Evaluación de la adecuación del calendario de vacunaciones y el cumplimiento de las recomendaciones adicionales, por su patología de base, en niños con problemas complejos de salud

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Pediatría. Fecha de lectura: 22-09-2017Esta tesis tiene embargado el acceso al texto completo hasta el 22-03-201

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Nanostructuration by Self-Assembly in <i>N</i>‑Alkyl Thiazolium and Triazolium Side-Chain Polymethacrylates

Amphiphilic polymers are tunable systems to construct supramolecular hierarchically self-assembled structures. Six families of heterocyclic polymethacrylates (PMTAs) bearing 1,3-thiazole and 1,2,3-triazole pendant groups with alkyl and succinate spacers were chemically modified by quaternization reaction of the azole heterocycles with five alkylating agents (methyl, butyl, octyl, dodecyl, and hexadecyl iodide) leading to a library of 30 different amphiphilic poly­(ionic liquid)­s (PMTAs-RI). These polymers have been characterized in bulk by small- and wide-angle X-ray scattering (SAXS, WAXS) and differential scanning calorimetry (DSC). Quaternization induces a dramatic effect (increase) on the glass-transition temperature <i>T</i>_g, being strongest for methyl iodide members. Increasing the length of the quaternizing agent, plasticization is first observed, followed by a further increase of <i><i>T</i></i>_g. This effect, together with evidence of a second <i>T</i>_g and crystallization for the members with the longest quaternizing agents, could be attributed to the presence of well-developed alkyl nanodomains evidenced by the structural investigation. WAXS and SAXS results have been consistently interpreted by assuming nanostructuration driven by the amphiphilicity balance of poly­(ionic liquid)­s. The different morphologies revealed by SAXS have been characterized, assigning a plausible chemical nature to the phases involved in each case. The nonpolar fraction has been considered as the control parameter defining the main features of the achieved morphology. By increasing this parameter, structures ranging from hexagonally packed nonpolar cylinders in a polar matrix to the inverse situation have been found, passing through lamellar phases. Under some conditions, within the polar lamellae a third phase formed by cylinders of heterocycles has even been determined. We have checked the validity of the scenario proposed by comparing the sizes deduced from the SAXS analysis with the expected characteristic lengths of the associated moieties, inferring thereby how alkyl side groups arrange within the nanodomains. On the basis of the complete picture achieved, the type of nanostructures formed by this class of polymers can be predicted, if the chemical composition including the quaternization degree is known

Probing Carbohydrate-Lectin Recognition in Heterogeneous Environments with Monodisperse Cyclodextrin-Based Glycoclusters

A series of β-cyclodextrin (βCD)-scaffolded glycoclusters exposing heterogeneous yet perfectly controlled displays of α-mannosyl (α-Man) and β-lactosyl (β-Lact) antennas were synthesized to probe the mutual influence of varying densities of the saccharide motifs in the binding properties toward different plant lectins. Enzyme-linked lectin assay (ELLA) data indicated that the presence of β-Lact residues reinforced binding of α-Man to the mannose-specific lectin concanavalin A (Con A) even though homogeneous β-Lact clusters are not recognized at all by this lectin, supporting the existence of synergic recognition mechanisms (<i>heterocluster effect</i>). Conversely, the presence of α-Man motifs in the heteroglycoclusters also resulted in a binding-enhancing effect of β-Lact toward peanut agglutinin (PNA), a lectin strongly binding multivalent lactosides but having no detectable affinity for α-mannopyranosides, for certain architectural arrangements. Two-site, sandwich-type ELLA data corroborated the higher lectin clustering efficiency of heterogeneous glycoclusters compared with homogeneous displays of the putative sugar ligand with identical valency. A turbidity assay was also consistent with the previous observations. Most revealingly, the lectin cross-linking ability of heterogeneous glycoclusters was sensitive to the presence of high concentrations of the non-ligand sugar, strongly suggesting that “mismatching” saccharide motifs may modulate carbohydrate-lectin specific recognition in a lectin-dependent manner when present in highly dense displays together with the “matching” ligand, a situation frequently encountered in biological systems

Effect of glycounits on the antimicrobial properties and toxicity behavior of polymers based on quaternized DMAEMA

Polymers with quaternary ammonium groups such as quaternized poly­(2-(dimethylamino)­ethyl methacrylate) (PDMAEMAQ) have been used as antimicrobial agents because of their demonstrated good antimicrobial activities against a huge number and types of microbes, although their cytotoxicity is also well-known. In this work block copolymers based on PDMAEMAQ were synthesized containing hydrophobic segments of poly­(butyl methacrylate) to improve the antimicrobial activity and glycomonomer units with the aim of decreasing the cytotoxicity of the polymers. Hydrophobic butyl methacrylate (BMA) blocks were chain extended by statistical and block copolymers of DMAEMA and 2-{[(d-glucosamin-2-<i>N</i>-yl)­carbonylethyl methacrylate (HEMAGl) glycomonomer of different compositions. In order to find the balance between antimicrobial activity and cytotoxicity, the selectivity index of each polymer was obtained from minimum inhibitory concentrations (MIC) and white and red blood cells toxicity measurements

Formation of Multigradient Porous Surfaces for Selective Bacterial Entrapment

Herein we describe the preparation of multigradient porous platforms by using the breath figures approach. In a single and straightforward step, we prepared porous surfaces in which three different parameters vary gradually from the edge of the sample to the center in a radial manner. Thus, we evidenced the gradual variation of the pore size and the shape of the pores that can be varied, depending on the sample concentration, but also depending on their radial position within the same sample. In addition, we succeeded in the control over the chemical composition inside and outside the pores as well as the variation of the concentration of block copolymer inside the pores as a function of their radial position. Moreover, the chemical composition and the variable cavity size of porous surfaces have been evaluated to analyze the influence of these variables on the selective bacterial immobilization. To the best of our knowledge this is the first example in which, by using a simple one-step strategy, a multigradient surface can be obtained. These initial results can be the base to construct platforms for selective immobilization and isolation of bacteria

Cryoconservation of Peptide Extracts from Trypsin Digestion of Proteins for Proteomic Analysis in a Hospital Biobank Facility

We tested a semiautomated protocol for the proper storage and conservation in a hospital biobank of tryptic peptide extracts coming from samples with low and high protein complexity for subsequent mass spectrometry analysis. Low-complexity samples (serum albumin, serotransferrin. and alpha-S1-casein) were loaded in replicates in SDS-PAGE and subjected to standard in-gel trypsin digestion. For LC–MALDI–TOF/TOF analysis, purified β-galactosidase and human serum samples were in-solution digested following standard procedures and desalted with C18 stage-tips. In both cases, peptides extracts were aliquoted in individually 2D coded tubes, vacuum-dried, barcode-read, and stored in an automated −20 °C freezer in the Biobank facility. Samples were kept dried at −20 °C until the corresponding time-point of analysis, then reconstituted in the proper buffer and analyzed by either MALDI-TOF/TOF (peptide fingerprinting and MS/MS) or LC–MALDI-TOF/TOF following a highly reproducible pattern to ensure the reproducibility of the results. Protein identification was done with either Mascot or Protein Pilot as search engines using constant parameters. Over a period of 1 year we checked six different time points at days 0, 7, 30, 90, 180, and 365. We compared MS and MS/MS protein score, number of identified peptides, and coverage of the identified proteins. In the low complexity samples, the number of peptides detected gradually decreased over time, especially affecting the MS score. However, two of the three proteins – serum albumin and serotransferrin – were identified by both PMF and MS/MS at day 90. By day 180, only MS/MS identification in some replicates was possible. By LC–MS/MS, β-galactosidase and the most abundant serum proteins were identified with good scores at all time points even by day 365, with no detectable peptide loss or decrease in the fragmentation efficiency, although a progressive decrease in peptide intensity indicates that detection of low abundant proteins could not be optimal after very long periods of time. Our results encourage us to use the biobank facility in the future for long-term storage – up to 3 months – of dried peptide extracts

Cryoconservation of Peptide Extracts from Trypsin Digestion of Proteins for Proteomic Analysis in a Hospital Biobank Facility

We tested a semiautomated protocol for the proper storage and conservation in a hospital biobank of tryptic peptide extracts coming from samples with low and high protein complexity for subsequent mass spectrometry analysis. Low-complexity samples (serum albumin, serotransferrin. and alpha-S1-casein) were loaded in replicates in SDS-PAGE and subjected to standard in-gel trypsin digestion. For LC–MALDI–TOF/TOF analysis, purified β-galactosidase and human serum samples were in-solution digested following standard procedures and desalted with C18 stage-tips. In both cases, peptides extracts were aliquoted in individually 2D coded tubes, vacuum-dried, barcode-read, and stored in an automated −20 °C freezer in the Biobank facility. Samples were kept dried at −20 °C until the corresponding time-point of analysis, then reconstituted in the proper buffer and analyzed by either MALDI-TOF/TOF (peptide fingerprinting and MS/MS) or LC–MALDI-TOF/TOF following a highly reproducible pattern to ensure the reproducibility of the results. Protein identification was done with either Mascot or Protein Pilot as search engines using constant parameters. Over a period of 1 year we checked six different time points at days 0, 7, 30, 90, 180, and 365. We compared MS and MS/MS protein score, number of identified peptides, and coverage of the identified proteins. In the low complexity samples, the number of peptides detected gradually decreased over time, especially affecting the MS score. However, two of the three proteins – serum albumin and serotransferrin – were identified by both PMF and MS/MS at day 90. By day 180, only MS/MS identification in some replicates was possible. By LC–MS/MS, β-galactosidase and the most abundant serum proteins were identified with good scores at all time points even by day 365, with no detectable peptide loss or decrease in the fragmentation efficiency, although a progressive decrease in peptide intensity indicates that detection of low abundant proteins could not be optimal after very long periods of time. Our results encourage us to use the biobank facility in the future for long-term storage – up to 3 months – of dried peptide extracts

Stellatolides, a New Cyclodepsipeptide Family from the Sponge Ecionemia acervus: Isolation, Solid-Phase Total Synthesis, and Full Structural Assignment of Stellatolide A

The marine environment is a rich source of metabolites with potential therapeutic properties and applications for humans. Here we describe the first isolation, solid-phase total synthesis, and full structural assignment of a new class of cyclodepsipeptides from the Madagascan sponge Ecionemia acervus that shows in vitro cytotoxic activities at submicromolar concentrations. Seven structures belonging to a new family of compounds, given the general name stellatolides, were characterized. The sequence and stereochemistry of all the amino acids in these molecules were established by a combination of spectroscopic analysis, chemical degradation, and derivatization studies. Furthermore, the complete structure of stellatolide A was confirmed by an efficient solid-phase method for the first total synthesis and the full structural assignment of this molecule, including the asymmetric synthesis of the unique β-hydroxy acid moiety (<i>Z</i>)-3-hydroxy-6,8-dimethylnon-4-enoic acid