Age differences in the association of comorbid burden with adverse outcomes in SARS-CoV-2.

BACKGROUND: Older age and comorbid burden are both associated with adverse outcomes in SARS-CoV-2, but it is not known whether the association between comorbid burden and adverse outcomes differs in older and younger adults. OBJECTIVE: To compare the relationship between comorbid burden and adverse outcomes in adults with SARS-CoV-2 of different ages (18-64, 65-79 and ≥ 80 years). DESIGN, SETTING, AND PARTICIPANTS: Observational longitudinal cohort study of 170,528 patients who tested positive for SARS-CoV-2 in the US Department of Veterans Affairs (VA) Health Care System between 2/28/20 and 12/31/2020 who were followed through 01/31/2021. MEASUREMENTS: Charlson Comorbidity Index (CCI); Incidence of hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and death within 30 days of a positive SARS-CoV-2 test. RESULTS: The cumulative 30-day incidence of death was 0.8% in cohort members < 65 years, 7.1% in those aged 65-79 years and 20.6% in those aged ≥80 years. The respective 30-day incidences of hospitalization were 8.2, 21.7 and 29.5%, of ICU admission were 2.7, 8.6, and 11% and of mechanical ventilation were 1, 3.9 and 3.2%. Median CCI (interquartile range) ranged from 0.0 (0.0, 2.0) in the youngest, to 4 (2.0, 7.0) in the oldest age group. The adjusted association of CCI with all outcomes was attenuated at older ages such that the threshold level of CCI above which the risk for each outcome exceeded the reference group (1st quartile) was lower in younger than in older cohort members (p < 0.001 for all age group interactions). LIMITATIONS: The CCI is calculated based on diagnostic codes, which may not provide an accurate assessment of comorbid burden. CONCLUSIONS: Age differences in the distribution and prognostic significance of overall comorbid burden could inform clinical management, vaccination prioritization and population health during the pandemic and argue for more work to understand the role of age and comorbidity in shaping the care of hospitalized patients with SARS-CoV-2.

Echocardiographic and pathologic identification of an aorto-left atrial fistula secondary to infective endocarditis in a canine patient.

A dog was presented for lameness, fever, and extreme lethargy. On physical exam, a new heart murmur, arrhythmia, and joint effusion were detected. These findings were not detected two months prior. A diagnostic work-up confirmed septic suppurative inflammation in multiple joints. Echocardiogram revealed aortic valvular endocarditis along with a communication, as a consequence of a fistula, that extended from just below the aortic sinotubular junction to the left atrial lumen. Due to a poor prognosis, humane euthanasia was elected. Necropsy and histopathology confirmed infective endocarditis of the aortic valve and an aorto-left atrial fistulous tract extending from the left coronary sinus of the aortic valve to the lumen of left atrium.

Recommended guidelines for submission, trimming, margin evaluation, and reporting of tumor biopsy specimens in veterinary surgical pathology.

Neoplastic diseases are typically diagnosed by biopsy and histopathological evaluation. The pathology report is key in determining prognosis, therapeutic decisions, and overall case management and therefore requires diagnostic accuracy, completeness, and clarity. Successful management relies on collaboration between clinical veterinarians, oncologists, and pathologists. To date there has been no standardized approach or guideline for the submission, trimming, margin evaluation, or reporting of neoplastic biopsy specimens in veterinary medicine. To address this issue, a committee consisting of veterinary pathologists and oncologists was established under the auspices of the American College of Veterinary Pathologists Oncology Committee. These consensus guidelines were subsequently reviewed and endorsed by a large international group of veterinary pathologists. These recommended guidelines are not mandated but rather exist to help clinicians and veterinary pathologists optimally handle neoplastic biopsy samples. Many of these guidelines represent the collective experience of the committee members and consensus group when assessing neoplastic lesions from veterinary patients but have not met the rigors of definitive scientific study and investigation. These questions of technique, analysis, and evaluation should be put through formal scrutiny in rigorous clinical studies in the near future so that more definitive guidelines can be derived.

A homolog of voltage-gated Ca(2+) channels stimulated by depletion of secretory Ca(2+) in yeast.

In animal cells, capacitative calcium entry (CCE) mechanisms become activated specifically in response to depletion of calcium ions (Ca(2+)) from secretory organelles. CCE serves to replenish those organelles and to enhance signaling pathways that respond to elevated free Ca(2+) concentrations in the cytoplasm. The mechanism of CCE regulation is not understood because few of its essential components have been identified. We show here for the first time that the budding yeast Saccharomyces cerevisiae employs a CCE-like mechanism to refill Ca(2+) stores within the secretory pathway. Mutants lacking Pmr1p, a conserved Ca(2+) pump in the secretory pathway, exhibit higher rates of Ca(2+) influx relative to wild-type cells due to the stimulation of a high-affinity Ca(2+) uptake system. Stimulation of this Ca(2+) uptake system was blocked in pmr1 mutants by expression of mammalian SERCA pumps. The high-affinity Ca(2+) uptake system was also stimulated in wild-type cells overexpressing vacuolar Ca(2+) transporters that competed with Pmr1p for substrate. A screen for yeast mutants specifically defective in the high-affinity Ca(2+) uptake system revealed two genes, CCH1 and MID1, previously implicated in Ca(2+) influx in response to mating pheromones. Cch1p and Mid1p were localized to the plasma membrane, coimmunoprecipitated from solubilized membranes, and shown to function together within a single pathway that ensures that adequate levels of Ca(2+) are supplied to Pmr1p to sustain secretion and growth. Expression of Cch1p and Mid1p was not affected in pmr1 mutants. The evidence supports the hypothesis that yeast maintains a homeostatic mechanism related to CCE in mammalian cells. The homology between Cch1p and the catalytic subunit of voltage-gated Ca(2+) channels raises the possibility that in some circumstances CCE in animal cells may involve homologs of Cch1p and a conserved regulatory mechanism.

The steroid alcohol and estrogen sulfotransferases in rodent and human mammary tumors.

Rodent and human mammary tumor systems were investigated to relate the steroid alcohol and estrogen sulfotransferase activities to the hormoanl dependency of the tumor as determined by estrogen receptor content. Unlike the normal mammary gland or the hyperplastic alveolar nodule, rodent mammary neoplasms displayed significant levels of these two sulfotransferases. In the hormone-independent mouse tumors produced from out-growth lines D1, D2, and D8, high dehydroepiandrosterone sulfotransferase activity was characteristic of the rapidity with which hyperplastic alveolar nodules developed into a neoplasms (V-max = 52.8 versus 1.8 fmoles/min/mg protein) while estrone sulfotransferase activity was either not detectable or low (V-max = 5.5 fmoles). After oophorectomy of mice bearing slowly developing tumors, both sulfotransferases in the nonregressing neoplasms showed marked increases in activity (V-max dehydroepiandrosterone = 30.0 fmoles; V-max estrone = 18.5 fmoles). Strain differences not the estrogen receptor content of hormone-dependent rat mammary tumors. In Wistar-Lewis rats the steroid alcohol sulfotransferase activity was at least 35 times higher than in the Sprague-Dawley strain. As was observed in the mouse mammary tumor, Sprague-Dawley rat neoplasms that grew in the absence of ovarian hormones contained significantly greater levels of the steroid alcohol sulfotransferase. Possible correlaion between presence of the steroid alcohol sulfotransferase and the estrogen receptor protein was observed in a limited number of human breast carcinomas.

Differential regulation of two Ca(2+) influx systems by pheromone signaling in Saccharomyces cerevisiae.

The budding yeast Saccharomyces cerevisiae generates calcium signals during the response to mating pheromones that promote survival of unmated cells. A Ca(2+) channel composed of Cch1p and Mid1p was previously shown to be necessary for the production of these calcium signals. However, we find that the Cch1p-Mid1p high-affinity Ca(2+) influx system (HACS) contributes very little to signaling or survival after treatment with alpha-factor in rich media. HACS activity was much greater after calcineurin inactivation or inhibition, suggesting the Cch1p-Mid1p Ca(2+) channel is subject to direct or indirect regulation by calcineurin. Instead a distinct low-affinity Ca(2+) influx system (LACS) was stimulated by pheromone signaling in rich medium. LACS activity was insensitive to calcineurin activity, independent of Cch1p and Mid1p, and sufficient to elevate cytosolic free Ca(2+) concentrations ([Ca(2+)]c) in spite of its 16-fold lower affinity for Ca(2+). Overexpression of Ste12p or constitutive activation of this transcription factor in dig1 dig2 double mutants had no effect on LACS activity but stimulated HACS activity when calcineurin was also inactivated. Ste12p activation had no effect on Cch1p or Mid1p abundance, suggesting the involvement of another target of Ste12p in HACS stimulation. LACS activation required treatment with mating pheromone even in dig1 dig2 double mutants and also required FAR1, SPA2, and BNI1, which are necessary for proper cell cycle arrest and polarized morphogenesis. These results show that distinct branches of the pheromone-signaling pathway independently regulate HACS and LACS activities, either of which can promote survival during long-term responses.

Phage display of intact domains at high copy number: a system based on SOC, the small outer capsid protein of bacteriophage T4.

Peptides fused to the coat proteins of filamentous phages have found widespread applications in antigen display, the construction of antibody libraries, and biopanning. However, such systems are limited in terms of the size and number of the peptides that may be incorporated without compromising the fusion proteins' capacity to self-assemble. We describe here a system in which the molecules to be displayed are bound to pre-assembled polymers. The polymers are T4 capsids and polyheads (tubular capsid variants) and the display molecules are derivatives of the dispensable capsid protein SOC. In one implementation, SOC and its fusion derivatives are expressed at high levels in Escherichia coli, purified in high yield, and then bound in vitro to separately isolated polyheads. In the other, a positive selection vector forces integration of the modified soc gene into a soc-deleted T4 genome, leading to in vivo binding of the display protein to progeny virions. The system is demonstrated as applied to C-terminal fusions to SOC of (1) a tetrapeptide; (2) the 43-residue V3 loop domain of gp120, the human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein; and (3) poliovirus VP1 capsid protein (312 residues). SOC-V3 displaying phage were highly antigenic in mice and produced antibodies reactive with native gp120. That the fusion protein binds correctly to the surface lattice was attested in averaged electron micrographs of polyheads. The SOC display system is capable of presenting up to approximately 10(3) copies per capsid and > 10(4) copies per polyhead of V3-sized domains. Phage displaying SOC-VP1 were isolated from a 1:10(6) mixture by two cycles of a simple biopanning procedure, indicating that proteins of at least 35 kDa may be accommodated.

Technetium-99m labeling of antibodies to cardiac myosin Fab and to human fibrinogen.

We have developed a method of labeling biologically active labile macromolecules, such as human fibrinogen (HF) and anticardiac-myosin Fab (AM-Fab), with Tc-99m at neutral pH. This method uses dithionite reduction of pertechnetate and subsequent labeling, to test the method with acid-labile macromolecules. Complexes of diethylene triamine pentaacetic acid with macromolecules such as human fibrinogen (D-HF) and anticardiac-myosin Fab (D-AM-Fab) were labeled and utilized in in vitro and in vivo studies. In biodistribution studies, the Tc-99m D-HF had a two-component blood clearance (half-times 1 hr and 15 hr) and was 80--88% coagulable. The Tc-99m AM-Fab retained its immunoreactivity as tested by affinity chromatography; also during in vivo localization in experimental myocardial infarction. This labeling technique provides an easy and efficient approach to the Tc-99m labeling of other biologically active and acid-labile macromolecules.

Localization of Fc and Fab fragments of nonspecific polyclonal IgG at focal sites of inflammation.

Intact IgG, Fc, Fab, and 1/2Fc (reduced and alkylated Fc) were coupled to DTPA, labeled with indium-111 and administered to rats to compare the ability of fragments of IgG to localize at focal sites of inflammation. Two sets of experiments were performed: First, 1, 6, 24, and 48 hr after injection, biodistribution was determined in healthy animals; second, localization at sites of inflammation was determined by scintillation camera imaging of animals with deep-thigh infection due to Escherichia coli. The biodistribution studies demonstrated differences in kidney and liver localization: IgG less than Fc less than Fab less than 1/2Fc (kidney), Fc less than 1/2Fc less than IgG less than Fab (liver). The imaging studies revealed that target-to-background ratio (T/B) and percent residual activity (%RA) for IgG was significantly greater (p less than 0.01) than 1/2 Fc or Fab, and T/B for IgG was greater (p less than 0.01) than Fc. These studies suggest that the Fc portion of IgG is the fragment with the best imaging properties.

Radionuclide imaging of experimental atherosclerosis with nonspecific polyclonal immunoglobulin G.

The utility of nonspecific polyclonal IgG for external imaging of experimental atherosclerosis was tested in a series of rabbits after balloon catheter deendothelialization of the abdominal aorta. Following injection of 111In-IgG, 111In-Fc, or 111In-Fab serial images were recorded. In addition, several animals received 125I-low density lipoproteins [125I-LDL], or 125I human serum albumin [125I-HSA] as positive and negative controls. Forty-eight hours after injection of the radiolabeled proteins, the aortas were removed, divided into abdominal and thoracic regions, counted, and autoradiographed. The images acquired after injection of 111In-IgG and 111In-Fc, showed clear focal accumulation of radioactivity in the healing abdominal aorta. In contrast, the images obtained after injection of 111In-Fab did not show focal radionuclide accumulation. For 111In-IgG and 111In-Fc there were three to six times as many counts in the abdominal as in the thoracic aorta, while for 111In-Fab and 125I HSA, the abdominal and thoracic counts were nearly equal. The results suggest that radiolabeled IgG and Fc can be used to image experimental atherosclerosis.

Money and subjective well-being: it's not the money, it's the motives.

Past researchers have argued that the relative importance a person attaches to money is negatively related to subjective well-being (SWB). However, the past research suffers from the theoretical problem of not including the diferent motives for making money. With a sample of 240 business students, the authors developed a set of scales to measure motives for making money. They used a sample of 492 business students to confirm the factor structure of these motives. With another sample of 266 business students, the authors found that the negative relationship between money importance and SWB was due to the two variables being the result of a common cause; namely, the motives of social comparison. seeking power, showing off, and overcoming self-doubt. This finding was replicated with a sample of 145 entrepreneurs.

Beyond determinism and materialism, or isn't it time we took consciousness seriously?

This essay argues: (1) that the fundamental conflict between the behaviorist and cognitive approaches to psychology are philosophical, not scientific; (2) that the philosophical premises underlying behaviorism (materialism, epiphenomenalism, functional model of causality, and the rejection of concepts referring to conscious states and processes) are false; and (3) that an objective, scientific approach to psychology must take consciousness and volition as axiomatic starting points.

Science, philosophy and man's mind.

This paper argues, in disagreement with most of the writers in the special issue [see Reyna (1995) Cognition, behavior and causality: A broad exchange of views stemming from the debate on the causal efficacy of human thought, Journal of Behavior Therapy and Experimental Psychiatry, 20(3)], that: (1) science cannot be separated from philosophy even for the purpose of trying to see which set of assumptions is more "pragmatically useful;" (2) a true understanding of causality eliminates skepticism and reveals why private, conscious events are causes of action; (3) consciousness is directly observable; and (4) the belief in cognition, far from divorcing man from the real world of action, points to the actual cause of action and of political change.

Personality and job satisfaction: the mediating role of job characteristics.

This study tested a model of the relationship between core self-evaluations, intrinsic job characteristics, and job satisfaction. Core self-evaluations was assumed to be a broad personality concept manifested in 4 specific traits: self-esteem, generalized self-efficacy, locus of control, and low neuroticism. The model hypothesized that both subjective (perceived) job characteristics and job complexity mediate the relationship between core self-evaluations and job satisfaction. Two studies were conducted to test the model. Results from Study 1 supported the hypothesized model but also suggested that alternative models fit the data well. Results from Study 2 revealed that core self-evaluations measured in childhood and in early adulthood were linked to job satisfaction measured in middle adulthood. Furthermore, in Study 2 job complexity mediated part of the relationship between both assessments of core self-evaluations and job satisfaction.

Dispositional effects on job and life satisfaction: the role of core evaluations.

Past research has suggested that dispositional sources of job satisfaction can be traced to measures of affective temperament. The present research focused on another concept, core self-evaluations, which were hypothesized to comprise self-esteem, generalized self-efficacy, locus of control, and nonneuroticism. A model hypothesized that core self-evaluations would have direct effects on job and life satisfaction. It also was hypothesized that core self-evaluations would have indirect effects on job satisfaction. Data were collected from 3 independent samples in 2 countries, using dual source methodology. Results indicated that core self-evaluations had direct and indirect effects on job and life satisfaction. The statistical and logical relationship among core evaluations, affective disposition, and satisfaction was explored.