST values for both breeds were used to identify enriched gene ontology terms. Over-enriched GO annotations were uncovered for functions indicative of breed-related traits of pathogen resistance and reproductive ability for Fayoumi and Leghorn, respectively. CONCLUSIONS: Variant analysis elucidated GO functions indicative of breed-predominant phenotypes related to genomic variation in the lines, showing a possible link between the genetic variants and breed traits.

Reversal of neurobehavioral social deficits in dystrophic mice using inhibitors of phosphodiesterases PDE5A and PDE9A.

Duchenne muscular dystrophy is caused by mutations in the DYSTROPHIN gene. Although primarily associated with muscle wasting, a significant portion of patients (approximately 25%) are also diagnosed with autism spectrum disorder. We describe social behavioral deficits in dystrophin-deficient mice and present evidence of cerebellar deficits in cGMP production. We demonstrate therapeutic potential for selective inhibitors of the cGMP-specific PDE5A and PDE9A enzymes to restore social behaviors in dystrophin-deficient mice.

Genomic analysis of Ugandan and Rwandan chicken ecotypes using a 600 k genotyping array.

BACKGROUND: Indigenous populations of animals have developed unique adaptations to their local environments, which may include factors such as response to thermal stress, drought, pathogens and suboptimal nutrition. The survival and subsequent evolution within these local environments can be the result of both natural and artificial selection driving the acquisition of favorable traits, which over time leave genomic signatures in a population. This study's goals are to characterize genomic diversity and identify selection signatures in chickens from equatorial Africa to identify genomic regions that may confer adaptive advantages of these ecotypes to their environments. RESULTS: Indigenous chickens from Uganda (n = 72) and Rwanda (n = 100), plus Kuroilers (n = 24, an Indian breed imported to Africa), were genotyped using the Axiom® 600 k Chicken Genotyping Array. Indigenous ecotypes were defined based upon location of sampling within Africa. The results revealed the presence of admixture among the Ugandan, Rwandan, and Kuroiler populations. Genes within runs of homozygosity consensus regions are linked to gene ontology (GO) terms related to lipid metabolism, immune functions and stress-mediated responses (FDR < 0.15). The genes within regions of signatures of selection are enriched for GO terms related to health and oxidative stress processes. Key genes in these regions had anti-oxidant, apoptosis, and inflammation functions. CONCLUSIONS: The study suggests that these populations have alleles under selective pressure from their environment, which may aid in adaptation to harsh environments. The correspondence in gene ontology terms connected to stress-mediated processes across the populations could be related to the similarity of environments or an artifact of the detected admixture.

Fluorescently labeled bacteria provide insight on post-mortem microbial transmigration.

Microbially mediated mechanisms of human decomposition begin immediately after death, and are a driving force for the conversion of a once living organism to a resource of energy and nutrients. Little is known about post-mortem microbiology in cadavers, particularly the community structure of microflora residing within the cadaver and the dynamics of these communities during decomposition. Recent work suggests these bacterial communities undergo taxa turnover and shifts in community composition throughout the post-mortem interval. In this paper we describe how the microbiome of a living host changes and transmigrates within the body after death thus linking the microbiome of a living individual to post-mortem microbiome changes. These differences in the human post-mortem from the ante-mortem microbiome have demonstrated promise as evidence in death investigations. We investigated the post-mortem structure and function dynamics of Staphylococcus aureus and Clostridium perfringens after intranasal inoculation in the animal model Mus musculus L. (mouse) to identify how transmigration of bacterial species can potentially aid in post-mortem interval estimations. S. aureus was tracked using in vivo and in vitro imaging to determine colonization routes associated with different physiological events of host decomposition, while C. perfringens was tracked using culture-based techniques. Samples were collected at discrete time intervals associated with various physiological events and host decomposition beginning at 1h and ending at 60 days post-mortem. Results suggest that S. aureus reaches its highest concentration at 5-7 days post-mortem then begins to rapidly decrease and is undetectable by culture on day 30. The ability to track these organisms as they move in to once considered sterile space may be useful for sampling during autopsy to aid in determining post-mortem interval range estimations, cause of death, and origins associated with the geographic location of human remains during death investigations.

The distribution of phosphodiesterase 2A in the rat brain.

The phosphodiesterases (PDEs) are a superfamily of enzymes that regulate spatio-temporal signaling by the intracellular second messengers cAMP and cGMP. PDE2A is expressed at high levels in the mammalian brain. To advance our understanding of the role of this enzyme in regulation of neuronal signaling, we here describe the distribution of PDE2A in the rat brain. PDE2A mRNA was prominently expressed in glutamatergic pyramidal cells in cortex, and in pyramidal and dentate granule cells in the hippocampus. Protein concentrated in the axons and nerve terminals of these neurons; staining was markedly weaker in the cell bodies and proximal dendrites. In addition, in both hippocampus and cortex, small populations of non-pyramidal cells, presumed to be interneurons, were strongly immunoreactive. PDE2A mRNA was expressed in medium spiny neurons in neostriatum. Little immunoreactivity was observed in cell bodies, whereas dense immunoreactivity was found in the axon tracts of these neurons and their terminal regions in globus pallidus and substantia nigra pars reticulata. Immunostaining was dense in the medial habenula, but weak in other diencephalic regions. In midbrain and hindbrain, immunostaining was restricted to discrete regions of the neuropil or clusters of cell bodies. These results suggest that PDE2A may modulate cortical, hippocampal and striatal networks at several levels. Preferential distribution of PDE2A into axons and terminals of the principal neurons suggests roles in regulation of axonal excitability or transmitter release. The enzyme is also in forebrain interneurons, and in mid- and hindbrain neurons that may modulate forebrain networks and circuits.

Detection of high frequency intensity oscillations at RESEDA using the CASCADE detector.

We have explored the technological potential of combining neutron resonance spin echo (NRSE) with the time-of-flight method in quasielastic neutron scattering (QENS) experiments. For these test measurements at the new NRSE instrument RESEDA (FRM II, Munich), we have employed CASCADE, one of the fastest neutron detectors in the world, developed at the University of Heidelberg. Conventionally, scintillation detectors are used, in order to detect neutron intensities with high time resolution. In contrast, we used the new CASCADE detector converting neutrons in thin (10)B layers being capable of resolving neutron intensity modulations up to the megahertz regime. This fast detector allows us to abandon the last resonance flip coil of a standard NRSE setup. The classical spin echo signal is replaced by a time-modulated signal. In this setup, fast intensity modulations are present at the detector position. In order to demonstrate, that NRSE-CASCADE operates well up to detector frequencies of 10 MHz, we performed elastic polarization test measurements on a standard sample. The CASCADE detector is a multidetector accumulating counts in 128 × 128 pixels on a surface of 200 mm × 200 mm. We have analyzed the signal in 600 pixels, providing information about the spin phase reaching the detector and about the resolution function of this new variant tested at RESEDA.

Comparison of a modern broiler line and a heritage line unselected since the 1950s.

Selecting chicken for improved meat production has altered the relative growth of organs in modern broiler lines compared with heritage lines. In this study, we compared the growth and feed efficiency of a heritage line, UIUC, with a modern production line, Ross 708, for 5 wk posthatch. During this period, the BW and feed efficiency of the modern strain was higher than that of the heritage line, indicating that the Ross 708 birds were more efficient than the UIUC birds at converting feed to body mass. The relative growth of the breast, heart, liver, and intestine were also compared during these 5 wk. The breast muscle of the heritage line constituted 9% of the total body mass at 5 wk, whereas in the modern line, the breast muscle was 18% of the total mass of the bird. In contrast, the relative size of the heart decreased after d 14 in the modern line, suggesting that selection for increased breast muscle has translated into relatively less weight of the heart muscle. The liver matured earlier in modern lines, possibly improving nutrient utilization as the birds shift from lipid- to carbohydrate-rich feed. Finally, jejunal and ileal sections of the intestine were 20% longer in the modern line, perhaps allowing for increased nutrient absorption.

Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia.

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

A double-screening method to identify reliable candidate non-synonymous SNPs from chicken EST data.

Discovery of non-synonymous single nucleotide polymorphisms (nsSNP), which cause amino acid substitutions, is important because they are more likely to alter protein function than synonymous SNPs (sSNP) or those SNPs that do not result in amino acid changes. By changing the coding sequences, nsSNP may play a role in heritable differences between individual organisms. In the chicken and many other vertebrates, the main obstacle for identifying nsSNP is that there is insufficient protein and mRNA sequence information for self-species referencing and thus, determination of the correct reading frame for expressed sequence tags (ESTs) is difficult. Therefore, in order to estimate the correct reading frame at nsSNP in chicken ESTs, a double-screening approach was designed using self- or cross-species protein referencing, in addition to the ESTScan coding region estimation programme. Starting with 23 427 chicken ESTs, 1210 potential SNPs were discovered using a phred/phrap/polyphred/consed pipeline process and among these, 108 candidate nsSNP were identified with the double screening method. A searchable SNP database (chicksnps) for the candidate chicken SNPs, including both nsSNPs and sSNPs is available at http://chicksnps.afs.udel.edu. The chicken SNP data described in this paper have been submitted to the data base SNP under National Center for Biotechnology Information assay ID ss4387050-ss4388259.

The effects of pyridostigmine bromide and permethrin, alone or in combination, on response acquisition in male and female rats.

It has been hypothesized that concurrent exposure to pyridostigmine bromide and permethrin may have contributed to the development of neurocognitive symptoms in Gulf War veterans. The present experiment was designed to investigate the effects of pyridostigmine bromide and permethrin alone, or in combination, on the acquisition of a novel response, one measure of normal cognitive functioning. Male and female Sprague-Dawley rats were treated with pyridostigmine bromide (1.5 mg/kg/day, by gavage in a volume of 5 ml/kg) or its vehicle for 7 consecutive days. They then also received an intraperitoneal injection of permethrin (0, 15, or 60 mg/kg) before they were exposed to an experimental session during which they could earn food by pressing a lever in an operant chamber. Serum permethrin levels increased as a function of its dose, and were higher in rats treated with pyridostigmine bromide. Sex differences were observed as permethrin levels were higher in female rats than in male rats following the highest dose. Pyridostigmine bromide delayed response acquisition in male and female rats, and resulted in higher response rates on the inactive lever in female rats than in male rats. Although permethrin levels were higher in subjects treated with pyridostigmine bromide than in those treated with vehicle, there were no differences in the behavioral effects of permethrin. Whether or not these behavioral effects of pyridostigmine bromide are of central or peripheral origin will need to be determined in future studies, as its effects on motor activity and/or gastro-intestinal motility may have affected response acquisition.

Carbonless copy paper: a review of its chemical components and health hazards.

The components of carbonless copy paper (CCP) and the chemistry involved in its manufacture are reviewed. Claims that the routine use of CCP can cause health problems ranging from skin, eye, and lung irritation to severe headaches and neurological damage are described; yet no definitive studies have been conducted that show correlation between CCP use and these symptoms. The toxicological properties of CCP components, many of them precursors to the dye-containing microcapsules or dye solvents that may be causing these problems, are discussed. Recommendations for the minimization of possible physiological reactions to CCP include reduction of usage time; use of the CCP in a well-ventilated area; storing large quantities of CCP, both new or archived, away from work area; and the practice good hand hygiene.

Interactions of pyridostigmine bromide, DEET and permethrin alter locomotor behavior of rats.

Drug interactions have been suggested as a cause of Gulf War Syndrome. Pyridostigmine bromide (PB), a prophylactic treatment against potential nerve gas attack, the insect repellent DEET, and permethrin (PERM) impregnated in soldiers' uniforms may have interacted and caused greater than expected toxicity. We tested those 3 drugs singly and in combinations on male and female Sprague-Dawley rats in open field arenas to find the effects on rate of locomotion and thigmotaxis. Administration rates were 10 mg PB/kg; 50, 200, or 500 mg DEET/kg; 15, 30, or 60 mg PERM/kg; 5 mg PB/kg + 100 mg DEET/kg; 5 mg PB/kg + 15 mg PERM/kg; 100 mg DEET/kg + 15 mg PERM/kg; or vehicle by gavage and i.p. injection. Locomotor behavior was quantified by video-computer analysis for 2 h post-treatment. Female rats were tested in either pro- or metestrus. Drug interactions were determined by the isobolographic method. Blood serum drug concentrations were estimated by high performance liquid chromatography or gas chromatography-mass spectrometry. Single drug effects were very limited within the ranges tested. Double-drug administrations at half the single-drug rates resulted in statistically significant interactions in male rats for both locomotion rate and thigmotaxis. Combination of PB + PERM and DEET + PERM significantly affected speed, whereas only the combination of DEET + PERM significantly affected thigmotaxis. Female rats did not show significant interactions. Our data suggest that serum concentrations of PB and DEET may have been higher in females than males. Administration of PB + DEET may have reduced the serum concentration of DEET, and administration of PB + PERM may have increased the serum concentration of PERM.

Structured settlement annuities, part 1: overview and the underwriting process.

Structured settlement underwriting is the underwriting of medically impaired lives for the purchase of an annuity to fund the settlement. Other than risk assessment, structured settlement (SS) underwriting has little in common with traditional life insurance underwriting. Most noteworthy of these differences is the relative lack of actuarial data on which to base decisions about mortality and the necessity for prospective thinking about risk assessment. The purpose of this paper is to provide a foundation for understanding the structured settlement business and to contrast the underwriting of structured settlements with that of traditional life insurance. This is the first part of a two-part article on SS annuities. Part 2 deals with the mortality experience in SS annuitants and the life-table methodology used to calculate life expectancy for annuitants at increased mortality risk.

Structured settlement annuities, part 2: mortality experience 1967--95 and the estimation of life expectancy in the presence of excess mortality.

BACKGROUND: the mortality experience for structured settlement (SS) annuitants issued both standard (Std) and substandard (SStd) has been reported twice previously by the Society of Actuaries (SOA), but the 1995 mortality described here has not previously been published. We describe in detail the 1995 SS mortality, and we also discuss the methodology of calculating life expectancy (e), contrasting three different life-table models. RESULTS: With SOA permission, we present in four tables the unpublished results of its 1995 SS mortality experience by Std and SStd issue, sex, and a combination of 8 age and 6 duration groups. Overall results on mortality expected from the 1983a Individual Annuity Table showed a mortality ratio (MR) of about 140% for Std cases and about 650% for all SStd cases. Life expectancy in a group with excess mortality may be computed by either adding the decimal excess death rate (EDR) to q' for each year of attained age to age 109 or multiplying q' by the decimal MR for each year to age 109. An example is given for men age 60 with localized prostate cancer; annual EDRs from a large published cancer study are used at duration 0-24 years, and the last EDR is assumed constant to age 109. This value of e is compared with e from constant initial values of EDR or MR after the first year. Interrelations of age, sex, e, and EDR and MR are discussed and illustrated with tabular data. CONCLUSIONS: It is shown that a constant MR for life-table calculation of e consistently overestimates projected annual mortality at older attained ages and underestimates e. The EDR method, approved for reserve calculations, is also recommended for use in underwriting conversion tables.

Aberrant antigen expression detected by multiparameter three color flow cytometry in intermediate and high grade B-cell lymphomas.

The aberrant expression of antigens (Ag) in lymphoproliferative disorders may cause a diagnostic problem when single parameter immunohistochemical assays are performed on frozen or paraffin sections because coexpression by relevant cells is not determined. This aberrant expression also raises the question as to whether mixed lineage (biphenotypic) lymphoid proliferations exist. Marrow (6) and extramedullary (20) tissues from 26 patients with diffuse, intermediate and high grade, B-cell lymphomas (IWF E=1, F=1, G=19, H=1 and J=4) were analyzed with 19 markers using 3-color flow cytometry. The percentages (%) of patients with double Ag coexpression in at least 20% of the CD19+ or CD20+ lymphoma cells were: stem cell (SC) Ag: CD10 = 58 and CD34 = 15; T-cell Ag: CD2 = 38, CD5 = 19 and CD7 = 19; myeloid (My) Ag: CD13 = 19 and CD33 = 8. The corresponding % with unusual triple Ag coexpression in at least 10% of the CD19+ B-cells were SC+T+ Ag: CD10CD2 = 50, CD10CD5 = 27, CD10CD7 = 38, CD34CD2 = 31, CD34CD5 = 19 and CD34CD7 = 27; T+T+ Ag: CD2CD5 = 35, CD2CD7 = 42 and CD5CD7 = 31; T+My+ Ag: CD2CD13 = 35 and CD2CD33 = 12; and My+My+ Ag: CD13CD33 = 12. Ten of 12 lymphomas tested showed clonal immunoglobulin (Ig) heavy chain gene rearrangements in the absence of clonal T-cell receptor (TCR) gene rearrangements. None (0%) of the My Ag positive cases showed immunoreactivity for myeloperoxidase. We conclude that the anomalous T and My Ag expression seen in the above B-cell lymphomas is not indicative of mixed lineage proliferation but represents the aberrant expression of these antigens by the malignant cells.

Pyridostigmine bromide alters locomotion and thigmotaxis of rats: gender effects.

Male rats and female rats in the proestrous and metestrous stages of estrus were tested to determine the effects of pyridostigmine bromide on locomotion rate and thigmotactic response using doses of 3.0, 10.0, and 30.0 mg/kg. Thirty minutes after administration of the pyridostigmine bromide the rats were videorecorded for 2 h in a 1 m2 open-field arena. The rats' activities were analyzed for the drug's effect on speed throughout the 2 h and during six 20-min segments. Also, the times that the rats were observed moving through the central 50% of the arena were determined. Locomotion rates decreased significantly, and thigmotaxses increased significantly in all groups of rats as a dose response to pyridostigmine bromide. Habituation occurred over 2 h for both responses, primarily during the first 40 min. Female rats were more affected than males, but metestrous and proestrous females did not differ significantly in their responses. At the 30 mg/kg the effect was persistent throughout the test period. Proestrous females dosed at 30 mg/kg had much higher pyridostigmine bromide serum levels than metestrous females and males.

Measurement of human myocardial perfusion by double-gated flow alternating inversion recovery EPI.

This paper presents a flow-sensitive alternating inversion recovery (FAIR) method for measuring human myocardial perfusion at 1.5 T. Slice-selective/non-selective IR images were collected using a double-gated IR echoplanar imaging sequence. Myocardial perfusion was calculated after T1 fitting and extrapolation of the mean signal difference SI(Sel - SI(NSel). The accuracy of the method was tested in a porcine model using graded intravenous adenosine dose challenge. Comparison with radiolabeled microsphere measurements showed a good correlation (r = 0.84; mean error = 20%, n = 6) over the range of flows tested (0.9-7 ml/g/min). Applied in humans, this method allowed for the measurement of resting myocardial flow (1.04+/-0.37 ml/g/min, n = 11). The noise in our human measurements (SE(flow) = 0.2 ml/g/min) appears to come primarily from residual respiratory motion. Although the current signal-to-noise ratio limits our ability to measure small fluctuations in resting flow accurately, the results indicate that this noninvasive method has great promise for the quantitative assessment of myocardial flow reserve in humans.