Heparin-induced DRESS syndrome in a paediatric patient and successful anaesthetic management in cardiovascular bypass surgery: case report.

BACKGROUND: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome is a severe adverse drug reaction marked by delayed hypersensitivity reactions causing skin and systemic complications. DRESS diagnosis is challenging due to the variety of clinical presentations and symptom overlap with other conditions. The perioperative period in these patients requires precise pharmacological strategies to prevent complications associated with this syndrome. The treatment of DRESS induced by unfractionated heparin during cardiopulmonary bypass (CPB) surgery presents some challenges that must be considered when selecting an anticoagulant to avoid side effects. In this case, bivalirudin, a direct thrombin inhibitor, is indicated as an alternative to heparin in patients undergoing CPB. However, in contrast to heparin/protamine, there is no direct reversal agent for bivalirudin. CASE PRESENTATION: We report the case of an 11-year-old male diagnosed with native aortic valve endocarditis and thrombosis in his left lower extremity. During valvular replacement surgery, systemic unfractionated heparin was administered. Postoperatively, the patient developed fever, eosinophilia and pruritic rash. Warm shock and elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels followed, leading to the diagnosis of DRESS syndrome. Treatment with methylprednisolone resulted in complete resolution of symptoms. Seven years later, the patient was readmitted due to insufficient anticoagulation and a thrombus in the prosthetic aortic valve, presenting a recurrent DRESS episode due to the administration of unfractionated heparin, which was later replaced with low-molecular-weight heparin during hospitalization. Treatment with corticosteroids and antihistamines was initiated, resulting in the resolution of this episode. Ultimately, the patient required the Ross procedure. During this intervention the anticoagulation strategy was modified, unfractionated heparin was replaced with bivalirudin during the procedure and fondaparinux was administered during the postoperative period. This resulted in stable transaminases levels and no eosinophilia. CONCLUSION: The severity of DRESS Syndrome underscores the importance of early recognition, heightened monitoring, and a comprehensive approach tailored to each patient's needs. This particular case highlights the significance of this approach and may have a substantial clinical impact since it provides alternatives to heparin, such as bivalirudin and fondaparinux, in the anticoagulation strategy of CPB for patients who have a hypersensibility reaction to this medication; thus, enhancing clinical outcomes by minimizing risks linked to adverse drug reactions.

Occurrence and risk assessment of pesticides and their transformation products related to olive groves in surface waters of the Guadalquivir river basin.

Pesticides are considered one of the main sources of contamination of surface waters, especially in rural areas highly influenced by traditional agricultural practices. The objective of this work was to evaluate the impact caused by pesticides and their transformation products (TPs) related to olive groves in surface waters with strong agricultural pressure. 11 streams were monitored during four sampling campaigns over 2 years. A solid-phase extraction, followed by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) analysis was used in the quantitative target approach, with more than 70 validated compounds. Target method was combined with a suspect screening strategy involving more than 500 pesticides and TPs, using ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) to identify additional pesticides and TPs out of the scope of analysis. A total of 43 different compounds were detected with the target method. The herbicide MCPA was present in all samples and at the highest concentration (1260 ng L-1), followed by the fungicide carbendazim (1110 ng L-1), and the herbicide chlorotoluron (706 ng L-1). The suspect screening strategy revealed the presence of 7 compounds out of the target analysis (1 pesticide and 6 TPs). 6 analytes were confirmed with the analytical standards. Semi-quantification results revealed that TPs exhibited higher concentrations than their corresponding parent compounds, indicating higher persistency. Some small streams showed a comparable number of pesticides and concentrations to the most polluted large river. The determined pesticide and TPs concentrations represented an estimated environmental hazard in almost all sampling sites under study. This work underscores the importance of including pesticide TPs and small streams impacted by extensive agricultural activities in water quality monitoring programs.

Miniaturized flexible micro-tube plasma ionization source for the effective ionization of non-easily ionizable pesticides in food with liquid chromatography/mass spectrometry.

In this article, we have studied the potential of flexible microtube plasma (FµTP) as ionization source for the liquid chromatography high-resolution mass spectrometry detection of non-easily ionizable pesticides (viz. nonpolar and non-ionizable by acid/basic moieties). Phthalimide-related compounds such as dicofol, dinocap, o-phenylphenol, captan, captafol, folpet and their metabolites were studied. Dielectric barrier discharge ionization (DBDI) was examined using two electrode configurations, including the miniaturized one based on a single high-voltage (HV) electrode and a virtual ground electrode configuration (FµTP), and also the two-ring electrode DBDI configuration. Different ionization pathways were observed to ionize these challenging, non-easily ionizable nonpolar compounds, involving nucleophilic substitutions and proton abstraction, with subtle differences in the spectra obtained compared with APCI. An average sensitivity increase of 5-fold was attained compared with the standard APCI source. In addition, more tolerance with matrix effects was observed in both DBDI sources. The importance of the data reported is not just limited to the sensitivity enhancement compared to APCI, but, more notably, to the ability to effectively ionize nonpolar, late-eluting (in reverse-phase chromatography) non-ionizable compounds. Besides o-phenylphenol ([M - H]-), all the parent species were efficiently ionized through different mechanisms involving bond cleavages through the effect of plasma reagent species or its combination with thermal degradation and subsequent ionization. This tool can be used to figure out overlooked nonpolar compounds in different environmental samples of societal interest through non-target screening (NTS) strategies.

Descending necrotizing mediastinitis: key points to reduce the high associated mortality in a consecutive case series.

Background: Descending necrotizing mediastinitis (DNM) is an acute life-threatening infection that originates in the oropharyngeal region. It is an uncommon disease with a mortality rate of about 20-40%. This high mortality is mainly attributed to delays in diagnosis and treatment and poor drainage of the mediastinum. We highlight key points that may help reduce mortality. Case Description: We analyze a retrospective case series of seven patients diagnosed with DNM between March 2019 and July 2022 at Hospital de la Santa Creu i Sant Pau. The primary oropharyngeal infection was peritonsillar abscess in three cases and odontogenic abscess in four. All patients showed symptoms of severe cervical infection and symptoms suggestive of mediastinitis. A cervicothoracic computed tomography (CT) scan confirmed the presence of cervical and mediastinal collections and emphysema in all cases. All patients were simultaneously evaluated by the otorhinolaryngology and thoracic surgery teams. Broad-spectrum antibiotic therapy was instituted pending culture. All the patients underwent urgent surgery, consisting of cervicotomy to control the cervical focus and unilateral or bilateral video-assisted thoracoscopic debridement and drain of the pleural cavities and mediastinum. Regarding the outcomes, no patients died, one patient (14.2%) underwent transcervical mediastino-thoracoscopy drainage only. In six patients (85.8%) we performed a combined transcervical and transthoracic approach. Reoperation was required in 3 (43%) cases. The parameter that indicated a poor clinical evolution in these patients was an increase in C-reactive protein and the infection extension on the cervicothoracic CT scan. The follow-up was 30 days from last surgery; there were no losses. Conclusions: Based on our experience, the key points that can help reduce the high mortality associated with DNM are a rapid multidisciplinary assessment and a combined surgical procedure, considering the minimally invasive approach as the first option to drain the pleural cavities and mediastinum.

Are the minimally invasive techniques the new gold standard in thymus surgery for myasthenia gravis? Experience of a reference single-site in VATS thymectomy.

The thymus is the primary lymphoid organ responsible for the maturation and proliferation of T lymphocytes. During the first years of our lives, the activation and inactivation of T lymphocytes occur within the thymus, facilitating the correct maturation of central immunity. Alterations in the positive and negative selection of T lymphocytes have been studied as the possible origins of autoimmune diseases, with Myasthenia Gravis (MG) being the most representative example. Structural alterations in the thymus appear to be involved in the initial autoimmune response observed in MG, leading to the consideration of thymectomy as part of the treatment for the disease. However, the role of thymectomy in MG has been a subject of controversy for many years. Several publications raised doubts about the lack of evidence justifying thymectomy's role in MG until 2016 when a randomized study comparing thymectomy via sternotomy plus prednisone versus prednisone alone was published in the New England Journal of Medicine (NEJM). The results clearly favored the group of patients who underwent surgery, showing improvements in symptoms, reduced corticosteroid requirements, and fewer recurrences over 3 years of follow-up. In recent years, the emergence of less invasive surgical techniques has made video-assisted or robotic-assisted thoracoscopic (VATS/RATS) thymectomy more common, replacing the traditional sternotomy approach. Despite the increasing use of VATS, it has not been validated as a technique with lower morbidity compared to sternotomy in the treatment of MG. The results of the 2016 trial highlighted the benefits of thymectomy, but all the patients underwent surgery via sternotomy. Our hypothesis is that VATS thymectomy is a technique with lower morbidity, reduced postoperative pain, and shorter postoperative hospital stays than sternotomy. Additionally, VATS offers better clinical improvement in patients with MG. The primary objective of this study is to validate the VATS technique as the preferred approach for thymectomy. Furthermore, we aim to analyze the impact of VATS thymectomy on symptoms and corticosteroid dosage in patients with MG, identifying factors that may predict a better response to surgery.

Dermatoglyphic Profiles of Competitive Athletes: CrossFit and Ultra-Marathon / Perfiles Dermatoglíficos de Deportistas Competitivos: CrossFit y Ultramaratón

SUMMARY: In the sports field, sports are usually classified according to the predominance of the energy system used during the competition; sports like Crossfit and ultra-marathon could be totally opposite due to the needs of athletes to achieve good places. Due to the above, the objective was established to compare the dermatoglyphic profiles of CrossFit and Ultra-marathon athletes according to the predisposition of the energy systems, aerobic and anaerobic, used in the competitions. Cross-sectional descriptive study, where the dermatoglyphic profile of 21 athletes of national presence (10 crossfit and 11 ultra-marathon runners) was determined, through the Computerized Dermatoglyphic System, brand Salus Dermatoglifia, according to the Cummins and Midlo protocol, which consists of taking the fingerprints of the 10 fingers of the hands. The fingerprint designs of the human being (arch, loop and whorl) and the elements contained in them (nucleus and delta) were analyzed, differences were established through the Analysis of Variance test in the SPSS V.25 statistical package. The results show significant differences between the average scores of the line count of both disciplines (108 and 165), being higher in ultra-marathon runners, associated with greater aerobic resistance. Another significant and relevant finding was the presence of arch-type fingerprints only in CrossFit athletes associated, along with low line count, with strength and power. It is concluded that Crossfit and Ultra-marathon athletes have dissimilar natural physical characteristics, which is why they participate and excel in different sports where they have enhanced their natural physical abilities through training.

En el ámbito deportivo, los deportes suelen clasificarse según el predominio del sistema energético utilizado durante la competición; Deportes como el Crossfit y la ultramaratón podrían ser totalmente opuestos debido a las necesidades de los deportistas de conseguir buenos lugares. Debido a lo anterior, se estableció como objetivo comparar los perfiles dermatoglíficos de atletas de CrossFit y Ultramaratón según la predisposición de los sistemas energéticos, aeróbico y anaeróbico, utilizados en las competencias. Estudio descriptivo transversal, donde se determinó el perfil dermatoglífico de 21 deportistas de presencia nacional (10 crossfit y 11 ultramaratonistas), a través del Sistema Dermatoglífico Computarizado, marca Salus Dermatoglifia, según el protocolo Cummins y Midlo, el cual consta de tomando las huellas dactilares de los 10 dedos de las manos. Se analizaron los diseños dactilares del ser humano (arco, asa y verticilo) y los elementos contenidos en ellos (núcleo y delta), se establecieron diferencias mediante la prueba de Análisis de Varianza en el paquete estadístico SPSS V.25. Los resultados muestran diferencias significativas entre las puntuaciones medias del recuento de líneas de ambas disciplinas (108 y 165), siendo superiores en los corredores de ultramaratón, asociado a una mayor resistencia aeróbica. Otro hallazgo significativo y relevante fue la presencia de huellas dactilares tipo arco sólo en atletas de CrossFit asociadas, junto con un bajo número de líneas, con fuerza y potencia. Se concluye que los atletas de Crossfit y Ultramaratón tienen características físicas naturales disímiles, por lo que participan y destacan en diferentes deportes donde han potenciado sus capacidades físicas naturales a través del entrenamiento.

Aqueous Fraction from Cucumis sativus Aerial Parts Attenuates Angiotensin II-Induced Endothelial Dysfunction In Vivo by Activating Akt.

BACKGROUND: Endothelial dysfunction (ED) is a marker of vascular damage and a precursor of cardiovascular diseases such as hypertension, which involve inflammation and organ damage. Nitric oxide (NO), produced by eNOS, which is induced by pAKT, plays a crucial role in the function of a healthy endothelium. METHODS: A combination of subfractions SF1 and SF3 (C4) of the aqueous fraction from Cucumis sativus (Cs-Aq) was evaluated to control endothelial dysfunction in vivo and on HMEC-1 cells to assess the involvement of pAkt in vitro. C57BL/6J mice were injected daily with angiotensin II (Ang-II) for 10 weeks. Once hypertension was established, either Cs-AqC4 or losartan was orally administered along with Ang-II for a further 10 weeks. Blood pressure (BP) was measured at weeks 0, 5, 10, 15, and 20. In addition, serum creatinine, inflammatory status (in the kidney), tissue damage, and vascular remodeling (in the liver and aorta) were evaluated. Cs-AqC4 was also tested in vitro on HMEC-1 cells stimulated by Ang-II to assess the involvement of Akt phosphorylation. RESULTS: Cs-AqC4 decreased systolic and diastolic BP, reversed vascular remodeling, decreased IL-1ß and TGF-ß, increased IL-10, and decreased kidney and liver damage. In HMEC-1 cells, AKT phosphorylation and NO production were increased. CONCLUSIONS: Cs-AqC4 controlled inflammation and vascular remodeling, alleviating hypertension; it also improved tissue damage associated with ED, probably via Akt activation.

Oxidative damage associated with exposure to heavy metals present in topsoils in central Chile.

Exposure to heavy metals may cause the overproduction of reactive oxygen species, generating oxidative stress and consequently, various harms to human health. The soil surrounding the Ventanas Industrial Complex, in Puchuncaví and Quintero municipal districts on the central Chilean coast, contains heavy metal concentrations (As, Cu, Pb, Zn, among others) that far exceed the maximum permissible levels established by Italian soil standards (used as a reference). This study aimed to investigate the potential association between heavy metal exposure in humans and the levels of oxidative stress biomarkers in inhabitants of these locations. We took blood samples from 140 adults living in sites with high concentrations of heavy metals in the soil and compared them with blood samples from 140 adults living in areas with normal heavy metal concentrations. We assessed lipid peroxidation, damage to genetic material, and Total Antioxidant Capacity in these blood samples. Our results indicate an association between oxidative damage and heavy metal exposure, where the inhabitants living in exposed areas have a higher level of DNA damage compared with those living in control areas. Given that DNA damage is one of the main factors in carcinogenesis, these results are of interest, both for public health and for public policies aimed at limiting human exposure to environmental pollution.

Case Report: Characterization of known (c.607G>C) and novel (c.416C>G) ELANE mutations in two Mexican families with congenital neutropenia.

The most common causes of congenital neutropenia are mutations in the ELANE (Elastase, Neutrophil Expressed) gene (19p13.3), mostly in exon 5 and the distal portion of exon 4, which result in different clinical phenotypes of neutropenia. Here, we report two pathogenic mutations in ELANE, namely, c.607G>C (p.Gly203Arg) and a novel variant c.416C>G (p.Pro139Arg), found in two Mexican families ascertained via patients with congenital neutropenia who responded positively to the granulocyte colony-stimulating factor (G-CSF) treatment. These findings highlight the usefulness of identifying variants in patients with inborn errors of immunity for early clinical management and the need to rule out mosaicism in noncarrier parents with more than one case in the family.

Effect of colchicine on perioperative atrial fibrillation and myocardial injury after non-cardiac surgery in patients undergoing major thoracic surgery (COP-AF): an international randomised trial.

BACKGROUND: Higher levels of inflammatory biomarkers are associated with an increased risk of perioperative atrial fibrillation and myocardial injury after non-cardiac surgery (MINS). Colchicine is an anti-inflammatory drug that might reduce the incidence of these complications. METHODS: COP-AF was a randomised trial conducted at 45 sites in 11 countries. Patients aged 55 years or older and undergoing major non-cardiac thoracic surgery were randomly assigned (1:1) to receive oral colchicine 0·5 mg twice daily or matching placebo, starting within 4 h before surgery and continuing for 10 days. Randomisation was done with use of a computerised, web-based system, and was stratified by centre. Health-care providers, patients, data collectors, and adjudicators were masked to treatment assignment. The coprimary outcomes were clinically important perioperative atrial fibrillation and MINS during 14 days of follow-up. The main safety outcomes were a composite of sepsis or infection, and non-infectious diarrhoea. The intention-to-treat principle was used for all analyses. This trial is registered with ClinicalTrials.gov, NCT03310125. FINDINGS: Between Feb 14, 2018, and June 27, 2023, we enrolled 3209 patients (mean age 68 years [SD 7], 1656 [51·6%] male). Clinically important atrial fibrillation occurred in 103 (6·4%) of 1608 patients assigned to colchicine, and 120 (7·5%) of 1601 patients assigned to placebo (hazard ratio [HR] 0·85, 95% CI 0·65 to 1·10; absolute risk reduction [ARR] 1·1%, 95% CI -0·7 to 2·8; p=0·22). MINS occurred in 295 (18·3%) patients assigned to colchicine and 325 (20·3%) patients assigned to placebo (HR 0·89, 0·76 to 1·05; ARR 2·0%, -0·8 to 4·7; p=0·16). The composite outcome of sepsis or infection occurred in 103 (6·4%) patients in the colchicine group and 83 (5·2%) patients in the placebo group (HR 1·24, 0·93-1·66). Non-infectious diarrhoea was more common in the colchicine group (134 [8·3%] events) than the placebo group (38 [2·4%]; HR 3·64, 2·54-5·22). INTERPRETATION: In patients undergoing major non-cardiac thoracic surgery, administration of colchicine did not significantly reduce the incidence of clinically important atrial fibrillation or MINS but increased the risk of mostly benign non-infectious diarrhoea. FUNDING: Canadian Institutes of Health Research, Accelerating Clinical Trials Consortium, Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario, Population Health Research Institute, Hamilton Health Sciences, Division of Cardiology at McMaster University, Canada; Hanela Foundation, Switzerland; and General Research Fund, Research Grants Council, Hong Kong.

Effect of Colchicine on the Risk of Perioperative Acute Kidney Injury: Clinical Protocol of a Substudy of the Colchicine for the Prevention of Perioperative Atrial Fibrillation Randomized Clinical Trial.

Background: Inflammation during and after surgery can lead to organ damage including acute kidney injury. Colchicine, an established inexpensive anti-inflammatory medication, may help to protect the organs from pro-inflammatory damage. This protocol describes a kidney substudy of the colchicine for the prevention of perioperative atrial fibrillation (COP-AF) study, which is testing the effect of colchicine versus placebo on the risk of atrial fibrillation and myocardial injury among patients undergoing thoracic surgery. Objective: Our kidney substudy of COP-AF will determine whether colchicine reduces the risk of perioperative acute kidney injury compared with a placebo. We will also examine whether colchicine has a larger absolute benefit in patients with pre-existing chronic kidney disease, the most prominent risk factor for acute kidney injury. Design and Setting: Randomized, superiority clinical trial conducted in 40 centers in 11 countries from 2018 to 2023. Patients: Patients (~3200) aged 55 years and older having major thoracic surgery. Intervention: Patients are randomized 1:1 to receive oral colchicine (0.5 mg tablet) or a matching placebo, given twice daily starting 2 to 4 hours before surgery for a total of 10 days. Patients, health care providers, data collectors, and outcome adjudicators will be blinded to the randomized treatment allocation. Methods: Serum creatinine concentrations will be measured before surgery and on postoperative days 1, 2, and 3 (or until hospital discharge). The primary outcome of the substudy is perioperative acute kidney injury, defined as an increase (from the prerandomization value) in serum creatinine concentration of either ≥26.5 µmol/L (≥0.3 mg/dL) within 48 hours of surgery or ≥50% within 7 days of surgery. The primary analysis (intention-to-treat) will examine the relative risk of acute kidney injury in patients allocated to receive colchicine versus placebo. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by pre-existing chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2. Limitations: The substudy will be underpowered to detect small effects on more severe forms of acute kidney injury treated with dialysis. Results: Substudy results will be reported in 2024. Conclusions: This substudy will estimate the effect of colchicine on the risk of perioperative acute kidney injury in older adults undergoing major thoracic surgery. Clinical trial registration number: NCT03310125.

Contexte: L'inflammation pendant et après une intervention chirurgicale peut causer des lésions aux organes, notamment de l'insuffisance rénale aiguë (IRA). La colchicine, un médicament anti-inflammatoire reconnu et bon marché, peut contribuer à protéger les organes contre les lésions pro-inflammatoires. Le présent protocole décrit une sous-étude rénale de l'essai Colchicine for the Prevention of Perioperative atrial fibrillation (COP-AF), qui examine l'effet de la colchicine, par rapport à un placebo, sur le risque de fibrillation auriculaire et de lésion myocardique chez les patients qui subissent une chirurgie thoracique. Objectif: Notre sous-étude rénale de l'essai COP-AF permettra de vérifier si la colchicine réduit le risque d'IRA périopératoire par rapport à un placebo. Nous tenterons également de déterminer si la colchicine présente un plus grand bénéfice absolu pour les patients atteints d'une insuffisance rénale chronique préexistante, laquelle constitue le plus important facteur de risque pour l'IRA. Cadre et type d'étude: Essai clinique à répartition aléatoire visant à démontrer une supériorité. L'étude, qui s'étend de 2018 à 2023, est menée dans 40 centers situés dans 11 pays. Sujets: Des patients (~3200) âgés de 55 ans et plus subissant une chirurgie thoracique majeure. Interventions: Les patients sont répartis 1:1 de façon aléatoire pour recevoir de la colchicine par voie orale (comprimé de 0.5 mg), ou un placebo correspondant, deux fois par jour à partir de 2 à 4 heures avant l'intervention chirurgicale, pour un total de 10 jours. Les patients, les prestataires de soins de santé, les personnes qui collectent les données et celles qui évaluent les résultats ne seront pas informés de l'attribution du traitement. Méthodologie: Les concentrations sériques de créatinine seront mesurées avant l'intervention et aux jours postopératoires 1, 2, et 3 (ou jusqu'au congé de l'hôpital). Le principal critère d'évaluation de cette sous-étude est une IRA périopératoires définie par une hausse (par rapport à la valeur mesurée avant la répartition aléatoire) d'au moins 26.5 µmol/L (≥0.3 mg/dL) de la créatinine sérique dans les 48 heures suivant l'intervention ou d'au moins 50% dans les 7 jours suivants. L'analyze primaire (intention de traiter) examinera le risque relatif d'IRA chez les patients recevant de la colchicine par rapport au placebo. L'analyze primaire sera répétée en utilisant d'autres définitions de l'IRA et nous examinerons la modification de l'effet en présence d'une insuffisance rénale préexistante, définie par un débit de filtration glomérulaire estimé (DFGe) inférieur à 60 mL/min/1.73 m2 avant la répartition aléatoire. Limites: Cette sous-étude ne sera pas assez puissante pour détecter de petits effets sur les formes plus graves d'insuffisance rénale aiguë traitées par dialyze. Résultats: Les résultats de cette sous-étude feront l'objet d'un rapport en 2024. Conclusion: Cette sous-étude permettra d'estimer l'effet de la colchicine sur le risque d'insuffisance rénale aiguë périopératoire chez les adultes âgés qui subissent une chirurgie thoracique majeure. Numéro d'enregistrement de l'essai clinique: NCT03310125.

Cost-Effectiveness of Pembrolizumab as an Adjuvant Treatment in Colombia for Melanoma Patients with Lymph Node Involvement After Complete Resection.

INTRODUCTION: The KEYNOTE-054 trial found that adjuvant treatment with pembrolizumab improved recurrence-free survival versus placebo in completely resected high-risk stage III melanoma patients. We assessed the cost-effectiveness of adjuvant pembrolizumab in Colombia compared with watchful waiting, a widely used strategy despite the high risk of recurrence with surgery alone. METHODS: A four-health state [recurrence-free (RF), locoregional recurrence (LR), distant metastases (DM), and death) Markov model was developed to assess the lifetime medical costs and outcomes (3% annual discount), along with cost-effectiveness ratios (ICERs). The transitions from the RF and LR states were modeled using KEYNOTE-054 data, and those from the DM state were modeled using data from the KEYNOTE-006 trial and a network meta-analysis of advanced treatments received after adjuvant pembrolizumab and watchful waiting. The health state utilities were derived from KEYNOTE-054 Euro-QoL data and literature. Costs are expressed in 2021 Colombian pesos (COP). RESULTS: Over a 46-year time horizon, patients on adjuvant pembrolizumab and watchful waiting were estimated to gain 9.69 and 7.56 quality-adjusted life-years (QALYs), 10.83 and 8.65 life-years (LYs), and incur costs of COP 663,595,726 and COP 563,237,206, respectively. The proportion of LYs spent in RF state was 84.63% for pembrolizumab and 72.13% for watchful waiting, yielding lower subsequent treatment, disease management, and terminal care costs for pembrolizumab. Adjuvant pembrolizumab improved survival by 2.18 LYs and 2.13 QALYs versus watchful waiting. The ICER per QALY was COP 47,081,917, primarily driven by recurrence rates and advanced melanoma treatments. The deterministic sensitivity analysis results were robust and consistent across various reasonable inputs and alternative scenarios. At a willingness-to-pay threshold of COP 69,150,201 per QALY, the probability of pembrolizumab being cost-effective was 65.70%. CONCLUSION: Pembrolizumab is cost-effective as an adjuvant treatment compared to watchful waiting among patients with high-risk stage III melanoma after complete resection in Colombia.

Peroxyl radicals modify 6-phosphogluconolactonase from Escherichia coli via oxidation of specific amino acids and aggregation which inhibits enzyme activity.

6-phosphogluconolactonase (6PGL) catalyzes the second reaction of the pentose phosphate pathway (PPP) converting 6-phosphogluconolactone to 6-phosphogluconate. The PPP is critical to the generation of NADPH and metabolic intermediates, but some of its components are susceptible to oxidative inactivation. Previous studies have characterized damage to the first (glucose-6-phosphate dehydrogenase) and third (6-phosphogluconate dehydrogenase) enzymes of the pathway, but no data are available for 6PGL. This knowledge gap is addressed here. Oxidation of Escherichia coli 6PGL by peroxyl radicals (ROO•, from AAPH (2,2'-azobis(2-methylpropionamidine) dihydrochloride) was examined using SDS-PAGE, amino acid consumption, liquid chromatography with mass detection (LC-MS), protein carbonyl formation and computational methods. NADPH generation was assessed using mixtures all three enzymes of the oxidative phase of the PPP. Incubation of 6PGL with 10 or 100 mM AAPH resulted in protein aggregation mostly due to reducible (disulfide) bonds. High fluxes of ROO• induced consumption of Cys, Met and Trp, with the Cys oxidation rationalizing the aggregate formation. Low levels of carbonyls were detected, while LC-MS analyses provided evidence for oxidation of selected Trp and Met residues (Met1, Trp18, Met41, Trp203, Met220 and Met221). ROO• elicited little loss of enzymatic activity of monomeric 6PGL, but the aggregates showed diminished NADPH generation. This is consistent with in silico analyses that indicate that the modified Trp and Met are far from the 6-phosphogluconolactone binding site and the catalytic dyad (His130 and Arg179). Together these data indicate that monomeric 6PGL is a robust enzyme towards oxidative inactivation by ROO• and when compared to other PPP enzymes.

Comparación de la eficacia y toxicidad del estibogluconato de sodio y antimoniato de meglumina en el tratamiento de leishmaniasis cutánea en Perú / Efficacy and safety of sodium stibogluconate compared to meglumine antimoniate in the treatment of cutaneous leishmaniasis in Peru

Objetivos : Comparar la eficacia y toxicidad del antimoniato de meglumina (AM) y estibogluconato sódico (EGS) en el tratamiento de leishmaniasis cutánea (LC) en un hospital general. Material y métodos : Serie de casos comparativa de 193 pacientes con LC tratados en tres ensayos clínicos con AM (n=69) y EGS (n=124) durante 2001-2010. La administración de ambas drogas fue vía endovenosa lenta de 20 mg Sb5+/kg/día por 20 días consecutivos siguiendo las normativas de la OPS y OMS. La información clínica, toxicidad y eficacia fue obtenida de las historias clínicas almacenadas en el centro de investigación según la normativa local e internacional. Resultados : Las características demográficas fueron similares entre grupos, pero el tamaño y número de lesiones fueron mayores en el grupo AM. La eficacia del tratamiento con AM fue 76,0% versus 68,4% con EGS (p=0,340) y 55,1% versus 50,8% (p=0,570) en el análisis por protocolo y de intención de tratar, respectivamente. No se observaron efectos adversos inmediatos. Los síntomas más frecuentemente reportados fueron disgeusia (37,0%), mareos (32,0%), cefalea (36,0%), artralgias (31,0%) y linfangitis (21,0%). Los tres primeros síntomas, así como elevación de transaminasas, leucopenia, trombocitopenia y QTc prolongado fueron frecuentes en el grupo EGS, pero clínica y estadísticamente no significativos. El tratamiento fue suspendido definitivamente por toxicidad severa únicamente con EGS por emesis refractaria (2 participantes) y QTc prolongado con extrasístoles (1 participante). Conclusiones : La eficacia del tratamiento con AM y EGS fue comparable. La administración endovenosa de ambos no produjo efectos adversos inmediatos, aunque sí alteraciones clínicas y laboratoriales usuales.

SUMMARY Objectives : To compare the efficacy and safety of sodium stibogluconate (SS) and meglumine antimoniate (MA) in the treatment of cutaneous leishmaniasis (CL) in a general hospital. Methods: Case-series of 193 patients with CL treated in three clinical trials with MA (n=69) and SS (n=124) during 2001-2010. Both study drugs were administered intravenously at a slow speed at 20 mg Sb5+/kg/day for 20 consecutive days following WHO-PAHO recommendations. Clinical and safety data were gathered from clinical files. Results: Demographic characteristics were similar between the study groups, but the size and number of lesions were higher in the MA group. Efficacy was 76.0% in the MA vs. 68.4% in the SS group (p=0.340) and 55.1% vs. 50.8% (p=0.570) in the per protocol and intention to treat analysis. respectively. Side effects more frequently reported were dysgeusia (37.0%). dizziness (32.0%). headache (36.0%). arthralgia (31.0%) and lymphangitis (21.0%). These first three symptoms as well as elevation of transaminases, leukopenia, thrombocytopenia and prolonged QTc were numerically more frequent in the SS group but without reaching statistical significance. Treatment was stopped definitively for severe toxicity in the SS group due to refractory emesis (two patients) and prolonged QTc (one patient). Conclusions: The efficacy of MA and SS is comparable. The intravenous administration of these compounds did not produce immediate reactions, but it was associated with unusual clinical and laboratory abnormalities.

Factors associated with tuberculosis disease in children from a hospital in Western Mexico / Factores asociados con enfermedad tuberculosa en niños de un hospital del occidente de México

Abstract Background: This study aimed to describe the clinical and demographic characteristics of children with confirmed tuberculosis disease and identify associated factors. Methods: We conducted a retrospective and observational study at the Hospital Civil de Guadalajara Dr. Juan I. Menchaca. Inpatient and outpatient children under 18 years of age who were reported to the National Epidemiological Surveillance System (SINAVE, for its Spanish acronym) for suspected tuberculosis and who had molecular or microbiological tests for mycobacteria were included in the study. Multivariate analysis with logistic regression was used to analyze associated factors. Results: One hundred and nine patients under 18 years of age with suspected tuberculosis were included in the study. About 50.5% (55/109) were male, and the median age was 11 years. Tuberculosis was confirmed in 55% (n = 60): 15% (9/60) had a pulmonary infection, and the rest (51/60) had an extrapulmonary infection. The diagnostic tests used were histopathological study (n = 26), expectoration or gastric aspirate stains (n = 17), polymerase chain reaction (n = 12), and cultures (n = 5). Positive purified protein derivative (PPD) or interferon-gamma release assay (IGRA) tests were found in 33.9%. Malnutrition (odds ratio [OR] 15.9, 95% confidence interval [CI]: 2.3-109), and consumption of unpasteurized products (OR 7.45, 95% CI: 1.02-54.3) were associated with tuberculosis disease in children. Conclusions: Malnutrition and consumption of unpasteurized dairy products are associated with tuberculosis.

Resumen Introducción: El objetivo de este estudio fue describir las características clínicas y demográficas de niños con enfermedad tuberculosa confirmada e identificar los factores asociados. Métodos: Se realizó un estudio observacional retrolectivo en el Hospital Civil de Guadalajara Dr. Juan I. Menchaca. Se incluyeron menores de 18 años hospitalizados y ambulatorios que se notificaron al Sistema Nacional de Vigilancia Epidemiológica (SINAVE) por sospecha de tuberculosis y que contaron con pruebas moleculares o microbiológicas para micobacterias. El estudio de los factores asociados se realizó mediante análisis multivariado con regresión logística. Resultados: Se incluyeron en el estudio 109 menores de 18 años con sospecha de tuberculosis. El 50.5% (55/109) fueron de sexo masculino y la mediana de edad fue de 11 años. Se confirmó enfermedad tuberculosa en el 55% (n = 60) de los casos: el 15% (9/60) presentaron infección pulmonar y el resto extrapulmonar. Las pruebas diagnósticas utilizadas fueron el estudio histopatológico (n = 26), tinciones de expectoración o aspirado gástrico (n = 17), reacción en cadena de la polimerasa (n = 12) y cultivos (n= 5). 33.9% de los pacientes presentaron prueba de derivado proteico purificado (PPD) o ensayo de liberación de interferón gamma (IGRA) positiva. Se observó que la desnutrición (razón de momios (RM) 15.9, intervalo de confianza (IC) 95% 2.3 - 109) y el consumo de productos no pasteurizados (RM 7.45, IC 95% 1.02 - 54.3) se asociaron con enfermedad tuberculosa en niños. Conclusiones: La desnutrición y el consumo de lácteos no pasteurizados se asocian con la enfermedad tuberculosa.

Current and Advanced Applications of Gadoxetic Acid-enhanced MRI in Hepatobiliary Disorders.

Gadoxetic acid is an MRI contrast agent that has specific applications in the study of hepatobiliary disease. After being distributed in the vascular and extravascular spaces during the dynamic phase, gadoxetic acid is progressively taken up by hepatocytes and excreted to the bile ducts during the hepatobiliary phase. The information derived from the enhancement characteristics during dynamic and hepatobiliary phases is particularly relevant in the detection and characterization of focal liver lesions and in the evaluation of the structure and function of the liver and biliary system. The use of new MRI sequences and advanced imaging techniques (eg, relaxometry, multiparametric imaging, and analysis of heterogeneity), the introduction of artificial intelligence, and the development of biomarkers and radiomic and radiogenomic tools based on gadoxetic acid-enhanced MRI findings will play an important role in the future in assessing liver function, chronic liver disease, and focal liver lesions; in studying biliary pathologic conditions; and in predicting treatment responses and prognosis. © RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Incidencia y factores asociados con las reacciones adversas tras la primera dosis de la vacuna Pfizer-BioNTech en trabajadores de la salud.

OBJECTIVE: To determine the incidence of adverse reactions (AR) after the first dose of Pfizer-BioNTech vaccine, and to identify some factors associated with AR. METHOD: A retrospective cohort study was conducted. Data were obtained through an epidemiological survey answered online. Multivariate analyses were performed to identify factors associated with early (< 2 h) and late (≥ 2 h) AR. RESULTS: A total of 2295 health care workers were included; in them, the cumulative incidence of AR was 18.2% (95% confidence interval: 16.6-19.8), where the majority were late (78.2%). The associated factors that increased the risk of early AR were being female (odds ratio [OR]: 2.23, p = 0.002) and belonging to the medical staff (OR: 1.56; p = 0.041). In late AR were being female (OR: 1.94; p < 0.0001); on the other hand, diabetes (OR: 0.46; p = 0.021), asthma (OR: 0.53; p = 0.040) and smoking (OR: 0.44, p = 0.002) were inversely associated factors. Interestingly, history of COVID-19 was not associated with either early or late AR. CONCLUSIONS: The risk of presenting some type of AR due to the Pfizer-BioNTech vaccine in health care workers is < 20%.

OBJETIVO: Determinar la incidencia de reacciones adversas (RA) tras la primera dosis de la vacuna Pfizer-BioNTech e identificar algunos factores asociados con ellas. MÉTODO: Se realizó un estudio de cohorte retrospectiva. Los datos fueron obtenidos mediante una encuesta epidemiológica contestada en línea. Se realizaron análisis multivariados para identificar factores asociados con las RA tempranas (< 2 h) y tardías (≥ 2 h). RESULTADOS: Se incluyeron 2295 trabajadores de la salud; en ellos, la incidencia acumulada de RA fue del 18.2% (intervalo de confianza del 95%: 16.6-19.8%) y la mayoría fueron tardías (78.2%). Las RA tempranas más frecuentes fueron dolor local, cefalea y mareo; en las tardías fueron dolor local, cefalea y fatiga. No se documentaron casos de anafilaxia; sin embargo, en el grupo de RA tempranas y tardías hubo un caso y tres casos, respectivamente, con síntomas sistémicos que afectaron a dos órganos diferentes. Los factores asociados que incrementaron el riesgo de RA tempranas fueron ser mujer (odds ratio [OR]: 2.23; p = 0.002) y pertenecer al personal médico (OR: 1.56; p = 0.041). En las RA tardías fue ser mujer (OR: 1.94; p < 0.0001); por su parte, la diabetes (OR: 0.46; p = 0.021), el asma (OR: 0.53; p = 0.040) y el tabaquismo (OR: 0.44; p = 0.002) fueron factores asociados inversamente. Es interesante que la historia de COVID-19 no se asoció con RA tempranas ni tardías. CONCLUSIONES: El riesgo de presentar algún tipo de RA debido a la vacuna Pfizer-BioNTech en trabajadores de la salud es < 20%.

Rationale and design of the colchicine for the prevention of perioperative atrial fibrillation in patients undergoing major noncardiac thoracic surgery (COP-AF) trial.

BACKGROUND: Perioperative atrial fibrillation (AF) and myocardial injury after noncardiac surgery (MINS) are common complications after noncardiac surgery. Inflammation has been implicated in the pathogenesis of both disorders. The COP-AF trial tests the hypothesis that colchicine reduces the incidence of perioperative AF and MINS in patients undergoing major noncardiac thoracic surgery. METHODS AND RESULTS: The 'COlchicine for the Prevention of Perioperative Atrial Fibrillation' (COP-AF) trial is an international, blinded, randomized trial that compares colchicine to placebo in patients aged at least 55 years and undergoing major noncardiac thoracic surgery with general anesthesia. Exclusion criteria include a history of AF and a contraindication to colchicine (eg, severe renal dysfunction). Oral colchicine at a dose of 0.5 mg or matching placebo is given within 4 hours before surgery. Thereafter, patients receive colchicine 0.5 mg or placebo twice daily for a total of 10 days. The 2 independent co-primary outcomes are clinically important perioperative AF (including atrial flutter) and MINS during 14 days of follow-up. The main safety outcomes are sepsis or infection and non-infectious diarrhea. We aim to enroll 3,200 patients from approximately 40 sites across 11 countries to have at least 80% power for the independent evaluation of the 2 co-primary outcomes. The COP-AF main results are expected in 2023. CONCLUSIONS: COP-AF is a large randomized and blinded trial designed to determine whether colchicine reduces the risk of perioperative AF or MINS in patients who have major noncardiac thoracic surgery.