How a single perioperative delirium case can make the difference.

This report describes how postoperative delirium in an elderly man during COVID-19 pandemic led to a serious event involving a central venous catheter. Delirium is a common cause of perioperative morbidity and mortality, and is characterised by an alteration in consciousness and perception and a reduced ability to focus, sustain or shift attention. The event was analysed by a multidisciplinary committee which developed a risk stratification delirium protocol in order to prevent similar events in the future.

Thermodynamic and kinetic analysis of the LAO binding protein and its isolated domains reveal non-additivity in stability, folding and function.

Substrate-binding proteins (SBPs) are used by organisms from the three domains of life for transport and signalling. SBPs are composed of two domains that collectively trap ligands with high affinity and selectivity. To explore the role of the domains and the integrity of the hinge region between them in the function and conformation of SBPs, here, we describe the ligand binding, conformational stability and folding kinetics of the Lysine Arginine Ornithine (LAO) binding protein from Salmonella thiphimurium and constructs corresponding to its two independent domains. LAO is a class II SBP formed by a continuous and a discontinuous domain. Contrary to the expected behaviour based on their connectivity, the discontinuous domain shows a stable native-like structure that binds l-arginine with moderate affinity, whereas the continuous domain is barely stable and shows no detectable ligand binding. Regarding folding kinetics, studies of the entire protein revealed the presence of at least two intermediates. While the unfolding and refolding of the continuous domain exhibited only a single intermediate and simpler and faster kinetics than LAO, the folding mechanism of the discontinuous domain was complex and involved multiple intermediates. These findings suggest that in the complete protein the continuous domain nucleates folding and that its presence funnels the folding of the discontinuous domain avoiding nonproductive interactions. The strong dependence of the function, stability and folding pathway of the lobes on their covalent association is most likely the result of the coevolution of both domains as a single unit.

Surface diffusion in narrow channels on curved domains.

We study the transport properties of diffusing particles restricted to confined regions on curved surfaces. We relate particle mobility to the curvature of the surface where they diffuse and the constraint due to confinement. Applying the Fick-Jacobs procedure to diffusion in curved manifolds shows that the local diffusion coefficient is related to average geometric quantities such as constriction and tortuosity. Macroscopic experiments can record such quantities through an average surface diffusion coefficient. We test the accuracy of our theoretical predictions of the effective diffusion coefficient through finite-element numerical solutions of the Laplace-Beltrami diffusion equation. We discuss how this work contributes to understanding the link between particle trajectories and the mean-square displacement.

Swim Bladder of Farmed Totoaba macdonaldi: A Source of Value-Added Collagen.

Finding strategies to use the swim bladder of farmed totoaba (Totoaba macdonaldi) is of the utmost need to reduce waste. Fish swim bladders are rich in collagen; hence, extracting collagen is a promising alternative with benefits for aquaculture of totoaba and the environment. The elemental biochemical composition of totoaba swim bladders, including their proximate and amino acid compositions, was determined. Pepsin-soluble collagen (PSC) was used to extract collagen from swim bladders, and its characteristics were analyzed. Alcalase and papain were used for the preparation of collagen hydrolysates. Swim bladders contained 95% protein, 2.4% fat, and 0.8% ash (on a dry basis). The essential amino acid content was low, but the functional amino acid content was high. The PSC yield was high, at 68% (dry weight). The amino acid composition profile, electrophoretic pattern, and structural integrity analyses of the isolated collagen suggested it is a typical type-I collagen with high purity. The denaturalization temperature was 32.5 °C, probably attributable to the imino acid content (205 residues/1000 residues). Papain-hydrolysates (≤3 kDa) of this collagen exhibited higher radical scavenging activity than Alcalase-hydrolysates. The swim bladder from the farmed totoaba could be an ideal source to produce high-quality type I collagen and may be considered an alternative to conventional collagen sources or bioactive peptides.

Autoadministración domiciliaria de biológicos. Una encuesta de satisfacción en una unidad de asma grave en tiempo de pandemia por COVID-19 / Home self-administration of biologics. A satisfaction survey in a severe asthma unit during a COVID-19 pandemic

Objetivo: Evaluar las preferencias y satisfacción de los pacientes con asma grave, relacionadas con el lugar de administración de fármacos biológicos subcutáneos: hospital, centro de salud y domicilio, durante la pandemia COVID-19. Métodos: Estudio observacional, descriptivo y transversal que analizó, mediante una encuesta telefónica realizada del 23 al 27 de noviembre de 2020, las preferencias y el grado de satisfacción con la administración de fármacos biológicos subcutáneos en pacientes asmáticos atendidos en la consulta de Alergología de un Hospital General. Resultados: Respondieron la encuesta 33 pacientes, edad media 51,5 años, 57,6% mujeres. Un 57,6% de los pacientes se administraron los fármacos (omalizumab, mepolizumab y benralizumab) en su domicilio, 21,2% en el Hospital de Día y en el Centro de Salud, respectivamente. Los motivos para la administración fuera del hospital fueron la comodidad y evitar el contagio por virus SARS-CoV-2 (30,7%).Tras la pandemia, los pacientes preferían continuar con la dispensación y autoadministración domiciliaria del biológico y tener consultas médicas presenciales. El grado de satisfacción fue 9,7 (escala 0 a 10). Conclusiones: Los pacientes prefieren autoadministrarse en su domicilio los fármacos biológicos para el AG con el apoyo de la dispensación domiciliaria de éstos, mostrando un alto grado de satisfacción por la comodidad que les aporta. Finalizada la pandemia, demandan que las visitas médicas sean presenciales pero desean continuar autoadministrándose el fármaco tras su dispensación domiciliaria por el Servicio de Farmacia. (AU)

Objective: To assess preferences and satisfaction of patients with severe asthma about the place of administration of subcutaneous biological drugs: hospital, health center and home, during the COVID-19 pandemic. Methods: Observational, descriptive and cross-sectional study that analyzed, from November 23 to 27, 2020, through a telephone survey, the preferences and degree of satisfaction with the administration of subcutaneous biological drugs in asthmatic patients treated in the Allergology consultation of a General Hospital. Results: A total of 33 patients responded to the survey, the mean age was 51.5 years, 57.6% were women. The patients that received subcutaneous biological drugs (omalizumab, mepolizumab and benralizumab) at home were 57,6%, at the Day Hospital and at the Health Center 21,2 %, in both cases. The reasons for the administration outside the hospital were comfort and to avoid the spread of the SAR-CoV-2 virus (30.7%). After the pandemic, patients prefer home deliveries, self-administration and face-to-face medical consultations. The degree of satisfaction with the treatment was very high. Conclusions: Patients prefer to self-administer biological drugs for GA at home with the support of their home dispensing, showing a high degree of satisfaction with the comfort it provides. Once the pandemic is over, they demand that medical visits be face-to-face but they want to continue self-administering the drug after it is dispensed at home by the Pharmacy Service. (AU)

Antibiotic delivery from bone-targeted mesoporous silica nanoparticles for the treatment of osteomyelitis caused by methicillin-resistant Staphylococcus aureus.

Osteomyelitis is a hard-to-treat infection of the bone and bone marrow that is mainly caused by Staphylococcus aureus, with an increasing incidence of methicillin-resistant S. aureus (MRSA). Owing to the aggressiveness of these bacteria in colonizing and destroying the bone, systemic antibiotic treatments fail to eradicate the infection. Instead, it normally entails surgery to remove the dead or infected bone. In this work, we report bone-targeted mesoporous silica nanoparticles for the treatment of osteomyelitis. The nanoparticles have been engineered with a functional gelatine/colistin coating able to hamper premature release from the mesopores while effectively disaggregating the bacterial biofilm. Because antibiotic resistance is a global emergency, we have designed two sets of identical nanoparticles, carrying each of them a clinically relevant antibiotic, that have demonstrated to have synergistic effect. The bone-targeted nanoparticles have been thoroughly evaluated in vitro and in vivo, obtaining a notable reduction of the amount of bacteria in the bone in just 24 h after only one dose, and paving the way for localized, nanoparticle-mediated treatment of MRSA-caused osteomyelitis. STATEMENT OF SIGNIFICANCE: In this work, we propose the use of bone-targeted mesoporous silica nanoparticles to address S. aureus-caused osteomyelitis that render synergistic therapeutic effect via multidrug delivery. Because the bacterial biofilm is responsible for an aggressive surgical approach and prolonged antibiotic treatment, the nanoparticles have been functionalized with a functional coating able to both disaggregate the biofilm, hamper premature antibiotic release and protect the intact bone. These engineered nanoparticles are able to effectively target bone tissue both in vitro and in vivo, showing high biocompatibility and elevated antibacterial effect.

Erratum: Publisher's Note: "Skin-on-a-chip models: General overview and future perspectives" [APL Bioengineering 5, 030901 (2021)].

[This corrects the article DOI: 10.1063/5.0046376.].

Engineering Concanavalin B to Release Bioactive Peptides against Metabolic Syndrome.

Metabolic syndrome is a severe public health issue characterized by multiple metabolic disturbances. Current treatments prescribe a particular drug for each of them, producing multiple side effects. As a first step towards a more integral approach, we applied our recently described methodology to design single proteins, based in the Concanavalin B scaffold (1CNV), that contain several bioactive peptides (BPs), including antioxidant and lipid-lowering activities as well as inhibitors of dipeptidyl peptidase IV (DPPIV) and the angiotensin converting enzyme. Modified Concanavalin (CNV44), the designed protein that showed the best in silico properties, was expressed in high yields in E. coli and purified to homogeneity. After in vitro digestion with gastrointestinal enzymes, all the biological activities tested where higher in CNV44 when compared to the non-modified protein 1CNV, or to other previous reports. The results presented here represent the first in vitro evidence of a modified protein with the potential to treat metabolic syndrome and open the venue for the design of proteins to treat other non-communicable diseases.

The Stability Landscape of de novo TIM Barrels Explored by a Modular Design Approach.

The ability to design stable proteins with custom-made functions is a major goal in biochemistry with practical relevance for our environment and society. Understanding and manipulating protein stability provide crucial information on the molecular determinants that modulate structure and stability, and expand the applications of de novo proteins. Since the (ß/⍺)8-barrel or TIM-barrel fold is one of the most common functional scaffolds, in this work we designed a collection of stable de novo TIM barrels (DeNovoTIMs), using a computational fixed-backbone and modular approach based on improved hydrophobic packing of sTIM11, the first validated de novo TIM barrel, and subjected them to a thorough folding analysis. DeNovoTIMs navigate a region of the stability landscape previously uncharted by natural TIM barrels, with variations spanning 60 degrees in melting temperature and 22 kcal per mol in conformational stability throughout the designs. Significant non-additive or epistatic effects were observed when stabilizing mutations from different regions of the barrel were combined. The molecular basis of epistasis in DeNovoTIMs appears to be related to the extension of the hydrophobic cores. This study is an important step towards the fine-tuned modulation of protein stability by design.

Skin-on-a-chip models: General overview and future perspectives.

Over the last few years, several advances have been made toward the development and production of in vitro human skin models for the analysis and testing of cosmetic and pharmaceutical products. However, these skin models are cultured under static conditions that make them unable to accurately represent normal human physiology. Recent interest has focused on the generation of in vitro 3D vascularized skin models with dynamic perfusion and microfluidic devices known as skin-on-a-chip. These platforms have been widely described in the literature as good candidates for tissue modeling, as they enable a more physiological transport of nutrients and permit a high-throughput and less expensive evaluation of drug candidates in terms of toxicity, efficacy, and delivery. In this Perspective, recent advances in these novel platforms for the generation of human skin models under dynamic conditions for in vitro testing are reported. Advances in vascularized human skin equivalents (HSEs), transferred skin-on-a-chip (introduction of a skin biopsy or a HSE in the chip), and in situ skin-on-a-chip (generation of the skin model directly in the chip) are critically reviewed, and currently used methods for the introduction of skin cells in the microfluidic chips are discussed. An outlook on current applications and future directions in this field of research are also presented.

A new microfluidic method enabling the generation of multi-layered tissues-on-chips using skin cells as a proof of concept.

Microfluidic-based tissues-on-chips (TOCs) have thus far been restricted to modelling simple epithelia as a single cell layer, but likely due to technical difficulties, no TOCs have been reported to include both an epithelial and a stromal component despite the biological importance of the stroma for the structure and function of human tissues. We present, for the first time, a novel approach to generate 3D multilayer tissue models in microfluidic platforms. As a proof of concept, we modelled skin, including a dermal and an epidermal compartment. To accomplish this, we developed a parallel flow method enabling the deposition of bilayer tissue in the upper chamber, which was subsequently maintained under dynamic nutrient flow conditions through the lower chamber, mimicking the function of a blood vessel. We also designed and built an inexpensive, easy-to-implement, versatile, and robust vinyl-based device that overcomes some of the drawbacks present in PDMS-based chips. Preliminary tests indicate that this biochip will allow the development and maintenance of multilayer tissues, which opens the possibility of better modelling of the complex cell-cell and cell-matrix interactions that exist in and between the epithelium and mesenchyme, allowing for better-grounded tissue modelling and drug screening.

The Folding Pathway of 6aJL2.

One-third of the reported cases of light chain amyloidosis are related to the germ line λ6 family; remarkably, healthy individuals express this type of protein in just 2% of the peripheral blood and bone marrow B-cells. The appearance of the disease has been related to the inherent properties of this protein family. A recombinant representative model for λ6 proteins called 6aJL2 containing the amino acid sequence encoded by the 6a and JL2 germ line genes was previously designed and synthesized to study the properties of this family. Previous work on 6aJL2 suggested a simple two-state folding model at 25 °C; no intermediate could be identified either by kinetics or by fluorescence and circular dichroism equilibrium studies, although the presence of an intermediate that is populated at ∼2.4 M urea was suggested by size exclusion chromatography. In this study we employed classic equilibrium and kinetic experiments and analysis to elucidate the detailed folding mechanism of this protein. We identify species that are kinetically accessible and/or are populated at equilibrium. We describe the presence of intermediate and native-like species and propose a five-species folding mechanism at 25 °C at short incubation times, similar to and consistent with those observed in other proteins of this fold. The formation of intermediates in the mechanism of 6aJL2 is faster than that proposed for a Vκ light chain, which could be an important distinction in the amyloidogenic potential of both germ lines.

Programación de cirugía electiva segura en tiempos de COVID-19. La importancia del trabajo colaborativo / Safe elective surgery during COVID-19. The relevance of collaborative work

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Magnetic resonance cholangiopancreatography identification of pancreaticobiliary maljunction in the colombian pediatric population. / Unión biliopancreática anómala por colangiorresonancia en población pediátrica colombiana.

OVERVIEW: Pancreaticobiliary maljunction (PBM) is a congenital malformation characterized by a long common pancreaticobiliary channel which causes sphincter of Oddi malfunction. In children, it is typically diagnosed using magnetic resonance cholangiopancreatography (MRCP). It is associated with congenital biliary dilatation, pancreatitis, and gallbladder and bile duct tumors at adulthood. Studies in the western population are rare. Given its morbidity rate, it should be searched for in the western pediatric population. The objective of this study was to look for and identify the presence of pancreaticobiliary maljunction through MRCP in pediatric patients with biliary or pancreatic disease, as well as to find out other associated factors. METHODS: MRCP was used to measure common channel length, pancreatic duct length, and bile duct diameter in 41 pediatric patients with biliary or pancreatic disease. RESULTS: The common channel could only be measured in 17.6% of cases, 50% of which were >8 mm long. All patients were female and had congenital biliary dilatation. No age-related differences were found in terms of bile duct length. CONCLUSIONS: PBM is present in the western pediatric population, but prevalence and morbidity are unknown. Larger studies are required to identify morbidity and mortality, as well as prevalence among patients.

OBJETIVO: La unión biliopancreática anómala (UBPA) es una malformación congénita caracterizada por un canal común pancreatobiliar largo que impide el adecuado funcionamiento del esfínter de Oddi. Su diagnóstico en niños se realiza comúnmente mediante colangiopancreatografía por resonancia magnética (CPRM). Se asocia a dilatación biliar congénita, pancreatitis y tumores de la vesícula y la vía biliar en la edad adulta. Los estudios en población occidental son escasos; debido a su morbilidad resulta de relevancia la búsqueda en población pediátrica occidental. Este estudio pretende buscar e identificar la presencia de unión biliopancreática anómala mediante CPRM de pacientes pediátricos con enfermedad de la vía biliar o pancreática, al igual que identificar otros factores asociados. METODOS: Se midió por CPRM la longitud del canal común, el conducto pancreático y el diámetro de la vía biliar de 41 pacientes pediátricos con patología biliar o pancreática. RESULTADOS: El canal común solo pudo ser medido en el 17,6% de los casos, de los cuales el 50% tuvo una longitud >8 mm, siendo todos ellos pacientes femeninos con dilatación biliar congénita; no se encontraron diferencias en la longitud de la vía biliar relacionado con la edad. CONCLUSIONES: La UBPA es una malformación que se encuentra presente en población pediátrica occidental con prevalencia y morbilidad desconocida; se requieren estudios a mayor escala para identificar morbimortalidad y prevalencia de pacientes con esta malformación.

Unión biliopancreática anómala por colangiorresonancia en población pediátrica colombiana / Magnetic resonance cholangiopancreatography identification of pancreaticobiliary maljunction in the colombian pediatric population

OBJETIVO: La unión biliopancreática anómala (UBPA) es una malformación congénita caracterizada por un canal común pancreatobiliar largo que impide el adecuado funcionamiento del esfínter de Oddi. Su diagnóstico en niños se realiza comúnmente mediante colangiopancreatografía por resonancia magnética (CPRM). Se asocia a dilatación biliar congénita, pancreatitis y tumores de la vesícula y la vía biliar en la edad adulta. Los estudios en población occidental son escasos; debido a su morbilidad, resulta de relevancia la búsqueda en población pediátrica occidental. Este estudio pretende buscar e identificar la presencia de unión biliopancreática anómala mediante CPRM de pacientes pediátricos con enfermedad de la vía biliar o pancreática, al igual que identificar otros factores asociados. MÉTODOS: Se midió por CPRM la longitud del canal común, el conducto pancreático y el diámetro de la vía biliar de 41 pacientes pediátricos con patología biliar o pancreática. RESULTADOS: El canal común solo pudo ser medido en el 17,6% de los casos, de los cuales el 50% tuvo una longitud >8 mm, siendo todos ellos pacientes femeninos con dilatación biliar congénita; no se encontraron diferencias en la longitud de la vía biliar relacionada con la edad. CONCLUSIONES: La UBPA es una malformación que se encuentra presente en población pediátrica occidental con prevalencia y morbilidad desconocida; se requieren estudios a mayor escala para identificar morbimortalidad y prevalencia de pacientes con esta malformación

OVERVIEW: Pancreaticobiliary maljunction (PBM) is a congenital malformation characterized by a long common pancreaticobiliary channel which causes sphincter of Oddi malfunction. In children, it is typically diagnosed using magnetic resonance cholangiopancreatography (MRCP). It is associated with congenital biliary dilatation, pancreatitis, and gallbladder and bile duct tumors at adulthood. Studies in the western population are rare. Given its morbidity rate, it should be searched for in the western pediatric population. The objective of this study was to look for and identify the presence of pancreaticobiliary maljunction through MRCP in pediatric patients with biliary or pancreatic disease, as well as to find out other associated factors. METHODS: MRCP was used to measure common channel length, pancreatic duct length, and bile duct diameter in 41 pediatric patients with biliary or pancreatic disease. RESULTS: The common channel could only be measured in 17.6% of cases, 50% of which were > 8 mm long. All patients were female and had congenital biliary dilatation. No age-related differences were found in terms of bile duct length. CONCLUSIONS: PBM is present in the western pediatric population, but prevalence and morbidity are unknown. Larger studies are required to identify morbidity and mortality, as well as prevalence among patients