Global COVID-19 Pandemic Outcomes: A Cross-Country Comparison Study of Policy Strategies.

This paper explores global COVID-19 treatment and containment strategies in 108 countries worldwide, specifically the correlation between COVID-19 deaths and the countries' vaccination rates. Comparison of data across states, provinces, territories, and countries relied upon a common method to evaluate data regarding the impact of COVID-19 policies in the last three years. Data from nine different databases were analyzed to determine if there were correlations between the percentage of countrywide COVID-19 deaths/population and countries' percent vaccinated. Secondary outcome measures include the effect of other variables on COVID-19 death rates per country population, including health expenditures and annual income per capita, COVID-19 tests per 1000 people, stringency index (a measure of each country's containment strategies), hydroxychloroquine/ivermectin scores (measure country use), hypertension, obesity, diabetes, and geographic locations. COVID-19 vaccination rates ranged from 0-99% in 108 countries. Bivariate analysis demonstrates the following independent variables to correlate with COVID-19 deaths/population (Spearman correlation coefficient, p value): countrywide COVID-19 vaccination rates (moderate relationship, r=0.39, P < .001); healthcare expenditures per capita per annum (US dollars) (moderate relationship, r=0.46, P < .001), net annual income per capita (moderate relationship, r=0.50, P < .001), COVID-19 tests per 1000 country population (moderate relationship, r=0.36, P < .003); stringency index per country (moderate relationship, r=0.28, P < .003); hydroxychloroquine index (negative relationship, r= 0.15, P = .125); and ivermectin index (negative relationship, r=0.23 P = .018). The authors found that the higher the percentage of a country's vaccination rate, stringent containment strategies, mass testing, etc., moderately correlated with higher COVID-19 death rates/population. Future studies are required to explore the findings of this study fully.

Morphogenic fields: A coming of age.

Morphogenesis, the coming-into-being of living organisms, was first described in the 4th century BC by Aristotle, progenitor of biology and embryology. Over the centuries it has been the subject of innumerable commentaries by philosophers, theologians and scientists but no consensus has ever been reached as to its causes. In the late 19th century, along with the emergence of cellular and molecular biology, embryology underwent a renaissance and became a topic of great interest and research. Early on the discipline divided into two opposing factions, those who attempted to explain fetal development on the basis of cellular and molecular mechanisms, and those who invoked the presence of organizing fields. The morphogenic field was first articulated in the early decades of the 20th century by multiple researchers independently of each other. The field became an extremely useful conceptual tool by which to explain a wide range of developmental phenomena. While embryology and genetics originally formed a unified discipline, during the 1930s and 1940s geneticists became progressively skeptical of the field notion. The discovery of the DNA structure by Watson and Crick in the early 1950s decisively settled matters and thereafter the two disciplines pursued different lines of inquiry. After World War II embryology and the field concept went into a decades-long decline. By the 1980s an increasing number of scientists began to critically reexamine the morphogenic field concept and it underwent a second renaissance. In this paper I examine the development and evolution of the field concept, both experimentally and conceptually, and highlight the failure of genetic mechanisms to explain morphogenesis. I provide three instances from the medical literature of developmental phenomena which are only explainable on the basis of morphogenic field dynamics and argue that the field concept must be readmitted into mainstream scientific discourse.

Plant chlorophyll fluorescence: active and passive measurements at canopy and leaf scales with different nitrogen treatments.

Most studies assessing chlorophyll fluorescence (ChlF) have examined leaf responses to environmental stress conditions using active techniques. Alternatively, passive techniques are able to measure ChlF at both leaf and canopy scales. However, the measurement principles of both techniques are different, and only a few datasets concerning the relationships between them are reported in the literature. In this study, we investigated the potential for interchanging ChlF measurements using active techniques with passive measurements at different temporal and spatial scales. The ultimate objective was to determine the limits within which active and passive techniques are comparable. The results presented in this study showed that active and passive measurements were highly correlated over the growing season across nitrogen treatments at both canopy and leaf-average scale. At the single-leaf scale, the seasonal relation between techniques was weaker, but still significant. The variability within single-leaf measurements was largely related to leaf heterogeneity associated with variations in CO2 assimilation and stomatal conductance, and less so to variations in leaf chlorophyll content, leaf size or measurement inputs (e.g. light reflected and emitted by the leaf and illumination conditions and leaf spectrum). This uncertainty was exacerbated when single-leaf analysis was limited to a particular day rather than the entire season. We concluded that daily measurements of active and passive ChlF at the single-leaf scale are not comparable. However, canopy and leaf-average active measurements can be used to better understand the daily and seasonal behaviour of passive ChlF measurements. In turn, this can be used to better estimate plant photosynthetic capacity and therefore to provide improved information for crop management.

Fiber-reinforced polymeric composites are susceptible to microbial degradation.

A mixed culture of fungi, enriched from degraded polymeric materials, formed biofilms on coupons of fiber-reinforced polymeric composites (FRPCs). They grew actively in aqueous extracts of the composites under ambient conditions. The data indicate that the fungi utilized the resins or fiber chemical sizing as carbon and energy sources. A progressive decline in impedance from above 10(7) Ohms to below 10(8) Ohms was detected in the inoculated FRPC panels by electrochemical impedance spectroscopy (EIS) after 179 days of incubation, but not on the sterile controls. The degradation proceeds through an initial ingress of water into the resins, followed by degradation of bonding between fiber surfaces and resins and finally separation of fibers from the resins. At the end of EIS study, the extent of disbonding in the inoculated composite was greater than the control observed by scanning electron microscopy. These results suggest that the composite materials are susceptible to microbial attack by providing nutrients for growth.

Fungal degradation of fiber-reinforced composite materials.

As described in a previous report, a fungal consortium isolated from degraded polymeric materials was capable of growth on presterilized coupons of five composites, resulting in deep penetration into the interior of all materials within five weeks. Data describing the utilization of composite constituents as nutrients for the microflora are described in this article. Increased microbial growth was observed when composite extract was incubated with the fungal inoculum at ambient temperatures. Scanning electron microscopic observation of carbon fibers incubated with a naturally developed population of microorganisms showed the formation of bacterial biofilms on the fiber surfaces, suggesting possible utilization of the fiber chemical sizing as carbon and energy sources. Electrochemical impedance spectroscopy was used to monitor the phenomena occurring at the fiber-matrix interfaces. Significant differences were observed between inoculated and sterile panels of the composite materials. A progressive decline in impedance was detected in the inoculated panels. Several reaction steps may be involved in the degradation process. Initial ingress of water into the resin matrix appeared to be followed by degradation of fiber surfaces, and separation of fibers from the resin matrix. This investigation suggested that composite materials are susceptible to microbial attack by providing nutrients for growth.

Protein kinase C isotype expression and regulation of lymphoid cell motility.

Lymphocyte migration into inflammatory sites involves a change from a spherical, non-motile phenotype to an irregular, constantly shape-changing, motile phenotype. We have previously shown that lymphocytes are maintained in the non-motile state by the constitutive activity of protein kinase C (PKC). In this paper we have attempted to identify the PKC isotype which regulates these morphological changes by three different approaches. (a) Motile and non-motile T-cell lines were compared for expression of the alpha, beta I, beta II, gamma, delta, epsilon, eta, zeta and theta isotypes by Western blotting. There was no obvious correlation of isotype expression with motility. (b) Two different PKC inhibitors, one specific for classical isotypes, Go6976 and the other GF109203X, which inhibits both classical and non-classical isotypes were compared for induction of motility in non-motile lymphocytes. Only GF109203X induced motility implying that a non-classical isotype is involved. (c) Non-motile lymphocytes were chronically treated with the PKC activator bryostatin and the time courses of induction of motility and downregulation of PKC isotypes were compared. Induction of motility correlated better with downregulation of epsilon, eta and theta than with alpha or beta. It is concluded that the data fit best with the involvement of a non-classical PKC isotype in regulating lymphocyte motility although no association with a particular isotype was found.

Inhibition of protein kinase C results in a switch from a non-motile to a motile phenotype in diverse human lymphocyte populations.

Circulating lymphocytes are rounded, non-motile cells which on contact with cytokines, specialized or activated endothelium, acquire a constantly shape-changing, polarized morphology which enables migration into appropriate sites. The biochemical mechanisms which regulate this switch are not understood but the various stimuli may have a common final pathway. In this study we show that protein kinase C (PKC) inhibitors of the bisindolylmaleimide type (GF 109203X, Ro 31-8220, CGP 41,251) induce resting, spherical lymphocytes to change rapidly (< 30 min) into polarized, locomotory cells. This phenomenon was seen with diverse populations of blood T lymphocytes, tonsillar B cells and Jurkat and Molt4 T-cell lines. Consistent with this, down-regulation of PKC by chronic treatment (44 hr) with bryostatin also induced the polarized phenotype in blood lymphocytes and non-motile Molt4 cells. Conversely, treatment of a spontaneously motile subline of Molt4 cells with various PKC activators caused a reversion to the non-motile phenotype within minutes. PKC activation must be sufficient to overcome the effects of a constitutively active phosphatase because bisindolylmaleimide induction of motility could be prevented by pretreatment of the cells with a phosphatase inhibitor, calyculin A. It is concluded that, in resting lymphocytes, chronic activation of a PKC offsets the action of a constitutively active phosphatase and the net result is maintenance of the non-motile state. Agents which alter the kinase/phosphatase balance in favour of dephosphorylation result in induction of the locomotory phenotype.

Effect of serine/threonine kinase inhibitors on motility of human lymphocytes and U937 cells.

Mononuclear cell migration across the endothelium and through connective tissue into inflammatory sites is a multi-step process. After adhesion to the endothelium, there is an initial change in shape from spherical to irregular, followed by the migratory phase itself in which the cells constantly change in shape. In this paper we have investigated the possibility that the shape-changing in this latter phase is controlled by serine/threonine phosphorylation. For this purpose, we used a spontaneously shape-changing variant of U937 monocytoid cells as well as human peripheral blood lymphocytes that had been previously activated by anti-CD3. To test the role of phosphorylation in shape-changing, a wide range of serine/threonine kinase inhibitors was tested, including ML-7, KT5720, KT823, H7, H8, staurosporine, calphostin C, sphingosine, bisindolylmaleimide, chelerythrine and KN-62. Only those compounds which inhibited protein kinase C prevented lymphocyte and U937 shape-change and transmigration across polycarbonate filters. However, one specific protein kinase C inhibitor, bisindolylmaleimide, stimulated lymphocyte shape-change. In conclusion, these studies show that activation of a serine/threonine kinase is necessary for the constant shape-changing required for motility of mononuclear cells. The kinase may be a protein kinase C isotype or a closely related enzyme.

Magnetic resonance angiography in intracranial vascular disease.

Magnetic resonance angiography (MRA) offers a noninvasive alternative for studying normal and pathological blood vessels within the brain. Insights from important clinical aspects of intracranial vascular disease enable the effective application of MRA. Several MRA techniques have demonstrated clinical utility for the detection and characterization of intracranial vascular pathology. Clinical protocols should comprise combinations of time-of-flight and phase-contrast acquisitions to achieve diagnostic sensitivity.

Tumour necrosis factor induction of ELAM-1 and ICAM-1 on human umbilical vein endothelial cells--analysis of tumour necrosis factor-receptor interactions.

Induction of the adhesion molecules ELAM-1 and ICAM-1 on endothelial cells is a key pro-inflammatory effect of tumour necrosis factor (TNF). Earlier work in non-human systems has suggested that unlike other cell types, endothelial cells interact with the N-terminus of the TNF molecule, thereby implying novel TNF receptors on endothelial cells. This is also supported by 125I-TNF cross-linking studies on bovine endothelial cells. The present study aimed to see whether TNF induction of ELAM-1 and ICAM-1 on human umbilical vein endothelial cells (HUVECs) involved novel TNF-receptor interactions. Three approaches were employed. First, antibodies directed at different sites on the TNF molecule were tested for inhibition of TNF-induction of ELAM-1 and ICAM-1 on HUVECs. Inhibition was seen only with antibodies reacting with epitopes outside the N-terminal region. Second, an N-terminal TNF peptide (residues 1-26) failed to induce ELAM-1 and ICAM-1 on HUVECs or antagonise TNF induction of these molecules. Third, HUVEC/125I-TNF cross-linking revealed a major complex characteristic of the known 55 kDa TNF receptor: this was confirmed with receptor-specific monoclonal antibodies. It is concluded that (a) the same part of the TNF molecule interacts with TNF-receptors on HUVECs and other cell types and (b) TNF induction of ELAM-1 and ICAM-1 on HUVECs is mediated via the well-characterized 55 kDa TNF receptor.

Immunosuppression with high doses of cyclophosphamide reduces the severity of myocarditis but increases the mortality in murine Coxsackievirus B3 myocarditis.

To test the therapeutic efficacy of immunosuppression with cyclophosphamide (CYP) on coxsackievirus B3 (CB3) myocarditis, 2-week-old DBA/2 mice were inoculated with 3 X 10(2) plaque-forming units of CB3 virus. CYP (100 mg/kg/day s.c.) was administered daily on days 0-8 (experiment 1; group 2), days 8-21 (experiment 2; group 4), and days 21-34 (experiment 3; group 6). Groups 1, 3, and 5 were infected control groups for each experiment. Spleen, thymus, and body weights were measured. In experiment 1, survival rate in group 2 on day 8 was low compared with group 1 (nine of 51 versus eight of 28; p = NS), and myocardial virus titers in group 2 on day 8 were higher (p less than 0.05) compared with group 1; however, cellular infiltration and myocardial necrosis in group 2 were less severe (p less than 0.05), and serum neutralizing antibody titers were decreased (p less than 0.01). In experiment 2, survival rate in group 4 on day 21 was significantly lower (six of 24 versus 12 of 16; p less than 0.01), but cellular infiltration, myocardial necrosis, and calcification in group 4 were significantly less severe, and serum neutralizing antibody titers were decreased (p less than 0.01). In experiment 3, survival rate, cardiac histopathology, and serum neutralizing antibody titers did not differ between groups 5 and 6. In experiments 1, 2, and 3, the treated groups were characterized by lower spleen-to-body-weight and thymus-to-body-weight ratios and by marked cellular depletion in spleen and thymus.(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium permeability and myocardial resistance to cell swelling during metabolic blockade.

The role of cell membrane permeability to sodium in cell volume regulation during inhibition of the sodium-potassium exchange pump with ouabain and during total metabolic blockade was evaluated in sections of guinea pig renal cortex, ventricle, and atrium incubated in Krebs-Henseleit solution. In all tissues, 2 and 3 h of ouabain and metabolic blockade resulted in similar marked losses of potassium and parallel continuous reductions in resting membrane potentials. Only metabolic blockade of renal cortex increased cell water, chloride, and total monovalent cations (potassium plus sodium) significantly. Compared to ouabain, metabolic blockade markedly increased the rate of cellular washout of 24Na+ from renal cortex (t 1/2 reduced by 47%), which was significantly greater than reductions in t 1/2 from ventricle (16%) and atrium (15%). Thus, inhibition of sodium-potassium exchange pump activity was not sufficient to produce cell swelling unless associated with marked increases in cell membrane permeability to sodium, in which case sodium influx exceeded potassium loss and substantial increases in monovalent cations, chloride, and water occurred.

Anion exchange and volume regulation during metabolic blockade of renal cortical slices.

1. The development of swelling of rat and guinea-pig renal cortical slices was studied after metabolic blockade (hypoxia plus glycolytic blockade with iodo-acetic acid) and/or exposure to 'isotonic' high potassium, no sodium solution. 2. Swelling was greater after exposure to oxygenated high potassium solution than after metabolic blockade in physiologic Krebs-Henseleit solution. Swelling was reduced after metabolic blockade in high potassium solution compared to incubation in oxygenated high potassium solution. Increasing periods of transient metabolic blockade in Krebs-Henseleit solution progressively blunted swelling when slices were subsequently incubated in oxygenated high potassium solution. 3. Metabolic blockade in Krebs-Henseleit solution resulted in marked reductions in potassium and increases in sodium. Incubation in high potassium solution resulted in marked increases in potassium and similar low levels of sodium regardless of associated interventions. Metabolic blockade in both media resulted in significantly greater increases in renal cortical chloride than in monovalent cations (potassium plus sodium). Incubation in oxygenated high potassium solution was associated with similar increases in renal cortical chloride and total monovalent cations. 4. Renal cortical losses of solids and protein and increases in renal cortical inulin space were greater after metabolic blockade than after incubation under oxygenated conditions regardless of the incubation media. 5. These data support the conclusion that during metabolic blockade there is a significant replacement of larger intracellular anions by extracellular chloride. The loss of osmotically active intracellular anions limits the increase in renal cortical volume during metabolic inhibition and exposure to high potassium solution.

Increased myocardial catalase in rats fed ethanol.

The effects of chronic intake of dietary ethanol upon catalase, an enzyme capable of metabolizing ethanol, as well as upon myocardial morphology and hemodynamics, were studied in the rat. Ethanol, comprising 36% of dietary calories, administered to rats for 5 weeks, was associated with increased myocardial catalase of 45.9 +/- 3.7 IU/mg protein, compared to 21.0 +/- 1.8 IU/mg protein in pair-fed controls. The enzyme activity remained significantly elevated after 18 weeks of ethanol. Hepatic catalase did not differ in these groups. Parallel cytochemical studies confirmed the increase in myocardial catalase by demonstrating an increase in peroxisomes. Gross and light-microscopic examinations revealed no abnormalities at either 5 or 18 weeks. Remarkably few ultrastructural abnormalities were seen in this material fixed by vascular perfusion. Hemodynamic studies after 5 weeks of ethanol revealed decreased left ventricle systolic pressure and decreased mean arterial pressure but no change in ventricular filling pressure. The possibility of catalase playing a metabolic and potentially protective role in rat myocardium chronically exposed to ethanol is discussed.

The effect of sodium salicylate on acute Chagasic myocarditis in C3H mice.

In two separate experiments, six months apart, utilizing different controls and different methods, sodium salicylate in anti-inflammatory doses was administered by gavage to mice with acute Chagasic myocarditis (T. cruz) at the onset of parasitemia. Sodium citrate was used as a control. Animals given salicylate showed decreased blood trypanosome counts and myocardial pseudocyst formation, both absolutely and in the rates of formation. Decreased inflammation and necrosis were associated with salicylate therapy. Survival of the animals was not increased by treatment. The effects cannot be explained by sodium ion concentration, the technique of gavage, or any factor except the presence of salicylate ion.

Heart muscle performance after experimental viral myocarditis.

As part of an inquiry into possible antecedents of idiopathic cardiomyopathy, acute experimental coxsackie virus myocarditis was studied for late structural and functional sequelae. Myocarditis was induced in 12- and 22-day-old hamsters by inoculation with coxsackie virus B3. Early viremia occurred, followed by virus replication in heart muscle. Maximum peak developed tension (Tpd) of isometrically contracting isolated heart muscle was depressed 17 and 43% in the animals inoculated at 12 days, and studied 18 and 90 days later, respectively, as compared to their uninoculated controls. In both infected groups, less muscle stretch was required to reach the length at which Tpd was produced. Animals studied 180 days after inoculation did not differ from controls. The muscles from animals inoculated at 22 days of age and studied 18 days later showed a 15% depression of Tpd compared to their controls. Glycerinated muscles from this infected group developed 50% less tension than their controls. The muscles of hamsters inoculated with virus at 22 days and studied 90 and 180 days later showed no change in Tpd. The data suggest that contractility and compliance of heart muscle are decreased 18 days after inoculation, but recover by 90 days if the animals are inoculated at age 22 days. However, if the animals are inoculated at a younger age (12 days), depression of myocardial performance persists for at least an additional 90 days. It is concluded that the inflammatory stage of experimental acute coxsackie virus B3 myocarditis in the Syrian golden hamster may be followed by residual alterations in contractile proteins and myocardial function.

Protective effect of coexistent thiamine deficiency upon the experimental cardiomyopathy associated with acute magnesium deficiency in the Syrian golden hamster.

Repeated efforts to induce beriberi heart disease by experimental thiamine deficiency (B1d) have failed in many species. To test the hypothesis that magnesium deficiency (Mgd) might be the cofactor necessary for heart failure, 10-week-old Syrian golden hamsters were divided into four groups-control (C), B1d, Mgd, and combined MgB1d-and were fed the diets ad libitum for 3 weeks. On day 21, animals were studied under intraperitoneal pentobarbital anesthesia (50 mg/kg). Electrocardiograms were taken and right and left ventricular pressures were measured by transthoracic needle puncture. Cardiac output was measured by the direct Fick method. The complete study was performed in 9 C, 13 B1d, 9 Mgd, and 14 MgB1d animals. B1d was proven by low red blood cell transketolate high B1 pyrophosphate effect, and was accompanied by tachycardia and hypercalcemia. B1 did not differ from C in any other parameter. Mgd was characterized by hypomagnesemia, hypercalcemia, prolongation of the PR interval, widening of the QRS interval, low O2 consumption, low cardiac output, and increased heart weight to body weight ratio (HW/BW) as compared to control. No differences were observed in right and left ventricular pressures or peak /dt. MgB1d was characterized by hypomagnesium, hypercalcemia, low red blood cell transkeotlase, and high B1 pyrophosphate effect. MgB1d minimized the deleterious effects of Mgd: animals were more active and the mortality was low, the PR interval remained normal, the QRS interval widened significantly less, cardiac output remained normal, and HW/BW increased significantly less. Although, once again, beriberi heart disease was not produced, B1d appeared to exert a protective effect upon the Mg-deficient myocardium.