[Management of Cytomegalovirus Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients]. / Abordagem à Infeção pelo Vírus Citomegálico em Doentes Submetidos a Transplante Alogénico de Progenitores Hematopoiéticos.

Cytomegalovirus (CMV) is a type of double-stranded deoxyribonucleic acid virus belonging to the herpesviridae family. Following a primary infection, the virus becomes latent in various types of white blood cells. Cytomegalovirus infection can remain latent or become active, especially in immunocompromised individuals, such as those undergoing hematopoietic stem cell transplantation (HSCT), where CMV reactivation can occur. In this context, CMV infection is common and associated with high rates of morbidity and mortality. Pneumonia is one of the most serious complications, with mortality rates exceeding 50%. Additionally, even in the absence of organ-specific disease, CMV infection is related to increased mortality unrelated to hematologic neoplasm recurrence. Given the frequency and severity of this infection in HSCT patients, it is crucial to implement effective strategies for monitoring, prevention, and treatment. This guideline was developed to identify patient groups that benefit from a systematic approach to CMV infection and to define the most appropriate strategy for each group. Monitoring CMV viral load in peripheral blood is crucial, especially in patients at moderate to high risk of active infection. Primary prophylaxis with letermovir (an antiviral drug) is recommended to reduce the incidence of active infection, especially in high-risk patients. Secondary prophylaxis with valganciclovir (antiviral drug) is recommended after an episode of active infection, while preemptive and disease treatment is based on monitoring viral load and clinical response. The aim of this guideline is to improve the approach to CMV infection in HSCT patients, ensuring an effective and safe preventive and therapeutic approach.

O vírus citomegálico (CMV) é um tipo de vírus de ácido desoxirribonucleico de dupla cadeia que pertence à família herpesviridae. Após uma infeção primária, o vírus torna-se latente em vários tipos de glóbulos brancos. A infeção por CMV pode permanecer latente ou tornar-se ativa, especialmente em indivíduos imunodeprimidos, como aqueles submetidos a transplantes de células progenitoras hematopoiéticas (TPH), onde a reativação do CMV pode ocorrer. Neste contexto, a infeção por CMV é comum e associada a elevadas taxas de morbilidade e mortalidade. A pneumonite é uma das complicações mais graves, com taxas de mortalidade superiores a 50%. Além disso, mesmo na ausência de doença específica do órgão, a infeção por CMV está relacionada com um aumento da mortalidade não relacionada com a recidiva da neoplasia hematológica. Dada a frequência e gravidade desta infeção em doentes submetidos a TPH, é crucial implementar estratégias eficazes de monitorização, prevenção e tratamento. Este protocolo foi desenvolvido para identificar os grupos de doentes que se beneficiam de uma abordagem sistematizada para a infeção por CMV e definir a estratégia mais adequada para cada grupo. A monitorização da carga viral de CMV no sangue periférico é fundamental, especialmente em doentes com risco moderado a elevado de infeção ativa. A profilaxia primária com letermovir (fármaco antiviral) é recomendada para reduzir a incidência de infeção ativa, especialmente em doentes com alto risco. A profilaxia secundária com valganciclovir (fármaco antiviral) é recomendada após um episódio de infeção ativa, enquanto o tratamento de antecipação e de doença é baseado na monitorização da carga viral e na resposta clínica. Este protocolo visa melhorar a abordagem da infeção por CMV em doentes submetidos a TPH, garantindo uma abordagem preventiva e terapêutica eficaz e segura.

Environmental impact of the diet of young Portuguese and its relationship with adherence to the Mediterranean Diet.

OBJECTIVE: To estimate, in a cohort of young Portuguese adults, the environmental impact (greenhouse gas (GHG) emissions, land use, energy used, acidification and potential eutrophication) of diet according to adherence to the Mediterranean Diet (MD). METHODS: Data from 1554 participants of the Epidemiologic Health Investigation of Teenagers in Porto (EPITeen) were analysed. Food intake and MD adherence were determined using validated questionnaires. The environmental impact was evaluated with the EAT-Lancet Commission tables, and the link between MD adherence and environmental impact was calculated using adjusted multivariate linear regression models. RESULTS: Higher adherence (high vs. low) to the MD was associated with lower environmental impact in terms of land use (7.8 vs. 8.5 m2, p = 0.002), potential acidification (57.8 vs. 62.4 g SO2-eq, p = 0.001) and eutrophication (21.7 vs. 23.5 g PO4-eq, p < 0.001). Energy use decreased only in the calorie-adjusted model (9689.5 vs. 10,265.9 kJ, p < 0.001), and GHG emissions were reduced only in a complementary model where fish consumption was eliminated (3035.3 vs. 3281.2 g CO2-eq, p < 0.001). Meat products had the greatest environmental impact for all five environmental factors analysed: 35.7% in GHG emissions, 60.9% in energy use, 72.8% in land use, 70% in acidification and 61.8% in eutrophication. CONCLUSIONS: Higher adherence to the MD is associated with lower environmental impact, particularly in terms of acidification, eutrophication, and land use. Reducing meat consumption can contribute to greater environmental sustainability.

A population pharmacokinetic model using allometric scaling for baricitinib in patients with juvenile idiopathic arthritis.

Baricitinib is approved for the treatment of rheumatoid arthritis (RA) in more than 70 countries, and juvenile idiopathic arthritis (JIA) in the European Union. Population pharmacokinetic (PK) models were developed in a phase 3 trial to characterize PK in pediatric patients with JIA and identify weight-based dosing regimens. The phase 3, randomized, double-blind, placebo-controlled withdrawal, efficacy and safety trial, JUVE-BASIS, enrolled patients (aged 2 to <18 years) with polyarticular course JIA. During a safety/PK period, baricitinib concentration data from age-based dose cohorts were compared to concentrations from adult patients receiving 4-mg QD. PK data were used to develop a population PK model with allometric scaling to determine a weight-based posology in pediatric patients with JIA that matched the adult 4-mg exposure. Baricitinib plasma concentrations from 217 pediatric patients were used to characterize PK. Based on the adult model, pediatric PK was best described using a 2-compartment model with allometric scaling on clearance and volume of distribution and renal function (estimated with glomerular filtration rate [GFR], a known covariate affecting PK of baricitinib) on clearance. The PK modeling suggested the optimal dosing regimen based on weight for pediatric patients as: 2-mg QD for patients 10 to <30 kg and 4-mg QD for patients ≥30 kg. The use of a population PK model of baricitinib treatment in adult patients with RA, with the addition of allometric scaling for weight on clearance and volume terms, was useful to predict exposures and identify weight-based dosing in pediatric patients with JIA.

Extraction, characterization and properties evaluation of pineapple leaf fibers from Azores pineapple.

Pineapple leaves can provide competitive and high-quality fibers for textile purposes. Despite pineapple being cultivated in the Portugues islands there is still a technology gap for the extraction and treatment of Pineapple Leaf Fibers (PALF) in Europe. Since Azorean Pineapple differs significantly from other plants in the bromeliad family, the properties and characterization of its leaf fibers were explored for the first time. Long fibers have been extracted by hand scraping and compared to biological retting at 25 °C for different time periods. It was explored the properties of PALF from plants of different ages (11- and 18-months) and from different zones of the leaves (beginning, middle, and tip). Physical-mechanical properties of Azores PALF were determined, including diameter, linear density, strength, Young's modulus, and elongation at break and characterized by ATR-FTIR, XRD, TGA/DTG, and FESEM to understand their chemical and morphological characteristics. While slight differences were observed between different ages, variations in physical-mechanical properties were notable among fibers extracted from different leaf positions. Extraction of Azores PALF through 25 °C biological retting for 14 days effectively eliminated non-fibrous matter and produced the thinnest and strongest fibers. These fibers ranged between 34.9 and 168.3 µm in diameter, 1.39 and 7.07 tex in linear mass density, 37-993 MPa in tensile strength, 1.0-3.9 % in elongation at break, and 2.4-21.8 GPa in Young's modulus.

Evaluation of Antitumor Activity of Xanthones Conjugated with Amino Acids.

Cancer is a complex disease characterized by several alterations, which confer, to the cells, the capacity to proliferate uncontrollably and to resist cellular death. Multiresistance to conventional chemotherapy drugs is often the cause of treatment failure; thus, the search for natural products or their derivatives with therapeutic action is essential. Chiral derivatives of xanthones (CDXs) have shown potential inhibitory activity against the growth of some human tumor cell lines. This work reports the screening of a library of CDXs, through viability assays, in different cancer cell lines: A375-C5, MCF-7, NCI-H460, and HCT-15. CDXs' effect was analyzed based on several parameters of cancer cells, and it was also verified if these compounds were substrates of glycoprotein-P (Pgp), one of the main mechanisms of resistance in cancer therapy. Pgp expression was evaluated in all cell lines, but no expression was observed, except for HCT-15. Also, when a humanized yeast expressing the human gene MDR1 was used, no conclusions could be drawn about CDXs as Pgp substrates. The selected CDXs did not induce significant differences in the metabolic parameters analyzed. These results show that some CDXs present promising antitumor activity, but other mechanisms should be triggered by these compounds.

Longitudinal tracking of diet quality from childhood to adolescence: The Interplay of individual and sociodemographic factors.

This study aimed to examine diet tracking from childhood to adolescence, using 4 time-points, and the influence of socioeconomic and individual characteristics in this transition. The sample included 6893 children from the Portuguese birth cohort Generation XXI with complete information on Food Frequency Questionnaire in at least one of the considered follow-ups. A Healthy Eating Index (HEI), previously developed to assess adherence to WHO's dietary recommendations, was applied at all ages (4, 7, 10 and 13y). The intraclass correlation coefficient (ICC) was used to analyse the tracking of diet quality. Linear mixed-effect models were performed to estimate the association of the child's socioeconomic and individual characteristics with the HEI score and respective trajectories over time. The overall diet quality decreased from childhood (22.2 ± 3.6 at 4y) to adolescence (18.2 ± 3.9 at 13y), with moderate tracking (ICC = 0.53), showing that children who start a healthy diet earlier might have a better diet quality as time goes by. Children of older mothers (ß = 0.079, 95%CI = 0.061-0.097) and with higher education (ß = 0.203, 95%CI = 0.178-0.229) and a higher household monthly income (ß = 0.024,95%CI = 0.007-0.041) had a higher diet quality over time. Besides family characteristics, the child's sedentary activities (ß = -0.009, 95%CI = -0.014--0.003) negatively influence diet quality throughout life. In contrast, being a girl (ß = -0.094, 95%CI = -0.132--0.056) and having higher sleep duration (ß = 0.039, 95%CI = 0.015-0.064) are associated with a higher diet quality over time. The presence of dietary tracking from childhood to adolescence implies that promoting healthy eating habits during the first years of life is crucial for a healthier diet quality during late childhood and early adolescence, focusing on maternal and individual child characteristics.

Design and Development of a Web-Based Prospective Nationwide Registry for Ocular Inflammatory Diseases: UVEITE.PT - The Portuguese Ocular Inflammation Registry.

Uveitis is a heterogeneous collection of infrequent diseases, which poses significant challenges to cost-effective research in the field. Medical registries are being increasingly recognized as crucial tools to provide high-quality data, thus enabling prospective clinical research. This paper describes the design and technical structure development of an innovative countrywide electronic medical record for uveitis, Uveite.pt, and gives an overview of the cohort registered since its foundation, March 2020.Uveite.pt is an electronic medical record platform developed by the Portuguese Ocular Inflammation Group (POIG), a scientific committee of the Portuguese Ophthalmology Society. This is a nationwide customized web-based platform for uveitis patients useful for both clinical practice and real-world-based research, working as a central repository and reporting tool for uveitis. This paper describes the technical principles, the design and the development of a web-based interoperable registry for uveitis in Portugal and provides an overview of more than 400 patients registered in the first 18 months since inception.In infrequent diseases, the existence of registries enables to gather evidence and increase research possibilities to clinicians. The adoption of this platform enables standardization and improvement of clinical practice in uveitis. It is useful to apprehend the repercussion of medical and surgical treatments in uveitis and scleritis, supporting clinicians in the strict monitoring of drug adverse reactions and surgical outcomes.

Effects of Probiotic-Enriched Minas Cheese (Lactobacillus acidophilus La-05) on Cardiovascular Parameters in 5/6 Nephrectomized Rats.

Dairy foods have become an interest in chronic kidney disease (CKD) due to their nutritional profile, which makes them a good substrate for probiotics incorporation. This study evaluated the effect of probiotic-enriched Minas cheese with Lactobacillus acidophilus La-05 in an experimental rat model for CKD on cardiac, inflammatory, and oxidative stress parameters. Male Wistar rats were divided into 4 groups (n = 7/group): 5/6 nephrectomy + conventional Minas cheese (NxC); 5/6 nephrectomy + probiotic Minas cheese (NxPC); Sham + conventional Minas cheese (ShamC); Sham + probiotic Minas cheese (ShamPC). Offering 20 g/day of Minas cheese with Lact. acidophilus La-05 (108-109 log CFU/g) for 6 weeks. The cardiomyocyte diameter was determined. Superoxide dismutase (SOD) activity in plasma, heart, kidney, and colon tissue was performed. At the end of supplementation, no significant changes in lipid profile and renal parameters were found. The NxPC group showed a decrease in cardiomyocyte diameter compared to the NxC group (16.99 ± 0.85 vs. 19.05 ± 0.56 µm, p = 0.0162); also they showed reduced plasmatic SOD activity (502.8 ± 49.12 vs. 599.4 ± 94.69 U/mL, p < 0.0001). In summary, probiotic-enriched Minas cheese (Lact. acidophilus La-05) consumption suggests a promisor cardioprotective effect and was able to downregulate SOD activity in a rat model of CKD.

Effect of Repeated Intravitreal Injections in Glaucoma Spectrum Diseases.

Purpose: To evaluate whether repeated intravitreal injections (IVI) with an anti-vascular endothelial growth factor (anti-VEGF) agent are associated with glaucomatous progression in eyes with glaucoma spectrum diseases (GSD). Methods: Single-center, retrospective, longitudinal study of patients with bilateral and similar GSD who: (1) received ≥8 IVI in only one eye during the study period; (2) had ≥2 retinal nerve fiber layer thickness (RNFL) measurements obtained by spectral-domain optical coherence tomography (SD-OCT) at least 12 months apart. The primary outcome was the absolute RNFL thickness change, comparing injected and fellow uninjected eyes. Linear mixed effects models were constructed, including a multivariable model. Results: Sixty-eight eyes from 34 patients were included, 34 injected and 34 fellow uninjected eyes. Average baseline age was 67.68±21.77 years with a follow-up of 3.66±1.89 years and 25.12±14.49 IVI. RNFL thickness decreased significantly from 80.92±15.78 to 77.20±17.35 µm (p<0.001; -1.18±1.93 µm/year) in injected eyes and from 79.95±17.91 to 76.61±17.97 µm (p<0.001; -1.07±0.98 µm/year) in uninjected eyes. In a multivariable linear mixed model of injected eyes, only higher baseline RNFL thickness (p < 0.001) significantly predicted higher absolute RNFL thickness loss. Neither absolute RNFL thickness variation (p=0.716) nor RNFL rate (p=0.779) was significantly different between paired injected and uninjected eyes. Absolute IOP variation was not significantly different between groups (16.62±4.77 to 15.09±4.34 mmHg in injected eyes and 17.68±5.01 to 14.50±3.39 mmHg in fellow uninjected eyes; p=0.248). The proportion of eyes receiving glaucoma medical treatment increased significantly in both groups (55.9% to 76.5% in injected eyes; p=0.039; 58.8% to 76.5% in uninjected eyes; p = 0.031). The number of glaucoma medications also increased significantly in both groups (1.03±1.11 to 1.59±1.18 glaucoma medications in injected eyes; p=0.003; 1.09±1.11 to 1.56±1.19 glaucoma medications in uninjected eyes; p=0.003). Conclusion: Repeated IVI do not seem to accelerate glaucomatous progression. Future studies with a longer follow-up are needed.

Monitoring Food Marketing Directed to Portuguese Children Broadcasted on Television.

Children are massively exposed to food marketing through television and other forms of media. Marketing strategies promote unhealthy eating behaviours and contribute to childhood obesity. The main aim of this study was to assess the potential exposure and power of food advertisements aimed at children, broadcasted on Portuguese television. Television data was recorded for two weekdays and two weekend days between 6 am and 10 pm during November 2021 from four free-access Portuguese television channels. Data was analysed according to the World Health Organization television protocol and Portuguese Legislation. We identified 5272 advertisements, of which 11.2% were for food and beverages (n = 590). Most advertised food categories for children and adolescents were chocolate and bakery products (42.0%), soft drinks (26.7%), and yoghurt (16.0%), and none met the nutritional profile outlined by the national legislation. Unhealthier food advertisements targeting youth were shown in children's non-peak time and morning during news and entertainment programmes. Product uniqueness, humour, and fun were the most frequent primary persuasive techniques. Most advertisements showed a high use of brand logos, product images, and premium offers. In conclusion, Portuguese children and adolescents are potentially exposed to large numbers of unhealthy food advertisements on television, despite marketing regulation and restriction policies.

Changes in screen time from 4 to 7 years of age, dietary patterns and obesity: Findings from the Generation XXI birth cohort.

BACKGROUND AND AIMS: Increased screen exposure is associated with unhealthy eating behaviours and obesity. Screen time (ST) changes from pre-school to school age, and associations with dietary patterns (DP) and obesity remain unknown. We, therefore, analysed ST changes from 4 to 7 years of age, associated factors, and the relation with DP and obesity. METHODS AND RESULTS: We included 4531 children evaluated at 4 and 7 years, as part of the Generation XXI birth cohort (Porto, Portugal). ST was assessed for weekdays and weekend, and average daily time was estimated. Associations between covariates and ST changes, and between ST changes and 3 DP previously identified (Energy-dense foods, Snacking, and Healthier) were estimated by odds ratios (OR) and 95% confidence interval (95%CI), using adjusted multinomial regression models. From 4 to 7 years, 31.5% of the children decreased their ST, 21.8% increased, 16.5% maintained low (≤60 min), and 30.2% maintained high (61-120 min or >120 min) ST. After adjustment, lower maternal education (OR = 2.33, 95%CI:1.82-2.99) and lower family income (OR = 1.72, 95%CI:1.35-2.21) were associated with higher odds of increasing ST, while being a girl was associated with 35% decreased odds of increasing ST. Children that increased and those that maintained high ST showed greater odds of presenting a Snacking DP at 7 years (OR = 2.34, 95%CI:1.64-3.35) and (OR = 2.65, 95%CI:1.89-3.72), respectively. No statistically significant differences were found regarding changes in ST and the child's BMI. CONCLUSION: Children increasing screen exposure during this period were more frequently from lower socioeconomic strata and presented unhealthier DP.

Baricitinib in juvenile idiopathic arthritis: an international, phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial.

BACKGROUND: Juvenile idiopathic arthritis can be refractory to some or all treatment regimens, therefore new medications are needed to treat this population. This trial assessed the efficacy and safety of baricitinib, an oral Janus kinase 1/2-selective inhibitor, versus placebo in patients with juvenile idiopathic arthritis. METHODS: This phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial was conducted in 75 centres in 20 countries. We enrolled patients (aged 2 to <18 years) with polyarticular juvenile idiopathic arthritis (positive or negative for rheumatoid factor), extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or juvenile psoriatic arthritis, and an inadequate response (after ≥12 weeks of treatment) or intolerance to one or more conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). The trial consisted of a 2-week safety and pharmacokinetic period, a 12-week open-label lead-in period (10 weeks for the safety and pharmacokinetic subcohort), and an up to 32-week placebo-controlled double-blind withdrawal period. After age-based dosing was established in the safety and pharmacokinetic period, patients received a once-daily 4 mg adult-equivalent dose of baricitinib (tablets or suspension) in the open-label lead-in period. Patients meeting Juvenile Idiopathic Arthritis-American College of Rheumatology (JIA-ACR) 30 criteria (JIA-ACR30 responders) at the end of the open-label lead-in (week 12) were eligible for random assignment (1:1) to receive placebo or continue receiving baricitinib, and remained in the double-blind withdrawal period until disease flare or up to the end of the double-blind withdrawal period (week 44). Patients and any personnel interacting directly with patients or sites were masked to group assignment. The primary endpoint was time to disease flare during the double-blind withdrawal period and was assessed in the intention-to-treat population of all randomly assigned patients. Safety was assessed in all patients who received at least one dose of baricitinib throughout the three trial periods. For adverse events in the double-blind withdrawal period, exposure-adjusted incidence rates were calculated. The trial was registered on ClinicalTrials.gov, NCT03773978, and is completed. FINDINGS: Between Dec 17, 2018 and March 3, 2021, 220 patients were enrolled and received at least one dose of baricitinib (152 [69%] girls and 68 [31%] boys; median age 14·0 years [IQR 12·0-16·0]). 219 patients received baricitinib in the open-label lead-in period, of whom 163 (74%) had at least a JIA-ACR30 response at week 12 and were randomly assigned to placebo (n=81) or baricitinib (n=82) in the double-blind withdrawal period. Time to disease flare was significantly shorter with placebo versus baricitinib (hazard ratio 0·241 [95% CI 0·128-0·453], p<0·0001). Median time to flare was 27·14 weeks (95% CI 15·29-not estimable) in the placebo group, and not evaluable for patients in the baricitinib group (<50% had a flare event). Six (3%) of 220 patients had serious adverse events during the safety and pharmacokinetic period or open-label lead-in period. In the double-blind withdrawal period, serious adverse events were reported in four (5%) of 82 patients (incidence rate [IR] 9·7 [95% CI 2·7-24·9] per 100 patient-years at risk) in the baricitinib group and three (4%) of 81 (IR 10·2 [2·1-29·7]) in the placebo group. Treatment-emergent infections were reported during the safety and pharmacokinetic or open-label lead-in period in 55 (25%) of 220 patients, and during the double-blind withdrawal period in 31 (38%) of 82 (IR 102·1 [95% CI 69·3-144·9]) in the baricitinib group and 15 (19%) of 81 (IR 59·0 [33·0-97·3]) in the placebo group. Pulmonary embolism was reported as a serious adverse event in one patient (1%; IR 2·4 [95% CI 0·1-13·3]) in the baricitinib group in the double-blind withdrawal period, which was judged to be related to study treatment. INTERPRETATION: Baricitinib was efficacious with an acceptable safety profile in the treatment of polyarticular juvenile idiopathic arthritis, extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, and juvenile psoriatic arthritis, after inadequate response or intolerance to standard therapy. FUNDING: Eli Lilly and Company under licence from Incyte.

MULT: A new BMI reference to assess nutritional status of multi-ethnic children and adolescents.

OBJECTIVES: To develop a new Body Mass Index (BMI) reference (MULT) based on longitudinal data of multi-ethnic populations and to compare it to international BMI references. METHODS: The MULT BMI reference was constructed through the LMS method and the Generalized Additive Models for Location Scale and Shape (GAMLSS), with 81 310 observations of 17 505 subjects aged 0-22 years old, from the United Kingdom, Ethiopia, Peru, India, Vietnam, Brazil, and Portugal. Outlier values were removed based on weight z-scores (population level) and based on BMI z-scores using the linear mixed effects model (individual level). The MULT M, S and L curves were compared to the ones of the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), International Obesity Task Force (IOTF), and Dutch Growth Study (DUTCH). The MULT BMI percentile cutoffs for overweight and obesity were calculated using the adult BMI values of 25 and 30 kg/m2 at 17, 18, 19, and 20 years old. RESULTS: MULT presented the lowest mean BMI values for the ages 102-240 months for boys and 114-220 months for girls. MULT S values were similar to the WHO and IOTF for children under 60 months of age and the highest during puberty, while the L curve showed to be more symmetric than the other BMI references. CONCLUSION: The MULT BMI reference was constructed based on recent data of populations from 10 countries, being a good option to assess the nutritional status of multi-ethnic populations.

Synthesis and Anti-Inflammatory Evaluation of a Library of Chiral Derivatives of Xanthones Conjugated with Proteinogenic Amino Acids.

In recent decades, the relationship between drug chirality and biological activity has been assuming enormous importance in medicinal chemistry. Particularly, chiral derivatives of xanthones (CDXs) have interesting biological activities, including enantioselective anti-inflammatory activity. Herein, the synthesis of a library of CDXs is described, by coupling a carboxyxanthone (1) with both enantiomers of proteinogenic amino esters as chiral building blocks (2-31), following the chiral pool strategy. The coupling reactions were performed at room temperature with good yields (from 44 to 99.9%) and very high enantiomeric purity, with most of them presenting an enantiomeric ratio close to 100%. To afford the respective amino acid derivatives (32-61), the ester group of the CDXs was hydrolyzed in mild alkaline conditions. Consequently, in this work, sixty new derivatives of CDXs were synthetized. The cytocompatibility and anti-inflammatory activity in the presence of M1 macrophages were studied for forty-four of the new synthesized CDXs. A significant decrease in the levels of a proinflammatory cytokine targeted in the treatment of several inflammatory diseases, namely interleukin 6 (IL-6), was achieved in the presence of many CDXs. The amino ester of L-tyrosine (X1AELT) was the most effective in reducing IL-6 production (52.2 ± 13.2%) by LPS-stimulated macrophages. Moreover, it was ≈1.2 times better than the D-enantiomer. Indeed, enantioselectivity was observed for the majority of the tested compounds. Thus, their evaluation as promising anti-inflammatory drugs should be considered.

Localized Therapeutic Approaches Based on Micro/Nanofibers for Cancer Treatment.

Cancer remains one of the most challenging health problems worldwide, and localized therapeutic approaches based on micro/nanofibers have shown potential for its treatment. Micro/nanofibers offer several advantages as a drug delivery system, such as high surface area, tunable pore size, and sustained release properties, which can improve drug efficacy and reduce side effects. In addition, functionalization of these fibers with nanoparticles can enhance their targeting and therapeutic capabilities. Localized delivery of drugs and/or other therapeutic agents via micro/nanofibers can also help to overcome the limitations of systemic administration, such as poor bioavailability and off-target effects. Several studies have shown promising results in preclinical models of cancer, including inhibition of tumor growth and improved survival rates. However, more research is needed to overcome technical and regulatory challenges to bring these approaches to clinical use. Localized therapeutic approaches based on micro/nanofibers hold great promise for the future of cancer treatment, providing a targeted, effective, and minimally invasive alternative to traditional treatments. The main focus of this review is to explore the current treatments utilizing micro/nanofibers, as well as localized drug delivery systems that rely on fibrous structures to deliver and release drugs for the treatment of cancer in a specific area.

Comparison of Trabeculectomy Outcomes Performed by Residents in Training and Ophthalmologists.

PRCIS: Resident-performed trabeculectomies present higher intraocular pressure and lower complete success rate at 1 year. PURPOSE: To compare the 1-year outcomes of ab externo trabeculectomy between residents in training and staff ophthalmologists. PATIENTS AND METHODS: This retrospective study included all consecutive eyes submitted to ab externo trabeculectomy between January 2015 to June 2020. A 1-year complete success rate was considered using all the following criteria: intraocular pressure (IOP)≤21 mm Hg and ≥6mm Hg without ocular hypotensive medications; IOP reduction≥30%; without loss of light perception, phthisis bulbi, and further glaucoma surgery (excluding suture lysis and bleb needling). RESULTS: One hundred and ten eyes from 99 patients were included. Thirty percent (n=33) of the trabeculectomies were performed by residents. There were no significant preoperative differences between groups, apart from age at surgery, which was higher in the residents' group (72.39±6.83 vs. 62.00±15.07 years, P<0.001), and visual field index (Humphrey Field Analyzer), which was lower in the ophthalmologists' group (51.81±34.74% vs. 32.04±33.83%, P=0.013). IOP at 1-, 3-, 6 months, and 1 year after surgery was significantly higher in the resident's group (P<0.05). Resident-performed trabeculectomies achieved a significantly lower complete success rate when compared with the ophthalmologists' group (39.39% vs. 64.94%, P=0.013). The overall rate of the postoperative complications and reintervention did not differ between groups, but the occurrence of a shallow anterior chamber was more frequent in the residents' group (15.15% vs. 4.05%, P=0.037). CONCLUSIONS: Resident-performed trabeculectomies present significantly higher postoperative IOP levels and a lower complete success rate when compared with staff ophthalmologists. It is, therefore, fundamental to adopt strategies to change this gap, improve patient safety, and strengthen resident confidence.

A carboxyl-functionalized covalent organic polymer for the efficient adsorption of saxitoxin.

Saxitoxin (STX), the most widely distributed neurotoxin in marine waters and emerging cyanotoxin of concern in freshwaters, causes paralytic shellfish poisoning in humans upon consumption of contaminated shellfish. To allow for the efficient monitoring of this biotoxin, it is of high importance to find high-affinity materials for its adsorption. Herein, we report the design and synthesis of a covalent organic polymer for the efficient adsorption of STX. Two ß-keto-enamine-based materials were prepared by self-assembly of 2,4,6-triformylphloroglucinol (Tp) with 2,5-diaminobenzoic acid (Pa-COOH) to give TpPa-COOH and with 2,5-diaminotoluene (Pa-CH3) to give TpPa-CH3. The carboxylic acid functionalized TpPa-COOH outperformed the methyl-bearing counterpart TpPa-CH3 by an order of magnitude despite the higher long-range order and surface area of the latter. The adsorption of STX by TpPa-COOH was fast with equilibrium reached within 1 h, and the Langmuir adsorption model gave a calculated maximum adsorption capacity, Qm, of 5.69 mg g-1, making this material the best reported adsorbent for this toxin. More importantly, the prepared TpPa-COOH also showed good reusability and high recovery rates for STX in natural freshwater, thereby highlighting the material as a good candidate for the extraction and pre-concentration of STX from aquatic environments.

Long-Term Safety and Efficacy of Ixekizumab in Patients With Axial Spondyloarthritis: 3-year Data From the COAST Program.

OBJECTIVE: To report safety and efficacy of ixekizumab (IXE) from the COAST program at 3 years, including 1 year from the originating studies (COAST-V, COAST-W, and COAST-X), and 2 years from COAST-Y. METHODS: In COAST-Y, patients continued with the dose received at the end of the originating study at week 52: 80 mg IXE either every 4 weeks (Q4W) or every 2 weeks (Q2W). Placebo-treated patients from COAST-X received IXE Q4W in COAST-Y. Starting at week 116 (week 64 of COAST-Y), patients receiving IXE Q4W could be escalated to Q2W. Safety for patients receiving ≥ 1 dose of IXE and efficacy for patients receiving ≥ 1 dose of IXE Q4W was assessed. Data are summarized as observed. RESULTS: For the 932 patients who received ≥ 1 dose of IXE (Q2W or Q4W) through 3 years, treatment-emergent adverse events (TEAEs) occurred at an incidence rate (IR) of 38.0 per 100 patient-years (PYs). The most frequently reported were infections (IR 25.7 per 100 PYs) and injection site reactions (IR 7.4 per 100 PYs); the majority of TEAEs were mild or moderate in severity. In total, 7.1% of TEAEs led to discontinuation (IR 3.1 per 100 PYs). All patient groups receiving IXE Q4W assessed through 3 years saw sustained improvements in Ankylosing Spondylitis Disease Activity Score, clinically important improvement, and other efficacy end points. CONCLUSION: The 3-year safety profile of IXE in the COAST program is consistent with the previously established long-term safety profile. IXE Q4W provided sustained improvement of disease activity in patients who received treatment through 3 years. (ClinicalTrials.gov: NCT02696785 [COAST-V], NCT02696798 [COAST-W], NCT02757352 [COAST-X], and NCT03129100 [COAST-Y]).

A lower energy intake contributes to a better cardiometabolic profile in adolescence: Data from the EPITeen cohort.

Caloric restriction has been associated with improved cardiometabolic health. Available data in humans are commonly based on short follow-up periods, specific diets, or population groups. We hypothesized that participants of a population-based cohort (Epidemiological Health Investigation of Teenagers in Porto) with a dietary pattern characterized by a lower energy intake during adolescence have a better cardiometabolic profile in adolescence and young adulthood than other dietary patterns. At aged 13 and 21 year evaluations, diet, anthropometric, and cardiometabolic measures were assessed. Diet was assessed through a food frequency questionnaire and, at 13 years, summarized in dietary patterns identified by cluster analysis. The lower intake dietary pattern included 40% of the participants. The energy intake misreport was estimated using the Goldberg method. Analysis of variance and analysis of covariance were used to compare cardiometabolic risk factors according to dietary patterns. The mean energy intake was 2394 and 2242 Kcal/d for the total sample at aged 13 years (n = 962) and 21 years (n = 862), respectively. Those belonging to the lower intake dietary pattern showed a 25% and 5% lower energy intake, respectively. In the cross-sectional analysis at aged 13, adolescents belonging to the lower intake dietary pattern presented lower glucose, insulin, triglycerides, and blood pressure values after adjusting for body mass index and parents' education level. Among the plausible reporters, differences were only statistically significant for glucose and systolic blood pressure. Our data support that a dietary pattern characterized by a lower energy intake may contribute to a better cardiometabolic profile in adolescents. However, no significant effect was found in young adulthood.