Understanding the age divide in COVID-19: why are children overwhelmingly spared?

The rapid emergence and subsequent global dissemination of SARS-CoV-2 disease (COVID-19) has resulted in over 4 million cases worldwide. The disease has a marked predilection for adults, and children are relatively spared. Understanding the age-based differences in pathophysiological pathways and processes relevant to the onset and progression of disease both in the clinical course and in experimental disease models may hold the key to the identification of therapeutic targets. The differences in the clinical course are highlighted by the lack of progression of the SARS-CoV-2 infection beyond mild symptoms in a majority of children, whereas in adults the disease progresses to acute lung injury and an acute respiratory distress syndrome (ARDS)-like phenotype with high mortality. The pathophysiological mechanisms leading to decreased lung injury in children may involve the decreased expression of the mediators necessary for viral entry into the respiratory epithelium and differences in the immune system responses in children. Specifically, decreased expression of proteins, including angiotensin-converting enzyme 2 (ACE2) and Transmembrane Serine Protease 2 (TMPRSS2) in the airway epithelium in children may prevent viral entry. The immune system differences may include a relative preponderance of CD4+ T cells, decreased neutrophil infiltration, decreased production of proinflammatory cytokines, and increased production of immunomodulatory cytokines in children compared with adults. Notably, the developing lung in children may have a greater capacity to recover and repair after viral infection. Understanding the relative contributions of the above processes to the protective phenotype in the developing lung can guide the trial of the appropriate therapies in adults.

Hierarchical complex self-assembly in binary nanoparticle mixtures.

Hierarchical self-assembly of soft matter provides a powerful route to create complex materials with enhanced physical properties. The understanding of the fundamental processes leading to such organization can provide design rules to create new functional materials. In this work, we use a simple model of polymer-grafted nanoparticles to explore the self-assembly of binary mixtures. By using Monte Carlo simulations we study the interplay of composition, density and particle sizes on the self-organization of such nanoparticle systems. It is found that complex hierarchical organization can take place for conditions where one-component systems form simple lattices. In particular, a mixture where one component forms a structure with 18-fold symmetry in a sea of an apparent disordered phase of the second component is observed to emerge for certain parameter combinations.

Thermodynamic properties of confined square-well fluids with multiple associating sites.

In this work, a molecular simulation study of confined hard-spheres particles with square-well (SW) attractive interactions with two and four associating SW sites based on the first-order perturbation form of Wertheim's theory is presented. An extended version of the Gibbs ensemble technique for inhomogeneous fluids [A. Z. Panagiotopoulos, Mol. Phys. 62, 701 (1987)] is used to predict the adsorption density profiles for associating fluids confined between opposite parallel walls. The fluid is confined in four kinds of walls: hard-wall, SW wall, Lennard-Jones (LJ) 12-6 wall potential, and LJ 10-4 wall potential. We analyze the behavior of the confined system for several supercritical temperatures as a function of variation of molecular parameters: potential range λ, bulk densities ρb*, pore width H, cutoff range interaction rc*, and range of the potential and depth of the particle-wall (λw, εw*). Additionally, we include predictions for liquid-vapor coexistence of bulk associative particles and how their critical properties are modified by the presence of associative sites in the molecule. The molecular simulation data presented in this work are of prime importance to the development of theoretical approaches for inhomogeneous fluids as classical density functional theory. The simulation results presented here are resourceful for predicting adsorption isotherms of real associating fluids such as water.

Self-assembly of kagome lattices, entangled webs and linear fibers with vibrating patchy particles in two dimensions.

A vibrating version of patchy particles in two dimensions is introduced to study self-assembly of kagome lattices, disordered networks of looping structures, and linear arrays. Discontinuous molecular dynamics simulations in the canonical ensemble are used to characterize the molecular architectures and thermodynamic conditions that result in each of those morphologies, as well as the time evolution of lattice formation. Several versions of the new model are tested and analysed in terms of their ability to produce kagome lattices. Due to molecular flexibility, particles with just attractive sites adopt a polarized-like configuration and assemble into linear arrays. Particles with additional repulsive sites are able to form kagome lattices, but at low temperature connect as entangled webs. Abundance of hexagonal motifs, required for the kagome lattice, is promoted even for very small repulsive sites but hindered when the attractive range is large. Differences in behavior between the new flexible model and previous ones based on rigid bodies offer opportunities to test and develop theories about the relative stability, kinetics of formation and mechanical response of the observed morphologies.

Spontaneous chiral resolution in two-dimensional systems of patchy particles.

Short ranged potentials and their anisotropy produce spontaneous chiral resolution in a two dimensional model of patchy particles introduced in this paper. This model could represent an equimolar binary mixture (racemic mixture) of two kinds of chiral molecules (enantiomers) adsorbed to a bi-dimensional domain where only lateral short ranged interactions are present. Most racemic mixtures undergo chiral resolution due to their spatial anisotropy, the combined effect of long range forces and the thermodynamic conditions. The patchy particles are modeled as a hard disk and four different bonding sites located to produce chirality. Phase behavior and structural properties are analysed using Discontinuous Molecular Dynamics in the canonical ensemble. When the four patchy particles are separated by the angles {60°, 120°, 60°, 120°}, spontaneous chiral resolution is produced, given by the formation of homochiral clusters, if started from the corresponding racemic mixture. Gel behavior is also obtained in all the systems for low temperatures and low densities.

Phase diagram of a square-well model in two dimensions.

The phase behavior of a two-dimensional square-well model of width 1.5σ, with emphasis on the low-temperature and/or high-density region, is studied using Monte Carlo simulation in the canonical and isothermal-isobaric ensembles, and discontinuous molecular-dynamics simulation in the canonical ensemble. Several properties, such as equations of state, Binder cumulant, order parameters, and correlation functions, were computed. Numerical evidence for vapor, liquid, hexatic, and triangular solid is given, and, in addition, a non-compact solid with square-lattice symmetry is obtained. The global phase diagram is traced out in detail (or sketched approximately whenever only inaccurate information could be obtained). The solid region of the phase diagram is explained using a simple mean-field model.

Liquid-vapor equilibrium and surface properties of short rigid chains with one long range attractive potential.

Liquid-vapor coexistence and interfacial properties of short lineal rigid vibrating chains with three tangent monomers in two and three dimensions are calculated. The effect of the range and position of a long ranged square well attractive potential is studied. Orthobaric densities, vapor pressures, surface tensions, and interfacial widths are reported. Two types of molecules are studied. Chains of three tangent hard sphere monomers and chains of three and five tangent hard sphere monomers interacting with a square well attractive potential with λ(∗) = λ∕σ = 1.5 in units of the hard core diameter σ. The results are reported in two and three dimensions. For both types of chains, a long ranged square well attractive potential is located at various positions in the chain to investigate its effect in the properties of the corresponding systems. Results for hard sphere chains are presented for a series of different sizes of λ(∗) between 2.5 and 5. For square well chains the position in the chain of the long ranged potential has no influence in the coexistence and interfacial properties. Critical temperatures increase monotonically with respect to λ(∗) and critical densities decrease systematically for both types of chains. When the long ranged potential is located in the middle monomer of the hard sphere chains no critical point is found for λ(∗) < 2.4. No critical point is found when the long ranged potential is located in one of the extremes of the hard sphere chains.

Effect of flexibility on liquid-vapor coexistence and surface properties of tangent linear vibrating square well chains in two and three dimensions.

The effect of flexibility on liquid-vapor and interfacial properties of tangent linear vibrating square well chains is studied. Surface tension, orthobaric densities, vapor pressures, and interfacial thicknesses are reported and analyzed using corresponding states principles. Discontinuous molecular dynamics simulations in two and three dimensions are performed on rigid tangent linear vibrating square well chains of different lengths. In the case of two dimensions, simulation results of completely flexible tangent linear vibrating square well chains are also reported. Properties are calculated for chains of 2-12 monomers. Rigidity is controlled by trapping the first and last monomer in the chain in a vibrating well at half of the distance of the whole chain. Critical property values are reported as obtained from orthobaric densities, surface tensions, and vapor pressures. For the fully flexible chains, the critical temperatures increase with chain length but the effect saturates. In contrast, the critical temperatures increase for the rigid chains until no more critical point is found.

Liquid-vapor equilibrium and interfacial properties of square wells in two dimensions.

Liquid-vapor coexistence and interfacial properties of square wells in two dimensions are calculated. Orthobaric densities, vapor pressures, surface tensions, and interfacial thicknesses are reported. Results are presented for a series of potential widths λ* = 1.4, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5, where λ* is given in units of the hard core diameter σ. Critical and triple points are explored. No critical point was found for λ* < 1.4. Corresponding states principle analysis is performed for the whole series. For λ* = 1.4 and 1.5 evidence is presented that at an intermediate temperature between the critical and the triple point temperatures the liquid branch becomes an amorphous solid. This point is recognized in Armas-Pérez et al. [unpublished] as a hexatic phase transition. It is located at reduced temperatures T* = 0.47 and 0.35 for λ* = 1.4 and 1.5, respectively. Properties such as the surface tension, vapor pressure, and interfacial thickness do not present any discontinuity at these points. This amorphous solid branch does not follow the corresponding state principle, which is only applied to liquids and gases.

Numerical evidence for nematic and smectic behavior of two-dimensional hard models.

The mesophases of two infinitely hard models with chiral and anisotropic characteristics in two dimensions are studied. Evidence for nematic and smectic behavior is provided via Monte Carlo simulations using restrictive values of the molecular parameters. Both models are geometrically chiral; one has polar structure. The concept of smectic phase considered in this work requires translational disorder in one direction and signs of translational order in the perpendicular one. The models presented in this paper show these characteristics. The isotropic-nematic phase transition satisfies the features of the Kosterlitz Thouless type. The smectic phase shows signs of quasi-long-range order.

Nematic and smectic ordering in a system of two-dimensional hard zigzag particles.

The orientational and positional ordering of the two-dimensional system of hard zigzag particles has been investigated by means of Onsager theory. Analytical results are obtained for the transition densities of the isotropic-nematic and the nematic-smectic phase transitions. It is shown that the stability of the nematic and smectic phases is very sensitive to the molecular shape. In the hard needle limit, only the isotropic-nematic phase transition takes place, while increasing the tail length and the bent angle between the central core and the tails destabilizes the nematic phase. On the other hand the stability of the smectic phase is due to the increasing excluded area cost with bent angle and the tail length. The zigzag particles pack in a layered structure such that they are tilted and form semi-ideal gas in the layers to push the high cost excluded area regions into the interstitial regions. The predictions of Onsager theory are in good agreement with MC simulation data.

In vivo pharmacological evaluation of compound 48/80-induced airways oedema by MRI.

BACKGROUND AND PURPOSE: Allergen-induced airways oedema in actively sensitized rats has been studied earlier by magnetic resonance imaging (MRI). We used MRI to follow the consequences of non-immunological mast cell activation induced by compound 48/80 in the rat lungs in vivo. EXPERIMENTAL APPROACH: Male naïve rats were scanned by MRI prior to and at several time points following intratracheal administration of the mast cell secretagogue, compound 48/80. The effects of a range of drugs on the response induced by compound 48/80 were studied. KEY RESULTS: Strong fluid signals were detected by MRI in the lungs at 24 h after compound 48/80, correlating with increased protein concentration and inflammatory cell infiltration in bronchoalveolar lavage, and with perivascular oedema observed histologically. Pharmacological intervention demonstrated that the increase in MRI signal volume induced by compound 48/80 24 h after challenge was blocked by disodium cromoglycate and the glucocorticoid, budesonide. Pretreatment with wortmannin, capsazepine, DNK333 (a dual neurokinin (NK) 1 and NK2 antagonist) or the anti-allergy drug CGS8515, but not indomethacin, resulted in partial inhibition. CONCLUSIONS AND IMPLICATIONS: Compound 48/80 induced a complex inflammatory reaction which did not solely involve mast cell degranulation but also activation of sensory nerves and was qualitatively similar to allergen challenge. Changes observed by MRI correlated with decreases in protein concentration in BAL fluid. However, the magnitude of the changes detected was greater using MRI. Our results demonstrate that MRI is a sensitive and efficient tool to assess the effects of drugs on lung inflammation.

Capsaicin-induced mucus secretion in rat airways assessed in vivo and non-invasively by magnetic resonance imaging.

BACKGROUND AND PURPOSE: An up-regulation of the sensory neural pathways in the lung has been implicated in asthma and chronic obstructive pulmonary disease (COPD) and is thought to contribute to mucus hypersecretion, an essential feature of both diseases. The aim of this study was to assess non-invasively the acute effects (up to 60 min) of sensory nerve stimulation by capsaicin in the lung, using magnetic resonance imaging (MRI). EXPERIMENTAL APPROACH: Male Brown Norway rats were imaged prior to and 10, 30 and 60 min after intra-tracheal challenge with capsaicin (30 microg kg(-1)) or vehicle (0.5% ethanol solution). In subsequent studies, pre-treatment with the transient receptor potential vanilloid (TRPV)-1 antagonist, capsazepine; the dual neurokinin (NK) 1 and NK2 receptor antagonist, DNK333 and the mast cell stabilizer, di-sodium cromoglycate (DSCG) was used to modulate the effects of capsaicin. KEY RESULTS: Diffuse fluid signals were detected by MRI in the lung as early as 10 min after capsaicin, remaining constant 30 and 60 min after treatment. Broncho-alveolar lavage (BAL) fluid analysis performed 60 min after capsaicin revealed increased mucin concentration. Capsazepine (3.5 mg kg(-1)), DNK333 (10 mg kg(-1)) but not DSCG (10 mg kg(-1)) administered prophylactically were able to block the effect of capsaicin in the airways. CONCLUSIONS AND IMPLICATIONS: These observations suggest that the fluid signals detected by MRI after capsaicin administration reflected predominantly the release of mucus following activation of sensory nerves. They point to the opportunity of non-invasively assessing with MRI the influence of neuronal mechanisms in animal models of asthma and COPD.

Two-dimensional chiral model for liquid crystals, bent hard needles: a Monte Carlo simulation.

The liquid crystalline behavior of a two dimensional (2D) model of hard needles bent into a "zigzag shape" is studied. This model, originally designed to study two dimensional chiral segregation, also shows liquid crystalline behavior and has some anomalous features which are contrasted in relation to the following: (i) Most of the microscopical models used to study liquid crystals have a symmetry axis that coincides with a molecular axis; (ii) in three-dimensions, chiral molecules can form cholesteric instead of nematic phases; (iii) the smectic phase is usually found when attractions are present or at least when the molecules have finite volume. Despite the fact that the present 2D model does not have any of these characteristics, numerical evidence is found for the occurrence of nematic and smectic phases. Since these molecules are athermal, infinitely repulsive, and infinitesimally thin, the liquid crystalline characteristics are attributed to excluded volume effects. To determine the mesophases of the model, both nematic and smectic order parameters as well as distribution functions are computed.

Effects of endotoxin and allergen alone and in combination on the sensitivity of the rat airways to adenosine.

1 The airways of patients with asthma are hyperresponsive to adenosine. The phenomenon can be mimicked in the actively sensitized Brown Norway rat by exposure to allergen or lipopolysaccharide (LPS). We wondered whether combined treatment with allergen and endotoxin would result in additive effects or synergism with respect to increasing the sensitivity of the airways of the Brown Norway rat to adenosine. 2 Animals actively sensitized to ovalbumin and challenged intratracheally with allergen or endotoxin manifested increased bronchoconstrictor responses to adenosine. A combination of ovalbumin and endotoxin also increased the response to adenosine but the effects were at best additive. 3 Changes in the response to adenosine were selective as responses to 5-hydroxytryptamine were unaltered following ovalbumin or LPS either alone or in combination. 4 Thus, endotoxin and allergen acting together could play a role in up-regulating the response of the human asthmatic airway to adenosine. However, our data suggest that the interaction would be additive rather than synergistic.

Encuesta sobre los métodos de diagnóstico microbiológico de la infección urinaria / Survey on methods for the microbiological diagnosis of urinary tract infection

La infeccióm del tracto urinario (ITU), patología infecciosa altamente prevalente, debe ser confirmada por un diagnóstico microbiológico. El Comité de Microbiología Clínica de la Sociedad Chilena de Infectología realizó una encuesta retrospectiva para conocer la situación actual de algunos laboratorios asistenciales sobre metodología y criterios diagnósticos empleados empleados en el diagnóstico de ITU. Respondieron la encuesta 15 centros hospitalarios y laboratorios privados recopilándose información sobre 49.632 urocultivos. Es destacable que la totalidad de los laboratorios consideraron como criterio microbiológico de ITU un recuento microbiano > 100.000 ufc/ml. No fue posible analizar datos con recuentos inferiores por no disponerse de datos métodos sobre obtención de muestra, resultados del estudio microscópico (sedimiento urinario) concominate y sintomatología clínica. Utilizando este criterio diagnóstico la positividad varió entre 2,3 por ciento en varones y 33 por ciento en mujeres, porcentajes con una mayor dispersión en niños. Sólo 13 por ciento de las intituciones procesaron la muestra de orina en conocimiento del tiempo transcurrido desde la obtención de la muestra. Todos los laboratorios utilizaron el mismo criterio para considerar contaminada una muestra: > 3 microorganismo; algunos de ellos registraron 17 por ciento de contaminación. Si bien esta encuesta fue retrospectiva limitando la calidad del diagnóstico de situación, ella motivó al Comite de Microbiología Clínica a elaborar recomendaciones para el diagnóstico microbiológico de la infección urinaria

Microbiological contamination of Araucanian and North Patagonian lakes. 10th Region. Chile.

The microbiological distribution in two lakes from the Xth Region of Chile is studied. In the Lake Ranco (Araucanian), the viable counts were high and ranged from 20 to 1050 CFU/ml. The numbers of total coliforms were high, with densities between 9 and 842 CFU/100 ml. The predominant bacterial flora in the water were Enterobacteriaceae (34.0%). In the sediment the bacterial densities were always higher. Sulphate-reducing bacteria were detected in the sediments. The Lake Yelcho (Nordpatagonic), presented a very high count in relation with its oligotrophic state. In some places there were fecal coliforms. The predominant bacterial flora in the water samples corresponded to Flavobacterium-Flexibacter (26.4%) and Pseudomonas (22.0%). In the sediment the higher viable counts and total coliforms were obtained in sites adjacent to a salmon farm; the MPN of sulphate-reducing bacteria was 29500 bacteria/100g.

Randomized, controlled trial of amitriptyline versus placebo for adolescents with "treatment-resistant" major depression.

OBJECTIVE: To assess the response to a serotonergic/noradrenergic tricyclic antidepressant, amitriptyline (AMI), in a group of adolescents with treatment-resistant major depressive disorder (MDD). METHOD: Twenty-seven depressed adolescents admitted to a state hospital underwent a 10-week randomized, controlled trial with a flexible dose of AMI or placebo. RESULTS: There were no differences between patients taking AMI (n = 13) and placebo (n = 14). Both treatment groups showed approximately 70% to 80% improvement on the clinical outcome measurements, and 65% to 70% showed functional improvement. At the end of the protocol, 30% of patients still fulfilled criteria for MDD and had impaired functioning. Patients taking AMI experienced significantly more dry mouth and tachycardia. The final AMI dose was 173.1 mg/day +/- 56.3 mg/day; blood levels were 226.2 ng/mL +/- 80.8 ng/mL. CONCLUSIONS: No significant differences were found between AMI and placebo, in part because of the high placebo response rate. Although both treatment groups showed substantial response, at the end of treatment a substantial proportion of patients still had MDD of subsyndromal symptoms of depression. This and other studies of tricyclic antidepressants question the use of this medication as first-line treatment for youths with MDD.

[Antibiotic effect of wild Streptomyces strains isolated from Chilean soils]. / Efecto antibiótico de cepas silvestres de Streptomyces aisladas de suelos chilenos.

BACKGROUND: The soils of the southern part of Chile, that are isolated, cold, humid, poorly oxygenated and with a low acidity, could contain new strains of antimicrobial producing Streptomyces. AIM: To demonstrate that the soil of the Southern region of Chile contains Streptomyces strains with antimicrobial activity towards pathogenic bacteria and fungi. MATERIAL AND METHODS: Two hundred fifty eight soil and sediment samples were collected from 148 places in Southern regions of Chile. They were cultured in Küster-Williams growth media and the presence of Streptomyces was confirmed by microscopic examination and biochemical characterization. The antimicrobial activity against reference microorganisms of each wild strain was tested using the disk method. Among active Streptomyces strains, 38 with the higher activity were selected and tested against 142 clinical microorganisms. RESULTS: Seventy seven percent of soils were positive and 542 wild strains of Streptomyces were isolated; of these, 266 had antimicrobial activity. Fifty three percent of isolates had activity against S aureus 43% against B subtilis and 0.7% against E coli. Most Streptomyces were active against more than one organism. When there was activity against single organisms, these were mostly eucariotic, such as C albicans and T mentagrophytes. Among clinical microorganisms, 29% of S aureus strains were inhibited, while P aeruginosa, Alternaria sp, P vulgaris and Y enterocolitica strains were not inhibited. The most frequent Streptomyces morphotypes were those showing pigmented colonies with flexuous and spiral shaped chains of arthrospores. CONCLUSIONS: Soils of the Southern region of Chile allow the growth of abundant native strains of Streptomyces with a promising antimicrobial activity.

Case study: risperidone in children and adolescents with schizophrenia.

Schizophrenia in children is an uncommon disorder with devastating effects. Study of the efficacy of treatment with neuroleptics in children with schizophrenia is only now beginning, and there are limited studies on the effectiveness of novel neuroleptics on the positive and negative symptoms of schizophrenia in children. Four patients with schizophrenia, aged 12 to 17 years, were treated with risperidone (4 to 5 mg/day), a 5-HT2/D2 receptor blocking agent, to determine its effectiveness. Three patients had substantial improvement in their negative symptoms without side effects.