The Combined SIRS + qSOFA (qSIRS) Score is More Accurate Than qSOFA Alone in Predicting Mortality in Patients with Surgical Sepsis in an LMIC Emergency Department.

BACKGROUND: qSOFA has been proposed as a prognostic tool in patients with sepsis. This study set out to assess the sensitivity of several scores, namely: the pre-ICU qSOFA, the qSOFA with lactate (qSOFA L), SIRS score, qSOFA + SIRS score (qSIRS) and qSIRS with lactate (qSIRS L) in predicting in-hospital mortality in patients with surgical sepsis as well as the sensitivity of these scores in predicting high-grade sepsis. The secondary aim was to determine which of these scores is best suited to predict high-grade surgical sepsis. METHODS: This was a retrospective cohort study that was conducted between December 2012 and August 2017 in a public metropolitan surgical service. Data from patients aged > 13 years, who were admitted to the hospital and who had an emergency surgical procedure for source control were retrieved from a prospectively maintained hybrid electronic database. The qSOFA, qSOFA plus lactate (qSOFA L), SIRS and qSOFA + SIRS (qSIRS), as well as the qSIRS plus lactate (qSIRS L), were calculated for each patient. A lactate level that was greater than 2mmol/L was deemed to be a positive finding. Any score ≥2 was deemed to be a positive score. The outcome measure was in-hospital mortality. The prognostic value of qSOFA, qSOFA L, SIRS, qSIRS and qSIRS L was studied. Receiver operating characteristic analyses were performed to determine the area under the curve (AUC), sensitivity, specificity and positive and negative likelihood ratios for positive qSOFA, qSOFA L, SIRS, qSIRS, and qSIRS L. Contingency tables were used to calculate the sensitivity, specificity, PPV and NPV for predicting severe or high-grade surgical sepsis. RESULTS: There were a total number of 1884 patients in the sample group of whom 855 were female (45.4%). The median patient age was 36 years (IQR 23-56). A total of 1489 patients (79%) were deemed to have high-grade sepsis based on an advanced EGS AAST grading, whilst 395 patients (21%) had low-grade sepsis. A total of 71 patients died (3.8%). Of these patients who died, 67 (94.4%) had high-grade sepsis and 4 (5.6%) had low-grade sepsis. The mortality rate in the high-grade sepsis group was 4.5%, whilst the mortality rate in the low-grade sepsis group was 1%. The scores with the greatest accuracy in predicting mortality were qSIRS (AUROC 0.731, 95% CI 0.68-0.78), followed by SIRS (AUROC 0.70, 95% CI 0.65-0.75). The qSOFA and qSOFA L were the least accurate in predicting mortality (AUROC 0.684, 95% CI 0.63-0.74 for both). The addition of lactate had no significant effect on the accuracy of the five scores in predicting mortality. Patients with a qSOFA ≥ 2 have an increased risk of dying (OR 5.8), as do patients with a SIRS score ≥2 (OR 2.7). qSIRS L had the highest sensitivity (69%) in predicting the presence of high-grade surgical sepsis, followed by qSIRS (65.5% sensitivity). qSOFA showed a very low sensitivity of only 4.5% and a high specificity of 99.2%. The addition of lactate to the score marginally improved the sensitivity. Lactate of 2mmol/L or more was also an independent predictor of high-grade sepsis. CONCLUSION: The qSIRS score is most accurate in predicting mortality in surgical sepsis. The qSOFA score is inferior to both the SIRS and the qSIRS scores in predicting mortality. The qSIRS score with the addition of lactate to the qSIRS score made it the most sensitive score in predicting high-grade surgical sepsis.

Morphine and pholcodine-specific IgE have limited utility in the diagnosis of anaphylaxis to benzylisoquinolines.

BACKGROUND: Investigation of immediate hypersensitivity reactions in the perioperative setting involves skin testing and measurement of specific IgE (sIgE) as standard practice. In the case of the neuromuscular blocking agents (NMBAs), the main allergenic epitopes have been shown to be substituted ammonium groups. Commercial assays are available for detection of sIgE to these epitopes using morphine and pholcodine substrates but questions have been raised about the effectiveness of these assays in the diagnosis of benzylisoquinoline anaphylaxis. This study was therefore undertaken to assess the effectiveness of these assays in the diagnosis of hypersensitivity reactions to this group of NMBAs. METHODS: Analysis was carried out on all available results for patients assessed at the Royal North Shore Hospital Anaesthetic Allergy Clinic during the period June 2009 to June 2016. Standardised intradermal skin tests were performed with a panel of NMBAs. Measurement of sIgE to morphine and pholcodine was performed via the Phadia ImmunoCAP® system. RESULTS: For all patients with positive skin test results to NMBAs which included a benzylisoquinoline NMBA (n = 24), 75% exhibited negative sIgE to both morphine and pholcodine. Where patients were reactive to benzylisoquinoline NMBAs alone (n = 12), 100% exhibited negative sIgE results, indicating 0% sensitivity of the assays relative to skin testing, in this subgroup. CONCLUSION: Use of sIgE testing to morphine and pholcodine in the assessment of NMBA immediate hypersensitivity is a valuable tool particularly in the case of reactions to the aminosteroid NMBAs. However, these assays are unreliable in detecting sensitisation to benzylisoquinoline NMBAs.

Spatial analysis of the exposure of dogs in rural north-coastal California to vectorborne pathogens.

Between 0 and 50 per cent of the dogs in eight rural villages in far northern California with a high risk of tickborne diseases were seropositive for Anaplasma phagocytophilum and Bartonella vinsonii subspecies berkhoffii, and between 0 and 10 per cent were seropositive for Borrelia burgdorferi. The odds ratio for the co-exposure of individual dogs to B vinsonii berkhoffii and A phagocytophilum was 18.2. None of the diseases was associated with the sex of the dogs, whether they slept out of doors, or whether tick-preventive measures were taken. When the villages were assessed for landscape risk factors, a particularly high seroprevalence for B vinsonii berkhoffii and A phagocytophilum was observed in a village at a relatively high altitude and greater distance from the Pacific coast, and montane hardwood conifer woodland was most associated with a high seroprevalence for these two pathogens.

Absence of mutations in the survival motor neuron cDNA from labrador retrievers with an inherited myopathy.

The clinical phenotype of hereditary myopathy of labrador retrievers is consistent, but the pathological changes within muscle biopsy specimens can vary from type 1 fibre predominance (type 2 fibre deficiency) to dystrophic changes or overt neurogenic atrophy. The condition shares many clinical and pathological features with the mildest form of human childhood spinal muscular atrophy, and the survival motor neuron gene was therefore evaluated in dogs with the disease. Direct sequencing and comparisons of cdna from the gene in seven labrador retrievers homozygous for the disease and four control dogs revealed no nucleotide mutations leading to changes in the deduced amino acid sequences. A single polymorphism was detected in two of the seven affected dogs, which was characterised by a nucleotide substitution at amino acid position 1155 within the non-coding 3' untranslated region of exon 8. Northern blot analysis indicated that there were no differences in the steady state levels of mrna from the gene of the affected labrador retrievers and control dogs.

Allelic variants of the canine heavy neurofilament (NFH) subunit and extensive phosphorylation in dogs with motor neuron disease.

Aberrant accumulation of extensively phosphorylated heavy (high molecular weight) neurofilament (NFH) and neurodegeneration are features of hereditary canine spinal muscular atrophy (HCSMA), an animal model of human motor neuron disease. In this study, the canine NFH gene was mapped, cloned, and sequenced, and electrospray/mass spectrometry was used to evaluate the phosphorylation state of NFH protein from normal dogs and dogs with HCSMA. The canine NFH gene was localized to a region on canine chromosome 26 that corresponds to human NFH on chromosome 22q. The predicted length of the canine NFH protein is 1135 amino acids, and it shares an 80.3% identity with human NFH and >74.6% with murine NFH proteins. Direct sequencing of NFH cDNA from HCSMA dogs revealed no mutations, although cDNA sequence and restriction fragment length polymorphism (RFLP) analysis indicates that there are at least three canine NFH alleles, differing in the position and number (61 or 62) of Lys-Ser-Proline (KSP) motifs. The two longest alleles (L1 and L2), each with 62 KSP repeats, contain an additional 24-base insert and were observed in both normal and HCSMA dogs. However, the shorter allele (the C allele), with 61 KSP sites and lacking the 24-base insertion, was absent in dogs with HCSMA. Mass spectrometry data indicated that almost all of the NFH KSP phosphorylation sites were occupied. No new or extra sites were identified in native NFH purified from the HCSMA dogs. The predominance of the two longest NFH alleles and the additional KSP phosphorylation sites they confer probably account for the presence of extensively phosphorylated NFs detected immunohistochemically in dogs with HCSMA.

Structure, chromosomal location, and analysis of the canine Cu/Zn superoxide dismutase (SOD1) gene.

Mutations in Cu/Zn superoxide dismutase (SOD1), a major cytosolic antioxidant enzyme in eukaryotic cells, have been reported in approximately 20% of familial amyotrophic lateral sclerosis (FALS) patients. Hereditary canine spinal muscular atrophy (HCSMA), a fatal inherited motor neuron disease in Brittany spaniels, shares many clinical and pathological features with human motor neuron disease, including FALS. The SOD1 coding region has been sequenced and cloned from several animal species, but not from the dog. We have mapped the chromosomal location, sequenced, and characterized the canine SOD1 gene. Extending this analysis, we have evaluated SOD1 as a candidate for HCSMA. The 462 bp SOD1 coding region in the dog encodes 153 amino acid residues and exhibits more than 83% and 79% sequence identity to other mammalian homologues at both the nucleotide and amino acid levels, respectively. The canine SOD1 gene maps to CFA31 close to syntenic group 13 on the radiation hybrid (RH) map in the vicinity of sodium myo/inositol transporter (SMIT) gene. The human orthologous SOD1 and SMIT genes have been localized on HSA 21q22.1 and HSA 21q21, respectively, confirming the conservation of synteny between dog syntenic group 13 and HSA 21. Direct sequencing of SOD1 cDNA from six dogs with HCSMA revealed no mutations. Northern analysis indicated no differences in steady-state levels of SOD1 mRNA.

Canine motor neuron disease: clinicopathologic features and selected indicators of oxidative stress.

Hereditary canine spinal muscular atrophy (HCSMA) is an inherited motor neuron disease affecting a kindred of Brittanies. We have examined the clinicopathologic abnormalities in 57 animals with HCSMA, including 43 affected adult dogs and 14 homozygote pups. We also measured selected biochemical indices of oxidative stress: serum vitamin E (alpha-tocopherol) and Se concentrations; serum concentrations of Cu, Zn, Mg, and Fe; and total superoxide dismutase and glutathione peroxidase activities in red blood cells. Dogs with HCSMA had the following abnormalities: regenerative anemia, hypoglobulinemia, hypochloremia, and abnormally high creatine kinase and liver alkaline phosphatase activities. Serum Cu concentration was significantly (P = .01) increased in adult dogs with HCSMA compared to control dogs. Serum vitamin E concentrations tended to be lower in adult dogs with HCSMA compared to controls, and were significantly (P = .01) lower in homozygote pups compared to control pups.

Suspected hypovitaminosis A in a colony of captive green anoles (Anolis carolinensis).

In a colony of 18 green anoles (Anolis carolinensis), 3 animals experienced focally thickened lips, ulcerative cheilitis, lethargy, depression, and weight loss over a 5-month period. In addition to crickets fed fresh fruit and leafy green vegetables, the diet of the green anoles consisted of a supply of mealworms that had been dusted with a commercial liquid vitamin supplement. The history, clinical findings, and histopathologic lesions were suggestive of hypovitaminosis A, which is known to cause squamous metaplasia of the mucus secreting glands and epithelial surfaces in many species.

Device-dependent activity estimation and decay correction of radionuclide mixtures with application to Tc-94m PET studies.

Multi-instrument activity estimation and decay correction techniques were developed for radionuclide mixtures, motivated by the desire for accurate quantitation of Tc-94m positron emission tomography (PET) studies. Tc-94m and byproduct Tc isotopes were produced by proton irradiation of enriched Mo-94 and natural Mo targets. Mixture activities at the end of bombardment were determined with a calibrated high purity germanium detector. The activity fractions of the greatest mixture impurities relative to 100% for Tc-94m averaged 10.0% (Tc-94g) and 3.3% (Tc-93) for enriched targets and 10.1% (Tc-94g), 11.0% (Tc-95), 255.8% (Tc-96m), and 7.2% (Tc-99m) for natural targets. These radioisotopes have different half-lives (e.g., 52.5 min for Tc-94m, 293 min for Tc-94g), positron branching ratios (e.g., 0.72 for Tc-94m, 0.11 for Tc-94g) and gamma ray emissions for themselves and their short-lived, excited Mo daughters. This complicates estimation of injected activity with a dose calibrator, in vivo activity with PET and blood sample activity with a gamma counter. Decay correction using only the Tc-94m half-life overestimates activity and is inadequate. For this reason analytic formulas for activity estimation and decay correction of radionuclide mixtures were developed. Isotope-dependent sensitivity factors for a PET scanner, dose calibrator, and gamma counter were determined using theoretical sensitivity models and fits of experimental decay curves to sums of exponentials with fixed decay rates. For up to 8 h after the end of bombardment with activity from enriched and natural Mo targets, decay-corrected activities were within 3% of the mean for three PET studies of a uniform cylinder, within 3% of the mean for six dose calibrator decay studies, and within 6% of the mean for four gamma counter decay studies. Activity estimation and decay correction for Tc-94m mixtures enable routine use of Tc-94m in quantitative PET, as illustrated by application to a canine Tc-94m sestamibi study.

p21(Cip1) and p27(Kip1) regulate cell cycle reentry after hypoxic stress but are not necessary for hypoxia-induced arrest.

We investigated the role of the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip1) in cell cycle regulation during hypoxia and reoxygenation. While moderate hypoxia (1 or 0.1% oxygen) does not significantly impair bromodeoxyuridine incorporation, at very low oxygen tensions (0.01% oxygen) DNA replication is rapidly shut down in immortalized mouse embryo fibroblasts. This S-phase arrest is intact in fibroblasts lacking the cyclin kinase inhibitors p21(Cip1) and p27(Kip1), indicating that these molecules are not essential elements of the arrest pathway. Hypoxia-induced arrest is accompanied by dephosphorylation of pRb and inhibition of cyclin-dependent kinase 2, which results in part from inhibitory phosphorylation. Interestingly, cells lacking the retinoblastoma tumor suppressor protein also display arrest under hypoxia, suggesting that pRb is not an essential mediator of this response. Upon reoxygenation, DNA synthesis resumes by 3.5 h and reaches aerobic levels by 6 h. Cells lacking p21, however, resume DNA synthesis more rapidly upon reoxygenation than wild-type cells, suggesting that this inhibitor may play a role in preventing premature reentry into the cell cycle upon cessation of the hypoxic stress. While p27 null cells did not exhibit rapid reentry into the cell cycle, cells lacking both p21 and p27 entered S phase even more aggressively than those lacking p21 alone, revealing a possible secondary role for p27 in this response. Cdk2 activity is also restored more rapidly in the double-knockout cells when returned to normoxia. These studies reveal that restoration of DNA synthesis after hypoxic stress, but not the S phase arrest itself, is regulated by p21 and p27.

p53 checkpoint-defective cells are sensitive to X rays, but not hypoxia.

X-ray-induced damage leads to cell-cycle "checkpoint" arrest by p53-dependent induction of the cyclin-dependent kinase inhibitor p21 (Waf1/Cip1/Sdi1). Human tumor cells that lack this response fail to arrest after exposure to DNA-damaging agents, undergo multiple rounds of endoreduplicative DNA synthesis, and eventually commit to an apoptotic cell death. Since low oxygen tension can also induce p53 protein accumulation, and can lead to cell-cycle arrest or apoptosis, we examined the expression of p21 in tumor cells under normoxic and hypoxic conditions. In a survey of cells, mRNA for the p21 gene was induced two- to threefold in response to hypoxia in a seemingly p53-independent manner. We therefore examined genetically matched cells that differ in their p21 and p53 status for response to ionizing radiation and hypoxia. We found that both p21-deficient and p53-deficient cells exhibit an increase in chromosome instability, an increased level of apoptosis, and a failure to arrest after exposure to ionizing radiation. However, cells that lack either p21 or p53 exhibit no increase in chromosome instability or elevated apoptosis and still arrest in response to hypoxia. Thus, the mechanism responsible for the differential response to either hypoxia or X rays presumably lies in the control of cell-cycle progression in response to stress and its dependence on p21. Since the loss of a DNA-damage-dependent checkpoint does not sensitize cells to killing by stresses that elicit a DNA-damage-independent checkpoint, targeting the function of p21 pharmacologically will not kill tumor cells in situ in the absence of a DNA damage signal.

Dilative cardiomyopathy leading to congestive heart failure in a male squirrel monkey (Saimiri sciureus).

A 17-year-old, 1-kg, colony-housed, male squirrel monkey (Samiri sciureus) developed clinical signs of congestive heart failure. The monkey presented with lethargy, increased heart and respiratory rates, and mild abdominal distention. The clinical history, laboratory analysis, and radiographic findings were consistent with heart failure due to dilative cardiomyopathy. Gross and microscopic examination of the heart confirmed a dilative cardiomyopathy. This is the first report describing congestive heart failure caused by dilative cardiomyopathy in a squirrel monkey. Spontaneous dilative cardiomyopathy may be infrequently observed in the squirrel monkeys because they are not routinely housed in the research environment during their advancing years.

Disease attributed to Mycobacterium chelonae in South African clawed frogs (Xenopus laevis).

The fast-growing nontuberculous mycobacterial species Mycobacterium chelonae was isolated from six captive South African clawed frogs (Xenopus laevis) with chronic weight loss and nonhealing ulcerative skin lesions. Three of the M. chelonae isolates were evaluated to confirm the species identification using polymerase chain reaction restriction analysis. Disease associated with M. chelonae is reported mainly in people and in fish. To our knowledge, this is the first report of disease associated with M. chelonae in a colony of captive Xenopus sp.

Animal models for motor neuron disease.

Motor neuron disease is a general term applied to a broad class of neurodegenerative diseases that are characterized by fatally progressive muscular weakness, atrophy, and paralysis attributable to loss of motor neurons. At present, there is no cure for most motor neuron diseases, including amyotrophic lateral sclerosis (ALS), the most common human motor neuron disease--the cause of which remains largely unknown. Animal models of motor neuron disease (MND) have significantly contributed to the remarkable recent progress in understanding the cause, genetic factors, and pathologic mechanisms proposed for this class of human neurodegenerative disorders. Largely driven by ALS research, animal models of MND have proven their usefulness in elucidating potential causes and specific pathogenic mechanisms, and have helped to advance promising new treatments from "benchside to bedside." This review summarizes important features of selected established animal models of MND: genetically engineered mice and inherited or spontaneously occurring MND in the murine, canine, and equine species.

Intersensory conflict between vision and touch: the response modality dominates when precise, attention-riveting judgments are required.

In four experiments, reducing lenses were used to minify vision and generate intersensory size conflicts between vision and touch. Subjects made size judgments, using either visual matching or haptic matching. In visual matching, the subjects chose from a set of visible squares that progressively increased in size. In haptic matching, the subjects selected matches from an array of tangible wooden squares. In Experiment 1, it was found that neither sense dominated when subjects exposed to an intersensory discrepancy made their size estimates by using either visual matching or haptic matching. Size judgments were nearly indentical for conflict subjects making visual or haptic matches. Thus, matching modality did not matter in Experiment 1. In Experiment 2, it was found that subjects were influenced by the sight of their hands, which led to increases in the magnitude of their size judgments. Sight of the hands produced more accurate judgments, with subjects being better able to compensate for the illusory effects of the reducing lens. In two additional experiments, it was found that when more precise judgments were required and subjects had to generate their own size estimates, the response modality dominated. Thus, vision dominated in Experiment 3, where size judgments derived from viewing a metric ruler, whereas touch dominated in Experiment 4, where subjects made size estimates with a pincers posture of their hands. It is suggested that matching procedures are inadequate for assessing intersensory dominance relations. These results qualify the position (Hershberger & Misceo, 1996) that the modality of size estimates influences the resolution of intersensory conflicts. Only when required to self-generate more precise judgments did subjects rely on one sense, either vision or touch. Thus, task and attentional requirements influence dominance relations, and vision does not invariably prevail over touch.

Endometriosis and a paraovarian cyst in a rhesus macaque.

We describe endometriosis in an aged rhesus macaque. There was a large mass and a related paraovarian cyst, typical of the disease. Endometriosis is a common finding in nonhuman primate. In this report, we also review the pathophysiology of the disease and summarize the historical and more recent relevant literature. Given the frequency of endometriosis in the rhesus monkey and the long-life spans (15-30 years) of nonhuman primates in captivity, endometriosis should be suspected in animals displaying the earliest signs of the disease: anorexia, dysmenorrhea, menorrhagia, irregular menstrual cycles, or infertility. Despite recent advances in the diagnosis and therapeutic strategies for endometriosis in women, the disease remains a significant cause of morbidity and ultimately, a cause of mortality, in the older nonhuman primate.

Hospital blood pressure measurement: staff and device assessment.

Evaluation of the ability of clinical staff to measure blood pressure as well as the functional state of hospital sphygmomanometers has consistently demonstrated marked deficiencies. In this study, the working order of all sphygmomanometers (manual and automated) in a teaching hospital was evaluated. Nursing staff were tested on their knowledge and use of such devices and were also asked to estimate the blood pressure from videotape. The accuracy of a commonly used automated device, Dinamap 8100, was also measured. Of 543 manual sphygmomanometers, 14% were in perfect working order although portable devices were more likely to be functional (47% of 36 units). In contrast, all 135 automated portable devices were in perfect working order although service requirements were seldom met. The mean time since last service was 18 months. There appeared to be an inverse correlation between the availability of automated and manual devices and the maintenance of wall-mounted bedside sphygmomanometers. Staff knowledge about manual devices was adequate as was their ability to accurately measure blood pressure using standardised videotape. Forty-two per cent of 31 nurses who completed the test were correct in 9 of 12 blood pressures. A comparison of this result with a comparable group of nurses tested in 1990 did not detect a significant change in competence. Direct evaluation of the commonly used Dinamap 8100 in 47 hospital patients demonstrated a poor correlation with a mercury sphygmomanometer with a D grade (fail) for systolic and a C grade for diastolic pressure. In summary, maintenance of manual sphygmomanometers was very poor, probably due to their lack of use by clinical staff. This was particularly true for units attached to bedside walls. Nursing staff demonstrated significant deficiencies in manual sphygmomanometer use although their skills were similar to those measured several years earlier. Because of the demonstrated inaccuracy of the Dinamap 8100 automated device, the strong trend towards the use of automated devices instead of manual sphygmomanometers within hospitals cannot be supported.