Reverse left ventricular remodeling after aortic valve replacement for aortic stenosis: a systematic review and meta-analysis.

Reverse left ventricular (LV) remodeling after aortic valve replacement (AVR), in patients with aortic stenosis, is well-documented as an important prognostic factor. With this systematic review and meta-analysis, we aimed to characterize the response of the unloaded LV after AVR. We searched on MEDLINE/PubMed and Web of Science for studies reporting echocardiographic findings before and at least 1 month after AVR for the treatment of aortic stenosis. In total, 1,836 studies were identified and 1,098 were screened for inclusion. The main factors of interest were structural and dynamic measures of the LV and aortic valve. We performed a random-effects meta-analysis to compute standardized mean differences (SMD) between follow-up and baseline values for each outcome. Twenty-seven studies met the eligibility criteria, yielding 11,751 patients. AVR resulted in reduced mean aortic gradient (SMD: - 38.23 mmHg, 95% CI: - 39.88 to - 36.58 , I 2 = 92 % ), LV mass (SMD: - 37.24 g, 95% CI: - 49.31 to - 25.18 , I 2 = 96 % ), end-diastolic LV diameter (SMD: - 1.78 mm, 95% CI: - 2.80 to - 0.76 , I 2 = 96 % ), end-diastolic LV volume (SMD: - 1.6 ml, 95% CI: - 6.68 to 3.51, I 2 = 91 % ), increased effective aortic valve area (SMD: 1.10 cm2, 95% CI: 1.01 to 1.20, I 2 = 98 % ), and LV ejection fraction (SMD: 2.35%, 95% CI: 1.31 to 3.40%, I 2 = 94.1 % ). Our results characterize the extent to which reverse remodeling is expected to occur after AVR. Notably, in our study, reverse remodeling was documented as soon as 1 month after AVR.

Erratum: New Perspectives on Spectroscopic Factor Quenching from Reactions [Phys. Rev. Lett. 131, 212503 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.131.212503.

New Perspectives on Spectroscopic Factor Quenching from Reactions.

The evolution of single-particle strengths as the neutron-to-proton asymmetry changes informs us of the importance of short- and long-range correlations in nuclei and has therefore been extensively studied for the last two decades. Surprisingly, the strong asymmetry dependence of these strengths and their extreme values for highly asymmetric nuclei inferred from knockout reaction measurements on a target nucleus are not consistent with what is extracted from electron-induced, transfer, and quasi-free reaction data, constituting a two-decade old puzzle. This work presents the first consistent analysis of one-nucleon transfer and one-nucleon knockout data, in which theoretical uncertainties associated with the nucleon-nucleus effective interactions considered in the reaction models are quantified using a Bayesian analysis. Our results demonstrate that, taking into account these uncertainties, the spectroscopic strengths of loosely bound nucleons extracted from both probes agree with each other and, although there are still discrepancies for deeply bound nucleons, the slope of the asymmetry dependence of the single-particle strengths inferred from transfer and knockout reactions are consistent within 1σ. Both probes are consistent with a small asymmetry dependence of these strengths. The uncertainties obtained in this work represent a lower bound and are already significantly larger than the original estimates.

Effects of the juçara fruit (Euterpe edulis Martius) pulp and lyophilized extract on NRF2, KEAP1, SOD1, and GPX2 expression in human colorectal cancer cell lines.

We investigated the effects of the juçara fruit (Euterpe edulis Martius) pulp and lyophilized extract on the expression of cytoprotective genes nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2), kelch-like ECH-associated protein 1 (KEAP1), superoxide dismutase (SOD1), and glutathione peroxidase (GPX2) in human colorectal cancer cell lines (HT-29 and Caco-2). Cells were cultured for 24 h in Dulbecco's Modified Eagle's Medium containing juçara fruit pulp (5, 10, or 50 mg/mL) or lyophilized extract (0.05, 0.1, or 0.5 mg/mL), and gene expression was quantified using real-time quantitative reverse transcription polymerase chain reaction. All studied genes showed significant variation in gene expression among different concentrations of pulp or lyophilized extract. Overall, the expression of the selected genes decreased in both cell lines following exposure to the pulp or lyophilized extract in a dose-dependent manner for most of the concentrations studied. In summary, our study showed that the compounds in juçara fruit inhibited the expression of cytoprotective genes associated with the antioxidant response and that, although not cytotoxic at the concentrations studied, they could potentially block the activation of the NRF2/KEAP1 pathway.

Estimands for atopic dermatitis clinical trials: Expert opinion on the importance of intercurrent events.

Despite the emergence of novel targeted treatments for atopic dermatitis (AD), there is a lack of guidelines on standardizing analysis of clinical trial data. To define and estimate meaningful treatment comparisons, several factors, including intercurrent events, must be taken into account. Intercurrent events are defined as events occurring after treatment initiation that affect either the interpretation or existence of the measurements associated with clinical questions of interest. Due to the relapsing, unpredictable nature of AD, intercurrent events frequently occur in AD trials, such as use of rescue therapy for intense itch and sleep deprivation. Despite the impact of intercurrent events in AD, they are often handled in an inconsistent manner across trials, which limits results interpretation. The estimand framework is increasingly used to estimate treatment effects while accounting for intercurrent events. This review explores how guidance from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) on the use of estimands can be applied to support AD clinical trial design and analysis. We propose that estimands are used in AD trials and defined early during trial design. The use of estimands can provide clinicians with interventional trial results that are more reflective of clinical practice, help facilitate comparisons across clinical trials, and are more informative to enable improved treatment selection for patients.

Effects of the juçara fruit (Euterpe edulis Martius) pulp and lyophilized extract on NRF2, KEAP1, SOD1, and GPX2 expression in human colorectal cancer cell lines

We investigated the effects of the juçara fruit (Euterpe edulis Martius) pulp and lyophilized extract on the expression of cytoprotective genes nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2), kelch-like ECH-associated protein 1 (KEAP1), superoxide dismutase (SOD1), and glutathione peroxidase (GPX2) in human colorectal cancer cell lines (HT-29 and Caco-2). Cells were cultured for 24 h in Dulbecco's Modified Eagle's Medium containing juçara fruit pulp (5, 10, or 50 mg/mL) or lyophilized extract (0.05, 0.1, or 0.5 mg/mL), and gene expression was quantified using real-time quantitative reverse transcription polymerase chain reaction. All studied genes showed significant variation in gene expression among different concentrations of pulp or lyophilized extract. Overall, the expression of the selected genes decreased in both cell lines following exposure to the pulp or lyophilized extract in a dose-dependent manner for most of the concentrations studied. In summary, our study showed that the compounds in juçara fruit inhibited the expression of cytoprotective genes associated with the antioxidant response and that, although not cytotoxic at the concentrations studied, they could potentially block the activation of the NRF2/KEAP1 pathway.

Baricitinib improves symptoms in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: patient-reported outcomes from two randomized monotherapy phase III trials.

BACKGROUND: Itch, skin pain, and sleep disturbance are burdensome symptoms in atopic dermatitis (AD) that negatively influence a patient's quality of life (QoL). OBJECTIVE: To evaluate the impact of baricitinib on patient-reported outcomes (PROs) in adult patients with moderate-to-severe AD, and explore the association between improvement in key signs and symptoms of AD with improvements in QoL and patient's assessment of disease severity. METHODS: Data were analyzed from two phase III monotherapy trials (BREEZE-AD1/BREEZE-AD2) in which patients were randomized 2:1:1:1 to once-daily placebo, baricitinib 1-mg, 2-mg, or 4-mg for 16 weeks and assessed using PRO measures. RESULTS: At week 16, baricitinib 4-mg and 2-mg significantly reduced itch severity (Itch Numeric Rating Scale (NRS) (BREEZE-AD1: percent change from baseline -36.6% and -29.4% vs. placebo (-12.0%), p≤.001 and p≤.05; BREEZE-AD2: -47.2% and -46.9% vs. placebo (-16.6%), p≤.001). Baricitinib significantly reduced SCORing AD (SCORAD) pruritus (4-mg in BREEZE-AD1 and 2-mg in BREEZE-AD2) and Patient Oriented Eczema Measure (POEM) itch (both doses). Improvements in skin pain severity and sleep disturbance were also observed. Improvements in AD symptoms showed higher correlations with patients' assessment of AD severity and QoL than improvements in skin inflammation. CONCLUSIONS: Baricitinib significantly improved symptoms in patients with moderate-to-severe AD. CLINICALTRIALS.GOV IDENTIFIERS: NCT03334396 (BREEZE-AD1) and NCT03334422 (BREEZE-AD2).

Active genic machinery for epigenetic RNA modifications in bees.

Epitranscriptomics is an emerging field of investigation dedicated to the study of post-transcriptional RNA modifications. RNA methylations regulate RNA metabolism and processing, including changes in response to environmental cues. Although RNA modifications are conserved from bacteria to eukaryotes, there is little evidence of an epitranscriptomic pathway in insects. Here we identified genes related to RNA m6 A (N6-methyladenine) and m5 C (5-methylcytosine) methylation machinery in seven bee genomes (Apis mellifera, Melipona quadrifasciata, Frieseomelitta varia, Eufriesea mexicana, Bombus terrestris, Megachile rotundata and Dufourea novaeangliae). In A. mellifera, we validated the expression of methyltransferase genes and found that the global levels of m6 A and m5 C measured in the fat body and brain of adult workers differ significantly. Also, m6 A levels were differed significantly mainly between the fourth larval instar of queens and workers. Moreover, we found a conserved m5 C site in the honeybee 28S rRNA. Taken together, we confirm the existence of epitranscriptomic machinery acting in bees and open avenues for future investigations on RNA epigenetics in a wide spectrum of hymenopteran species.

The longevity of Aedes aegypti mosquitoes is determined by carbohydrate intake / [A longevidade de mosquitos Aedes aegypti é determinada pela ingestão de carboidrato]

Aedes aegypti is the vector of several viral diseases. The main way to control these diseases is to fight the vector. Thus, it is necessary to breed mosquitoes in the laboratory in order to develop strategies to control these insects. In laboratories, different carbohydrates are used for feeding mosquitoes. The aim of this study is to evaluate the longevity and the weight of Ae. aegypti fed with different carbohydrates diets. As methods, 120 mosquitoes were distributed in insectaries and each group received a different diet, based on honey, dextrose or maltodextrin. To assess the longevity, survival analysis was performed using the Long Rank test and chi square test. To assess the weight, the dead insects were frozen and weighed at the end of the experiment. As results it was observed that mosquitoes fed with the honey, maltodextrin and dextrose diet lived on average 33, 35 and 47 days respectively. When weight was assessed, mosquitoes fed with honey weighed 125 ± (35.3) µg, while those fed with dextrose and maltodextrin weighed 225 ± (35.3) µg and 275 ± (35.3) µg respectively. The results show that the intake of dextrose and maltodextrin by Ae. aegypti adults increases their survival and their weight.(AU)

O Aedes aegypti é vetor de várias doenças virais. A principal maneira de controlar essas doenças é combatendo o seu vetor. Nesse sentido, é necessário criar esses mosquitos em laboratório, visando desenvolver estratégias de controle. Nos laboratórios, diferentes carboidratos são utilizados na alimentação de mosquitos. O objetivo deste estudo é avaliar longevidade e peso de Ae. aegypti alimentados com diferentes fontes de carboidratos. Como método, distribuíram-se 120 mosquitos insetários. Cada grupo recebeu uma dieta diferente à base de mel, dextrose ou maltodextrina. Para avaliar a longevidade, a análise de sobrevida foi realizada pelo teste de Logrank e pelo teste de qui quadrado. Para avaliar o peso, os insetos mortos foram congelados e pesados ​​no final do experimento. Como resultado, observou-se que os mosquitos alimentados com a dieta à base de mel, maltodextrina e dextrose viveram em média 33, 35 e 47 dias, respectivamente. Com relação ao peso, os mosquitos alimentados com mel pesavam 125 ± (35,3)µg, enquanto os alimentados com dextrose e maltodextrina pesavam 225 ± (35,3)µg e 275 ± (35,3)µg, respectivamente. Os resultados mostram que a ingestão de dieta à base de dextrose e maltodextrina por Ae. aegypti adultos aumenta sua sobrevivência e seu peso.(AU)

Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials.

BACKGROUND: Janus kinase (JAK) inhibition is a new mode of action in atopic dermatitis (AD); clarity about drug class safety considerations in the context of AD is important. Baricitinib, an oral, reversible, selective inhibitor of JAK1/JAK2, is in late-stage development for adult patients with moderate-to-severe AD. OBJECTIVE: To report pooled safety data for baricitinib in patients with moderate-to-severe AD in the clinical development program including long-term extension (LTE) studies. METHODS: This analysis included patient-level safety data from six double-blinded, randomized, placebo-controlled studies (one phase 2 and five phase 3), one double-blinded, randomized, LTE study and one open-label LTE study, reported in three data sets: placebo-controlled, 2-mg - 4-mg extended and All-bari AD. Safety outcomes include treatment-emergent adverse events, adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates were calculated. RESULTS: Data were collected for 2531 patients who were given baricitinib for 2247 patient-years (median duration 310 days). The frequency of serious infections, opportunistic infections and conjunctival disorders was low and similar between treatment groups in the placebo-controlled period. The most common serious infections were eczema herpeticum [n = 11, incidence rates (IR) = 0.5], cellulitis (n = 6, IR = 0.3) and pneumonia (n = 3, IR = 0.1). There were four opportunistic infections (IR = 0.2). No malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events or tuberculosis were reported in the placebo-controlled period in baricitinib-treated patients. Frequency of herpes simplex was higher in the 4-mg group (6.1%) vs. the 2-mg (3.6%) and placebo group (2.7%); IRs in the extended data set (2-mg IR = 9.6; 4-mg IR = 14.5) were lower vs. the placebo-controlled data set (2-mg IR = 12.4; 4-mg IR = 21.3). In the All-bari AD data set, there were two positively adjudicated major adverse cardiovascular events (2-mg group): two venous thrombosis events (4-mg group) and one death. CONCLUSION: This integrated safety analysis in patients with moderate-to-severe AD confirms the established safety profile of baricitinib.

Expression profiles of neotropical termites reveal microbiota-associated, caste-biased genes and biotechnological targets.

Termites are well recognized by their complex development trajectories, involving dynamic differentiation process between non-reproductive castes, workers and soldiers. These insects are associated with endosymbiotic microorganisms, which help in lignocellulose digestion and nitrogen metabolism. Aiming to identify genes harbouring biotechnological potential, we analyzed workers and soldiers RNA-Seq data of three neotropical termites: Heterotermes tenuis (Isoptera: Rhinotermitidae), Velocitermes heteropterus (Isoptera: Termitidae) and Cornitermes cumulans (Isoptera: Termitidae). We observed differences in the microbiota associated with each termite family, and found protists' genes in both Termitidae species. We found an opposite pattern of caste-biased gene expression between H. tenuis and the termitids studied. Moreover, the two termitids are considerably different concerning the number of differentially expressed genes (DEGs). Functional annotation indicated considerable differences in caste-biased gene content between V. heteropterus and C. cumulans, even though they share similar diet and biological niche. Among the most DEGs, we highlighted those involved in caste differentiation and cellulose digestion, which are attractive targets for studying more efficient technologies for termite control, biomass digestion and other biotechnological applications.

Azithromycin for chronic eosinophilic rhinosinusitis with nasal polyp: a placebo-controlled trial.

BACKGROUND: Chronic eosinophilic rhinosinusitis with nasal polyps (CRSwNP eosinophilic) is characterised by the formation of benign and bilateral nasal polyps. We aimed to compare the effectiveness of azithromycin as an immunomodulator with the use of a placebo in patients presenting with CRSwNP concomitant with asthma and aspirin intolerance after 3 months of treatment and at a 1-year follow-up. METHODOLOGY: We performed a randomised, double-blind, placebo-controlled trial. Patients received 500 mg azithromycin orally three times/week for 12 weeks. Improvement was evaluated by staging, the Sino-Nasal Outcome Test (SNOT-22), and nasal polyp biopsy. Data collected at pretreatment and 3 months posttreatment were compared. Quality of life was evaluated at the 1-year follow-up. RESULTS: Twenty-seven and 21 patients were treated with azithromycin and a placebo, respectively. The medication was well tolerated overall. Twenty patients (74%) in the azithromycin group and three patients (14%) in the placebo group were not refer- red for surgery at the end of the 3-month treatment. Regarding subjective improvement, there was a median decrease only in the azithromycin group, and the between-group difference was significant. SNOT-22 improvement was maintained in the azithromy- cin group at the 1-year follow-up. CONCLUSIONS: Azithromycin could be considered a therapeutic option for patients presenting with CRSwNP concomitant with asthma and aspirin intolerance.

[Electroconvulsive therapy in combination with psychotropic and non-psychotropic pharmacological treatments: Review of the literature and practical recommendations]. / Électroconvulsivothérapie en association avec des traitements pharmacologiques psychotropes et non psychotropes : revue de la littérature et recommandations pratiques.

CONTEXT: Electro-convulsive therapy (ECT) is the most effective treatment for treatment resistant mood disorders and catatonia. ECT also appears to be an effective treatment in combination with clozapine in the context of treatment resistant schizophrenia spectrum disorders. Although increasingly codified (guidelines on indications, contraindications, methods of implementation), the practice of ECT still lacks consensual protocols. The concomitant use of psychotropic and/or non-psychotropic medication is a common situation when ECT treatment is considered. To our knowledge, there is to date no summary of studies or case reports in France, nor any proposal for guidelines concerning the management of medication of the patient to whom ECT sessions are offered. Indeed, several particularities must be considered. This article proposes to specify for each pharmacological class the possible interaction between ECT and medication. A first section of this article will be devoted to non-psychotropic treatments, and a second section to psychotropic treatments. A practical summary table is also provided. METHOD: A review of the literature was conducted including all articles published prior to January 2019 referenced in Pub Med database, combining research with Medical Subject Headings "Electroconvulsive Therapy" and each following pharmacological class: "Cardiovascular Agents" "Bronchodilator Agents" "Bronchoconstrictor Agents" "Theophylline" "Anticoagulants" "Hypoglycemic Agents" "Insulin" "Potassium" "Benzodiazepines" "Valproic Acid" "Carbamazepine" "Lamotrigine" "Lithium" "Antidepressive Agents" "Antipsychotic Agents". RESULTS: After reading the titles, abstracts and whole articles, then searching for additional articles in the references, 50 articles were selected. A summary table summarizing the main risks and proposing a course of action has been produced. DISCUSSION: It is essential to take into account the specificity and the different physiological mechanisms involved in the ECT treatment in order to adjust the associated pharmacological treatments. The prescription for each molecule should be reviewed when ECT treatment is initiated.

Development of the Scalp Hair Assessment PRO™ measure for alopecia areata.

BACKGROUND: Valid patient-reported outcome (PRO) measures are required to evaluate alopecia areata (AA) treatments. OBJECTIVES: To develop a content-valid and clinically meaningful PRO measure to assess AA scalp hair loss with scores comparable with the five-response-level Alopecia Areata Investigator Global Assessment (AA-IGA™). METHODS: A draft PRO measure was developed based on input from 10 clinical experts in AA. The PRO measure was cognitively debriefed, modified and finalized through two rounds of qualitative semistructured interviews with patients with AA who had experienced ≥ 50% scalp hair loss. Data were thematically analysed. RESULTS: Adults (round 1: n = 25; round 2: n = 15) and adolescents aged 15-17 years (round 1: n = 5) in North America participated. All patients named scalp hair loss as a key AA sign or symptom. Patients demonstrated the ability to self-report their current amount of scalp hair using percentages. In round 1 not all patients interpreted the measurement concept consistently; therefore, the PRO was modified to clarify the measurement concept to improve usability. Following modifications, patients in round 2 responded without difficulty to the PRO measure. Patients confirmed that they could use the five-level response scale to rate their scalp hair loss: no missing hair, 0%; limited, 1-20%; moderate, 21-49%; large, 50-94%; nearly all or all, 95-100%. Almost all patients deemed hair regrowth resulting in ≤ 20% scalp hair loss a treatment success. CONCLUSIONS: The Scalp Hair Assessment PRO™ is a content-valid, clinically meaningful assessment of distinct gradations of scalp hair loss for evaluating AA treatment for patients with ≥ 50% hair loss at baseline.

The Alopecia Areata Investigator Global Assessment scale: a measure for evaluating clinically meaningful success in clinical trials.

BACKGROUND: Content-valid and clinically meaningful instruments are required to evaluate outcomes of therapeutic interventions in alopecia areata (AA). OBJECTIVES: To develop an Investigator's Global Assessment (IGA) to interpret treatment response in AA treatment studies. METHODS: Qualitative interviews were conducted in the USA with expert dermatologists and with patients with AA who had experienced ≥ 50% scalp-hair loss. Thematic data analysis identified critical outcomes and evaluated the content validity of the new IGA. RESULTS: Expert clinicians (n = 10) judged AA treatment success by the amount of scalp-hair growth (median 80% scalp hair). Adult (n = 25) and adolescent (n = 5) patients participated. Scalp-hair loss was the most bothersome AA sign/symptom for most patients. Perceived treatment success - short of 100% scalp hair - was the presence of ~ 70-90% scalp hair (median 80%). Using additional clinician and patient insights, the Alopecia Areata Investigator Global Assessment (AA-IGA™) was developed. This clinician-reported outcome assessment is an ordinal, static measure comprising five severity categories of scalp-hair loss. Nearly all clinicians and patients in this study agreed that, for patients with ≥ 50% scalp-hair loss, successful treatment would be hair regrowth resulting in ≤ 20% scalp-hair loss. CONCLUSIONS: We recommend using the Severity of Alopecia Tool to assess the extent (0-100%) of scalp-hair loss. The AA-IGA is a robust ordinal measure providing distinct and clinically meaningful gradations of scalp-hair loss that reflects patients' and expert clinicians' perspectives and treatment expectations. What is already known about this topic? The Severity of Alopecia Tool is widely used to assess the extent of scalp-hair loss in patients with alopecia areata. Guidelines define treatment success as a 50% improvement in scalp hair, and clinical trials have used dynamic thresholds of 50% and 90%. However, there is no clinical consensus on these endpoints, and patient perspectives on treatment success are unknown. What does this study add? Through qualitative interviews with 10 expert dermatologists and 30 patients with alopecia areata who had experienced ≥ 50% scalp-hair loss, we developed the Alopecia Areata Investigator Global Assessment (AA-IGA™) to measure five clinically meaningful gradations of alopecia areata scalp-hair loss that reflects patients' and clinicians' perspectives and expectations of treatment success in alopecia areata treatment studies. What are the clinical implications of this work? The AA-IGA is a robust ordinal measure that can inform clinical evaluation of alopecia areata treatment outcomes. The AA-IGA can be used to determine clinically meaningful treatment success for alopecia areata, with success defined by patients and clinicians as reaching ≤ 20% scalp-hair loss. Linked Comment: Blome. Br J Dermatol 2020; 183:609.

Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.

BACKGROUND: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids. OBJECTIVES: To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD who had an inadequate response to topical therapies. METHODS: In two independent, multicentre, double-blind, phase III monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomized 2 : 1 : 1 : 1 to once-daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks. RESULTS: At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE-AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE-AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night-time awakenings, skin pain and quality-of-life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage. CONCLUSIONS: Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.

Impact of markers of endothelial injury and hypercoagulability on systemic lupus erythematosus.

We have explored the relationship between possible hemostatic changes and clinical manifestation of the systemic lupus erythematosus (SLE) as a function of greater or lesser disease activity according to Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) criteria. Endothelial injury and hypercoagulability were investigated in patients with SLE by measuring thrombomodulin (TM), D-dimer (DDi) and thrombin generation (TG) potential. A total of 90 participants were distributed into three groups: 1) women with SLE presenting with low disease activity (laSLE) (SLEDAI-2K ≤ 4), 2) women with SLE presenting with moderate to high disease activity (mhaSLE) (SLEDAI-2K > 4), and 3) a control group comprising healthy women. Levels of TM and DDi were higher both in the laSLE and mhaSLE groups compared to controls and in mhaSLE compared to the laSLE group. With respect to TG assay, lagtime and endogen thrombin potential, low concentrations of tissue factor provided the best results for discrimination among groups. Analysis of these data allow us to conclude that TM, DDi and TG are potentially useful markers for discriminating patients with very active from those with lower active disease. Higher SLE activity may cause endothelial injury, resulting in higher TG and consequently a hypercoagulability state underlying the picture of thrombosis common in this inflammatory disease.

Acute embryonic exposure of zebrafish to permethrin induces behavioral changes related to anxiety and aggressiveness in adulthood.

Permethrin (PM) is one of the most used synthetic pyrethroid worldwide. Exposure to this compound during pregnancy and early childhood has been indicated as a risk factor for neurodevelopmental disorders. We evaluated the long-term effects of embryonic PM exposure in different stages of zebrafish development. Briefly, embryos (3 hpf) were exposed to sub-lethal concentrations of PM (25 and 50 µg.L-1) during 24 h and then behavioral parameters were evaluated during embryonic (28 hpf), eleutheroembryonic (3 dpf), larval (7 dpf), and adult stages (90 dpf). PM exposure decreased spontaneous movement at 28 hpf and decreased thigmotaxis in eleutheroembryos. The long-term effects of PM include changes in non-motor behaviors such as fear and anxiety in larva and adults. Adults embryonically exposed to PM also showed a significant increase in aggressiveness parameters. These results demonstrated that embryonic exposure to PM induces persistent neurotoxic effects in adulthood, which can impair the cognitive and behavioral fitness of non-target species contributing to a rise in neurodevelopmental disorders.

Incorporation of Cró thermal water in a dermocosmetic formulation: cytotoxicity effects, characterization and stability studies and efficacy evaluation.

OBJECTIVE: Development of cosmetic formulations to provide a controlled release of hydrophilic active compounds from mineral medicinal waters constitutes an attractive challenge. The objective of this study was the development and the characterization of a dermocosmetic gel formulation with Cró thermal water, from Beira Interior of Portugal, as a major functional ingredient. METHODS: Concentrations of mineral chemical elements of Cró thermal water were previously determined by inductively coupled plasma-optical emission spectrometry or mass spectrometry and cytotoxicity assays using thermal water were carried out on normal human dermal fibroblasts (NHDF) cells. Then, the Cró thermal water was included (more than 90%) in a developed gel formulation that was characterized through rheological and texture analysis and submitted to stability assays during 30 days. The effects on the skin volunteers, namely skin pH, the degree of hydration, transepidermal water loss and skin relief, were evaluated through non-invasive biometric techniques. A gel formulation including purified water was used as a control. RESULTS: Cró thermal water is rich on several chemical elements in particular sodium, silica, potassium and calcium besides some trace elements, with important functions for the skin. NHDF cells adhered and proliferated in the presence of thermal water confirming the biocompatibility of the major component of the gel formulation. The developed gel formulation based on thermal water resulted in an improvement of textural parameters, comparing with the purified water-based one. Significant improvements in the cutaneous biometric parameters (degree of hydration, transepidermal water loss and skin relief) of volunteers were also registered for the gel formulation containing thermal water. CONCLUSION: This study demonstrated for the first time the potential benefits of Cró thermal water in a gel formulation to be used in cosmetic and dermatological applications.

OBJECTIF: Le développement de formulations cosmétiques permettant une libération contrôlée des substances actives hydrophiles à partir d'eaux médicinales minérales constitue un défi attractif. L'objectif de cette étude était le développement et la caractérisation d'une formulation de gel dermocosmétique avec l'eau thermale de Cró, de Beira Interior au Portugal, comme ingrédient fonctionnel majeur. MÉTHODES: Les concentrations en éléments chimiques minéraux de l'eau thermale de Cró ont étés préalablement déterminées par spectrométrie d'émission optique avec plasma couplé par induction ou spectrométrie de masse et des essais de cytotoxicité utilisant de l'eau thermale ont été réalisés sur des cellules de fibroblastes dermiques humains normaux (NHDF). Ensuite, l'eau thermale de Cró a été incluse (plus de 90%) dans une formulation de gel développée qui a été caractérisée par analyse rhéologique et texture et soumise à des tests de stabilité pendant 30 jours. Les effets sur la la peau des volontaires, à savoir le pH de la peau, le degré d'hydratation, la perte d'eau transépidermique et le relief cutané, ont été évalués à l'aide de techniques biométriques non invasives. Une formulation de gel comprenant de l'eau purifiée a été utilisée comme témoin. RÉSULTATS: L'eau thermale de Cró est riche en plusieurs éléments chimiques, en particulier le sodium, la silice, le potassium et le calcium, en plus de certains oligo-éléments, avec des fonctions importantes pour la peau. Les cellules NHDF ont adhéré et ont proliféré en présence d'eau thermale, confirmant la biocompatibilité du composant principal de la formulation du gel. La formulation de gel développée à base d'eau thermale a permis une amélioration des paramètres de texture comparée à celle à base d'eau purifiée. Des améliorations significatives des paramètres biométriques cutanés (degré d'hydratation, perte en eau transépidermique et relief cutané) des volontaires ont également été enregistrées avec la formulation en gel contenant de l'eau thermale. CONCLUSION: Cette étude a démontré pour la première fois les avantages potentiels de l'eau thermale de Cró dans une formulation de gel destinée aux applications cosmétiques et dermatologiques.

Hormonal and Psychogenic Risk Factors for Erectile Dysfunction in Men with HTLV-1.

INTRODUCTION: Erectile dysfunction (ED) is associated with neurological damage due to human T-lymphotropic virus 1 (HTLV-1) infection, but hormonal and psychogenic factors also cause ED. AIM: To evaluate the association of psychogenic and hormonal factors with ED in men infected with HTLV-1. METHODS: In this cross-sectional study, we compared total testosterone, follicle stimulating hormone, luteinizing hormone, prolactin, anxiety symptoms, depressive symptoms, and neurologic manifestations in HTLV-1-infected men with or without ED. The International Index of Erectile Function was used to determine the degree of ED. Participants were grouped according to Osame's Motor Disability Scale and the Expanded Disability Status Scale: HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP), probable HAM/TSP, or HTLV-1 carrier. Chi-square and Fisher's exact tests were used to compare the groups, and regression analyses were used to show predictors of ED. MAIN OUTCOME MEASURE: Sexual hormonal levels, psychogenic factors, and neurologic disabilities were found to be associated with ED. RESULTS: ED was associated with age older than 60 years (P < .001), degree of neurologic involvement (P < .001), depression (P = .009), and anxiety (P = .008). In the multivariate analyses, only age and degree of neurological injury remained as risk factors for ED. CLINICAL IMPLICATIONS: Neurological manifestations are a stronger predictor of ED than hormonal and psychogenic factors in HTLV-1-infected men. STRENGTHS & LIMITATIONS: The statistical power of the study was limited due to the low number of participants, but neurologic manifestations were clearly associated with ED. There was no strong association between hormonal and psychogenic factors and ED. CONCLUSION: Hormonal and psychogenic factors did not show a strong association with ED in individuals with HTLV-1, but neurological manifestations were strongly associated with ED in these individuals. de Oliveira CJV, Neto, JAC, Andrade RCP, et al. Hormonal and Psychogenic Risk Factors for Erectile Dysfunction in Men with HTLV-1. J Sex Med 2019; 16:1763-1768.