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BackgroundValid patient-reported outcome (PRO) measures are required to evaluate alopecia areata (AA) treatments.ObjectivesTo 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™).MethodsA 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.ResultsAdults (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.ConclusionsThe 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.

BackgroundContent-valid and clinically meaningful instruments are required to evaluate outcomes of therapeutic interventions in alopecia areata (AA).ObjectivesTo develop an Investigator's Global Assessment (IGA) to interpret treatment response in AA treatment studies.MethodsQualitative 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.ResultsExpert 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.ConclusionsWe 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.

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., (© 2023 European Academy of Dermatology and Venereology.)

Advancing functional ecology depends fundamentally on the availability of data on reproductive traits, including those from tropical plants, which have been historically underrepresented in global trait databases. Although some valuable databases have been created recently, they are mainly restricted to temperate areas and vegetative traits such as leaf and wood traits. Here, we present Rock n' Seeds, a database of seed functional traits and germination experiments from Brazilian rock outcrop vegetation, recognized as outstanding centers of diversity and endemism. Data were compiled through a systematic literature search, resulting in 103 publications from which seed functional traits were extracted. The database includes information on 16 functional traits for 383 taxa from 148 genera, 50 families, and 25 orders. These 16 traits include two dispersal, six production, four morphological, two biophysical, and two germination traits-the major axes of the seed ecological spectrum. The database also provides raw data for 48 germination experiments, for a total of 10,187 records for 281 taxa. Germination experiments in the database assessed the effect of a wide range of abiotic and biotic factors on germination and different dormancy-breaking treatments. Notably, 8255 of these records include daily germination counts. This input will facilitate synthesizing germination data and using this database for a myriad of ecological questions. Given the variety of seed traits and the extensive germination information made available by this database, we expect it to be a valuable resource advancing comparative functional ecology and guiding seed-based restoration and biodiversity conservation in tropical megadiverse ecosystems. There are no copyright restrictions on the data; please cite this paper when using the current data in publications; also the authors would appreciate notification of how the data are used in publications., (© 2022 The Ecological Society of America.)

Background: The validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD™) is a standardized severity assessment for use in clinical trials and registries for atopic dermatitis (AD)., Objectives: To investigate the reliability, validity, responsiveness and within-patient meaningful change of the vIGA-AD., Methods: Data were analysed from adult patients with moderate-to-severe AD in the BREEZE-AD1 (N = 624 patients; NCT03334396), BREEZE-AD2 (N = 615; NCT03334422) and BREEZE-AD5 (N = 440; NCT03435081) phase III baricitinib clinical studies., Results: Across studies, test-retest reliability for stable patients showed moderate-to-good agreement [range of Kappa values for Patient Global Impression of Severity-Atopic Dermatitis (PGI-S-AD), 0·516-0·639; for Eczema Area and Severity Index (EASI), 0·658-0·778]. Moderate-to-large correlations between vIGA-AD and EASI or body surface area (range at baseline, 0·497-0·736; Week 16, 0·716-0·893) supported convergent validity. Known-groups validity was demonstrated vs. EASI and PGI-S-AD (vIGA-AD for severe vs. moderate EASI categories at baseline, P < 0·001). Responsiveness was demonstrated vs. EASI (P < 0·001 for much improved vs. improved and improved vs. stable). Anchor- and distribution-based methods supported a vIGA-AD change of -1·0 as clinically meaningful. These findings are limited to populations defined by the studies' inclusion and exclusion criteria., Conclusions: The vIGA-AD demonstrated sufficient reliability, validity, responsiveness and interpretation standards for use in clinical trials. What is already known about this topic? A description of the development of the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD™) has been published previously. What does this study add? The current study validates the vIGA-AD by demonstrating appropriate test-retest reliability, convergent validity, known-groups validity and responsiveness across three baricitinib clinical studies. In addition, a 1-point change was identified as a clinically meaningful patient-perceived change minimal clinically important difference in the vIGA-AD. What are the clinical implications of the work? The vIGA-AD is a measure for investigator assessment of atopic dermatitis suitable for use in clinical research., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

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).

Background: The current classification for alopecia areata (AA) does not provide a consistent assessment of disease severity., Objective: To develop an AA severity scale based on expert experience., Methods: A modified Delphi process was utilized. An advisory group of 22 AA clinical experts from the United States was formed to develop this AA scale. Representatives from the pharmaceutical industry provided feedback during its development., Results: Survey responses were used to draft severity criteria, aspiring to develop a simple scale that may be easily applied in clinical practice. A consensus vote was held to determine the final AA severity statement, with all AA experts agreeing to adopt the proposed scale., Limitations: The scale is a static assessment intended to be used in clinical practice and not clinical trials., Conclusion: The final AA disease severity scale, anchored in the extent of hair loss, captures key features commonly used by AA experts in clinical practice. This scale will better aid clinicians in appropriately assessing severity in patients with this common disease., Competing Interests: Conflicts of interest Dr King reports serving on advisory boards and/or is a consultant and/or is a clinical trial investigator for Aclaris Therapeutics Inc, Almirall, Arena Pharmaceuticals, Bioniz Therapeutics, Bristol-Meyers Squibb, Concert Pharmaceuticals Inc, Dermavant Sciences Inc, Eli Lilly and Company, Incyte Corp, Pfizer Inc, TWi Biotechnology Inc, and Viela Bio and is on speaker bureaus for Pfizer Inc, Regeneron, and Sanofi Genzyme. Dr Mesinkovska reports receiving honoraria and/or fees from Eli Lilly and Company outside the submitted work, serving as chief scientific officer for the National Alopecia Areata Foundation, and serves on advisory boards for Arena Pharmaceuticals, Concert Pharmaceuticals, Eli Lilly and Company, and Nutrafol. Dr Craiglow reports receiving honoraria and/or fees from Eli Lilly and Company outside the submitted work, Aclaris Therapeutics Inc, Arena Pharmaceuticals Inc, Pfizer Inc, Regeneron Pharmaceuticals Inc, and Sanofi Genzyme. Dr Kindred reports receiving honoraria and/or fees from Eli Lilly and Company outside the submitted work, serves on advisory boards for Eli Lilly and Company and UCB, is a speaker for Selphyl and Aerolase, and is the Chair of the National Medical Association, Dermatology Section. Dr Ko serves on advisory boards and is a consultant and clinical investigator for Eli Lilly and Company, and he has served as a clinical investigator and/or consultant for AbbVie, Sanofi, Regeneron, Dermira, BMS, and Arena Pharmaceuticals and has received consulting fees from Eli Lilly and Company, Concert Pharmaceuticals, and Arena Pharmaceuticals outside the submitted work. Dr McMichael reports receiving honoraria and/or fees from Eli Lilly and Company outside the submitted work, serving as a consultant for Eli Lilly and Company, and Pfizer Inc, and as a researcher for Concert Pharmaceuticals. Dr Shapiro reports serving as a consultant for Eli Lilly and Company, as a consultant and investigator for Pfizer Inc, and has received honoraria from Pfizer Inc, Eli Lilly and Company, Applied Biology, and DS Laboratories outside the submitted work, and served as an investigator for RegenLab and received stock options for Eirion and Replicel Life Sciences. Dr Mirmirani reports acting as a Principal Investigator, clinical trials for Concert Pharmaceuticals, Eli Lilly and Company, and Pfizer Inc, is a compensated consultant/advisory board member for Eli Lilly and Company, and a consultant for DS Laboratories, Monat Global, Almirall, Thirty Madison, Leo Pharmaceuticals, Bristol Myers Squibb, P&G. Dr Hordinsky reports being an investigator for alopecia areata clinical trials sponsored by Pfizer Inc, Eli Lilly and Company, and Concert Pharmaceuticals and being a consultant for CASSIOPEA S.p.A., and the immediate past president of the American Hair Research Society. Dr Huang reports royalty payments to her institution from Pfizer for licensing of the ALTO tool and consulting fees from Concert Pharmaceuticals, Pfizer Inc, and Eli Lilly and Company. Dr Castelo-Soccio reports receiving fees for alopecia-related presentations, participating in a scientific advisory panel for Pfizer Inc and on the medical advisory board for the National Alopecia Areata Foundation. Dr Bergfeld reports personal and other fees from Eli Lilly and Company, Chairing the International Federation of Hair Research, and being a former president of the American Hair Research Society. Dr Paller reports being an investigator for AbbVie, AnaptysBio, Eli Lilly, Incyte, KrystalBio, Janssen, and Regeneron, on a data safety monitoring board for AbbVie and Galderma, and a consultant with honorarium for AbbVie, Abeona, Almirall, Amagma, Anaptysbio, Arena, Bausch, Bristol Myer Squibb, Dermavant, Dermira, Eli Lilly, Exicure, Forte, Leo, Lifemax, Phoenix, Pierre Fabre, Pfizer, Rapt, Regeneron, Sanofi, Sol-Gel, UCB, and Venthera. Dr Mackay-Wiggan reports receiving honoraria and/or fees from Eli Lilly and Company, being a consultant for Pfizer Inc, Eli Lilly and Company, and Concert Pharmaceuticals, and participating in an advisory board for Eli Lilly and Company, and receipt of site-related equipment and consumables from Pfizer Inc and Concert Pharmaceuticals. Dr Glashofer reports serving as a consultant for Eli Lilly and Company. Dr Piliang reports receiving grants/contract for study sites from Pfizer Inc, and Eli Lilly and Company. Dr Lo Sicco reports receiving a grant from Pfizer Education for alopecia areata-related work, and being a RegenLab, and Pfizer Inc. Dr Cassella reports being an employee and stockholder of Concert Pharmaceuticals. Author Koenigsberg reports being an employee and stockholder of Concert Pharmaceuticals. Dr Ghorayeb reports being an employee and stockholder of Janssen Global Services, LLC. Dr Fakharzadeh reports being a current employee and stockholder of Janssen Global Services, LLC. Dr Napatalung reports being a current employee and stockholder of Pfizer Inc. Author Gandhi reports being an employee and stockholder of Pfizer Inc. Dr DeLozier reports being an employee and stockholder at Eli Lilly and Company. Dr Nunes reports being an employee and stockholder at Eli Lilly and Company during manuscript development and being a current employee and stockholder at Janssen Global Services, LLC. Dr Senna reports clinical trial funding and SAB consulting fees from Eli Lilly and Company, during the conduction of the study and reported clinical trial funding from Concert Pharmaceuticals and SAB consulting fees from Pfizer Inc. Drs Tosti, Aguh, and Ahluwalia do not have conflicts of interest to disclose., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, is indicated in the European Union and Japan for treatment of moderate-to-severe atopic dermatitis (AD) in adults who are candidates for systemic therapy. In the ongoing, placebo-controlled, phase 3 trial BREEZE-AD5, once-daily oral baricitinib 2-mg monotherapy improved disease in moderate-to-severe AD patients who had an inadequate response or intolerance to topical corticosteroids. This post-hoc analysis aimed to identify responders to baricitinib 2 mg, using a proposed clinical tailoring approach based on baseline body surface area (BSA) affected and early clinical improvement, in BREEZE-AD5., Methods: Classification and regression tree method was used to evaluate baseline predictors for the proportion of patients achieving ≥ 75% improvement in Eczema Area and Severity Index (EASI75) at week 16 among baricitinib 2-mg-treated patients. Two-by-two contingency tables evaluated the association between early response, defined as ≥ 50% improvement in BSA or ≥ 3-point improvement in Itch Numeric Rating Scale from baseline at weeks 4 or 8, and response at week 16 for the proportion of patients achieving EASI75, validated Investigator Global Assessment for AD (vIGA-AD) score of 0 or 1, or ≥ 4-point improvement in Itch (Itch ≥ 4), respectively. Missing data were imputed as non-responder., Results: At week 16, EASI75 and vIGA-AD (0,1) were achieved by 37.5% and 31.7% of baricitinib 2-mg-treated patients with baseline BSA 10-50% compared with 9.5% and 4.8% with BSA > 50%. Early response in skin inflammation or itch at week 4 was associated with corresponding EASI75, vIGA-AD (0,1), and Itch ≥ 4 of 55.4%, 48.2%, and 39.3% at week 16, while early response at week 8 was associated with 66.7%, 56.1%, and 42.1% of patients achieving these endpoints., Conclusion: Baseline BSA of 10-50% and early clinical improvement after 4 or 8 weeks of baricitinib 2-mg treatment may identify patients most likely to benefit from long-term baricitinib 2-mg therapy., Clinical Trial Registration: NCT03435081., (© 2021. The Author(s).)

Background: The Itch Numeric Rating Scale (NRS), Skin Pain NRS, and Atopic Dermatitis Sleep Scale (ADSS) are self-administered patient-reported outcome (PRO) instruments developed to assess symptoms in patients with atopic dermatitis (AD). The objective of this study was to evaluate the psychometric properties (reliability, validity, and responsiveness) and interpretability thresholds of these PROs using data from three pivotal Phase 3 studies in adults., Methods: BREEZE-AD1, BREEZE-AD2, and BREEZE-AD5 evaluated the safety and efficacy of baricitinib in adults with moderate-to-severe AD. Clinician-reported outcomes and other PROs commonly assessed in patients with AD were used to estimate meaningful changes and evaluate test-retest reliability, convergent and divergent validity, known-groups validity, responsiveness, and meaningful change thresholds (MCTs) of the Itch NRS, Skin Pain NRS, and ADSS., Results: The test-retest reliability of the Itch NRS, Skin Pain NRS, and ADSS was evidenced by generally large intraclass correlation coefficients (> 0.7) in stable groups of patients between baseline and Week 1 and Weeks 4 and 8. Moderate-to-large correlations (r > 0.4) at baseline and Week 16 were generally observed between each measure and other PROs measuring the same concept, supporting convergent validity. Small-to-moderate correlations with clinician-reported outcomes demonstrated divergent validity. Each instrument was able to distinguish between known groups of disease severity as assessed using other indicators of AD severity. The responsiveness of the Itch NRS, Skin Pain NRS, and ADSS scales was demonstrated through significant differences in their change scores from baseline to Week 16 between categories of change in another PRO also from baseline to Week 16. Thresholds for interpreting meaningful change were estimated as - 4.0 for the 0-10 Itch and Skin Pain NRS items; - 1.25 for the 0-4 ADSS Items 1 and 3 and; - 1.50 for the 0-29 ADSS Item 2, these equivalent to moderate degrees of change., Conclusions: Results of this study demonstrate that the psychometric properties of the Itch NRS, Skin Pain NRS, and ADSS are good to excellent. These findings support the use of these instruments in daily assessment of AD symptoms in adults with moderate-to-severe AD. Trial registration ClinicalTrials.gov numbers: NCT03334396, NCT03334422, and NCT03435081., (© 2021. The Author(s).)

Background: Baricitinib, an oral selective Janus kinase 1/Janus kinase 2 inhibitor, is being studied for moderate-to-severe atopic dermatitis (AD) in adults., Objective: To evaluate the efficacy and safety of baricitinib monotherapy in a North American phase 3 trial (BREEZE-AD5/NCT03435081) of adults with moderate-to-severe AD who responded inadequately or were intolerant to topical therapy., Methods: Patients (N = 440) were randomized 1:1:1 to once-daily placebo or baricitinib (1 mg or 2 mg). The primary endpoint was the proportion of patients achieving ≥75% reduction in the Eczema Area and Severity Index at week 16. A key secondary endpoint was the proportion of patients achieving a validated Investigator Global Assessment for AD score of 0 (clear)/1(almost clear) with ≥2-point improvement., Results: At week 16, the proportion of patients achieving Eczema Area and Severity Index was 8%, 13%, and 30% (P < .001, 2 mg vs placebo) and those with a validated Investigator Global Assessment for AD score of 0/1 were 5%, 13%, and 24% (P < .001, 2 mg vs placebo) for placebo, baricitinib 1 mg, and baricitinib 2 mg, respectively. Safety findings were similar to those of other baricitinib AD studies., Limitations: Short-term clinical trial results may not be generalizable to real-world settings., Conclusion: Baricitinib was efficacious for patients with moderate-to-severe AD with no new safety findings over 16 weeks., Competing Interests: Conflicts of interest Dr Simpson reports grants and fees for participation as a consultant and principal investigator from Eli Lilly and Company, LEO Pharma, Pfizer, and Regeneron; grants for participation as a principal investigator from Galderma and Merck & Co; and fees for consultant services from AbbVie, Boehringer Ingelheim, Dermavant Incyte, Forte Bio, Pierre Fabre Dermo, and Sanofi Genzyme. Dr Forman is a consultant, investigator, advisory board member, and/or speaker for and receives funding and/or honoraria from AbbVie, Aclaris Therapeutics Inc, Asana BioSciences, AstraZeneca, Athenex, Celgene Corporation, Cutanea Life Sciences, Eli Lilly and Company, Incyte Corporation, Innovaderm Research Inc, Novartis, Pfizer Inc, Promius Pharma LLC, Regeneron, UCB, Valeant Pharmaceuticals North America LLC, and XBiotech. Dr Silverberg served as a consultant and/or advisory board member for AbbVie, Arena, Asana, Bluefin, Boehringer Ingelheim, Dermavant, Dermira, Eli Lilly and Company, Galderma, GlaxoSmithKline, Glenmark, Incyte, Kiniksa, Leo, Luna, Novartis, Pfizer, RAPT, Regeneron, and Sanofi, receiving honoraria; served as a speaker for Regeneron-Sanofi; and received research grants from Galderma. Dr Zirwas is a consultant, investigator, and/or speaker for Regeneron, Sanofi, Genench, Novartis, L'Oreal, Menlo, Leo, Eli Lilly and Company, Ortho Derm, and Arcutis and is a part owner of AsepticMD. Dr Han is a consultant for Eli Lilly and Company, Regeneron, Sanofi, and Pfizer. Dr Guttman-Yassky is a consultant for AbbVie, Almirall, Amgen, Asana Biosciences, Boehringer Ingelhiem, Cara Therapeutics, Celgene, Concert, DBV, Dermira, DS Biopharma, Eli Lilly and Company, EMD Serono, Escalier, Galderma, Glenmark, Kyowa Kirin, LEO Pharma, Mitsubishi Tanabe, Pfizer, RAPT Therapeutics, Regeneron, Sanofi, Sienna Biopharma, and Union Therapeutics and reports institute grants for research from AbbVie, Almirall, Amgen, AnaptysBio, Asana Biosciences, Boehringer Ingelhiem, Celgene, Dermavant, DS Biopharma, Eli Lilly and Company, Glenmark, Galderma, Innovaderm, Janssen, Kiniska, Kyowa Kirin, Leo Pharma, Novan, Pfizer, Ralexar, Regeneron, Sienna Biopharma, UCB, and Union Therapeutics. Dr Bissonnette is an advisory board member, consultant, speaker and/or investigator for and receives honoraria and/or grant from AbbVie, Arcutis, Arena Pharma, Asana BioSciences, Bellus Health, Boehringer Ingelheim, CARA, Dermavant, Eli Lilly, EMD Serono, Galderma, Incyte, Kiniksa, Kyowa Kirin, LEO Pharma, Novan, Pfizer, Ralexar, RAPT, Regeneron, Sanofi Genzyme, and Sienna and is an employee and shareholder of Innovaderm Research. Dr Waibel is an investigator, consultant speaker for, and/or receives honoraria from AbbVie, Pfizer, Candela, Cytrellis, Dominion, Eli Lilly and Company, Novartis, Sebacia, and Sciton. Dr Papp is a consultant, speaker, investigator, scientific officer, steering committee member, and/or advisory board member for AbbVie, Akros, Amgen, Anacor, Arcutis, Astellas, Bausch Health/Valeant, Baxalta, Boehringer Ingelheim, Bristol-Myers Squibb, Can-Fite Biopharma, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly and Company, Evelo, Galapagos, Galderma, Genentech, Gilead, GSK, Janssen, Kyowa Hakko Kirin, Leo, Medimmune, Meiji Seika Pharma, Merck (MSD), Merck- Serono, Mitsubishi Pharma, Moberg Pharma, Novartis, Pfizer, PRCL Research, Regeneron, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, Takeda, UCB. Drs Nunes, Holzwarth, and Janes and authors DeLozier and Angle are employees and shareholders of Eli Lilly and Company. Drs Gamalo and Goldblum were employees of Eli Lilly and Company during the study. Drs Maverakis and Marnell and author Zhong have no conflicts of interest to declare., (Copyright © 2021. Published by Elsevier Inc.)

Importance: Baricitinib, an oral selective Janus kinase inhibitor, improved the clinical signs and symptoms of moderate to severe atopic dermatitis in the 16-week, phase 3 monotherapy studies, BREEZE-AD1 and BREEZE-AD2. Long-term efficacy has not yet been examined., Objective: To evaluate the long-term (68-week) efficacy of baricitinib in adults with moderate to severe atopic dermatitis who were treatment responders or partial responders in BREEZE-AD1 and BREEZE-AD2., Design, Setting, and Participants: Patients completing BREEZE-AD1/BREEZE-AD2 entered the ongoing, multicenter, double-blind, long-term extension study BREEZE-AD3. The study was initiated on March 28, 2018. Data were analyzed on December 13, 2019., Interventions: Responders and partial responders (patients achieving validated Investigator Global Assessment for Atopic Dermatitis [vIGA-AD] score of 0 or 1 [0,1], or 2) at BREEZE-AD1/BREEZE-AD2 completion remained on originally assigned treatment for 52 weeks (68 total weeks of continuous therapy)., Main Outcomes and Measures: The primary end point was the proportion of patients achieving a vIGA-AD score of 0,1 at weeks 16, 36, and 52 of BREEZE-AD3. Secondary end points included the proportion of patients achieving 75% or more improvement in the Eczema Area and Severity Index [EASI75] score and 4-point or more improvement in the itch numeric rating scale (NRS), using originating study baseline data. Itch data were collected during the first 16 weeks in BREEZE-AD3. The last originating study visit was the first BREEZE-AD3 visit; therefore, data are presented for continuous weeks of therapy, including the 16-week originating study period. Missing data were imputed by last observation carried forward. Modified intention-to-treat analysis was used., Results: Of the responder/partial responder population, the proportion of patients treated with baricitinib, 4 mg (n = 70) (mean [SD] age, 36.7 [15.5] years; 42 [60%] were men), achieving vIGA-AD (0,1) at week 16 was 45.7% (BREEZE-AD3 baseline) and, at week 68, 47.1%. Improvement of 75% or more in the EASI score was 70.0% at week 16 and 55.7% at week 68. The proportion of patients achieving an itch NRS improvement greater than or equal to 4 points at week 16 was 52.5% and, at week 32, 45.9%. Of the responder/partial responder population, the proportion of patients treated with baricitinib, 2 mg (n = 54) (mean [SD] age, 32.8 [12.7] years; 28 [51.9%] were men), achieving vIGA-AD (0,1) at week 16 was 46.3% and, at week 68, 59.3%. Improvement in the EASI75 score was 74.1% at week 16 and 81.5% at week 68. The proportion of patients achieving an itch NRS improvement greater than or equal to 4 points at week 16 was 44.2% and, at week 32, 39.5%., Conclusions and Relevance: In this long-term double-blind extension study of 2 randomized clinical trials, baricitinib, 4 and 2 mg, demonstrated sustained long-term efficacy in patients with moderate to severe atopic dermatitis., Trial Registration: ClinicalTrials.gov Identifier: NCT03334435.

Background: Baricitinib, a selective Janus kinase 1/Janus kinase 2 inhibitor, is indicated in the European Union and Japan for the treatment of moderate-to-severe atopic dermatitis (AD) in adults who are candidates for systemic therapy., Objective: The objective of this study was to evaluate the safety of baricitinib 2 mg in the AD clinical program., Methods: Six double-blind, randomized, placebo-controlled studies, and two long-term extension studies were summarized in two datasets. Placebo comparison was based on six 16-week studies with baricitinib 2 mg. All-bari-2-mg-AD included patients who received baricitinib 2 mg at any time during the eight studies., Results: In total, 1598 patients received once-daily baricitinib 2 mg for 1434.2 patient-years of exposure (median 330 days/maximum 2.4 years). Treatment-emergent adverse events were higher for baricitinib 2 mg (57.9%) vs placebo (51.6%). Serious adverse events, serious infections, and opportunistic infections were low in frequency and similar between baricitinib 2 mg and placebo. There were no malignancies, gastrointestinal perforations, or major adverse cardiovascular events with baricitinib 2 mg in the placebo-controlled period. Herpes simplex (cluster) was higher for baricitinib 2 mg (3.8%) vs placebo (2.8%); rates decreased with extended 2 mg exposure. In All-bari-2-mg-AD, there were five malignancies other than non-melanoma skin cancer, two major adverse cardiovascular events, one peripheral venous thrombosis, one arterial thrombosis, and no pulmonary embolisms, deep vein thromboses, or deaths., Conclusions: This integrated analysis in patients with moderate-to-severe AD confirms the established safety profile of baricitinib 2 mg. Longer exposure to treatment is required to evaluate risks of malignancies and major adverse cardiovascular events., Clinical Trial Registration: ClinicalTrials.gov identifiers: NCT02576938 (first posted 15 October, 2015); NCT03334396 (7 November, 2017); NCT03334422 (7 November, 2017); NCT03428100 (9 February, 2018); NCT03435081 (15 February, 2018); NCT03733301 (7 November, 2018); NCT03334435 (7 November, 2017); NCT03559270 (18 June, 2018).

Importance: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced disease severity in moderate to severe atopic dermatitis (AD) in 2 phase 3 monotherapy studies., Objective: To assess the efficacy and safety of 4 mg and 2 mg of baricitinib in combination with background topical corticosteroid (TCS) therapy in adults with moderate to severe AD who previously had an inadequate response to TCS therapy., Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial, BREEZE-AD7 (Study of Baricitinib [LY3009104] in Combination With Topical Corticosteroids in Adults With Moderate to Severe Atopic Dermatitis) was conducted from November 16, 2018, to August 22, 2019, at 68 centers across 10 countries in Asia, Australia, Europe, and South America. Patients 18 years or older with moderate to severe AD and an inadequate response to TCSs were included. After completing the study, patients were followed up for up to 4 weeks or enrolled in a long-term extension study., Interventions: Patients were randomly assigned (1:1:1) to receive 2 mg of baricitinib once daily (n = 109), 4 mg of baricitinib once daily (n = 111), or placebo (n = 109) for 16 weeks. The use of low-to-moderate potency TCSs was allowed., Main Outcomes and Measures: The primary end point was the proportion of patients achieving a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 (clear) or 1 (almost clear), with a 2-point or greater improvement from baseline at week 16., Results: Among 329 patients (mean [SD] age, 33.8 [12.4] years; 216 [66%] male), at week 16, a vIGA-AD score of 0 (clear) or 1 (almost clear) was achieved by 34 patients (31%) receiving 4 mg of baricitinib and 26 (24%) receiving 2 mg of baricitinib compared with 16 (15%) receiving placebo (odds ratio vs placebo, 2.8 [95% CI, 1.4-5.6]; P = .004 for the 4-mg group; 1.9 [95% CI, 0.9-3.9]; P = .08 for the 2-mg group). Treatment-emergent adverse events were reported in 64 of 111 patients (58%) in the 4-mg group, 61 of 109 patients (56%) in the 2-mg group, and 41 of 108 patients (38%) in the placebo group. Serious adverse events were reported in 4 patients (4%) in the 4-mg group, 2 (2%) in the 2-mg group, and 4 (4%) in the placebo group. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and folliculitis., Conclusions and Relevance: A dose of 4 mg of baricitinib in combination with background TCS therapy significantly improved the signs and symptoms of moderate to severe AD, with a safety profile consistent with previous studies of baricitinib in AD., Trial Registration: ClinicalTrials.gov Identifier: NCT03733301.

Background: Eyebrow and eyelash hair loss and nail damage-in addition to scalp hair loss-are important signs/symptoms of alopecia areata (AA) to patients and deserve assessment in AA clinical trials., Objectives: Our objective was to develop clinician-reported outcome (ClinRO) and patient-reported outcome (PRO) measures and accompanying photoguides to aid in the assessment of AA-related eyebrow, eyelash and nail signs/symptoms., Methods: Iterative rounds of qualitative, semi-structured interviews were conducted with US expert dermatologists and North American patients with AA. Patients with eyebrow, eyelash and nail involvement were purposefully sampled. Interview transcripts were qualitatively analyzed., Results: Dermatologists (n = 10) described eyebrow and eyelash loss as concerning for affected patients and, along with nail appearance, as deserving assessment. Dermatologist data informed the development of single item, 4-point Likert-type ClinRO and PRO measures of current eyebrow loss, eyelash loss and nail appearance and a PRO measure of eye irritation. Patients (n = 45, age 15-72 years) confirmed the importance and relevance of these signs/symptoms. Interim revision resulted in measures that were understood by and relevant to patients. Dermatologists (n = 5) and patients (n = 10, age 21-54 years) participated in the development of the eyebrow, eyelash and nail photoguides and confirmed that they included photos that appropriately represented different severity levels and were helpful to derive and standardize ratings across raters., Conclusions: The ClinRO and PRO measures for eyebrow, eyelash and nail appearance, with their accompanying photoguides and the PRO Measure for Eye Irritation provide clear and meaningful assessments of outcomes important to patients with AA.

Background: Alopecia areata (AA) is characterized by hair loss that can affect the scalp and body. This study describes the psychosocial burden of AA., Methods: Participants diagnosed with AA who had experienced ≥50% scalp hair loss according to the Severity of Alopecia Tool (SALT) were identified by clinicians. A semi-structured interview guide, developed with expert clinician input, included open-ended questions to explore patients' experiences of living with AA. Data were thematically analyzed to identify concepts and relationships., Results: Participants (n = 45, 58% female, mean age 33.3 years [range 15-72], mean SALT 67.2 [range 0-100]) described the AA diagnosis as "devastating". Both males and females reported emotional and psychological impacts of AA including feeling sad/depressed (n = 21), embarrassed/ashamed (n = 10) and angry/frustrated (n = 3). Patients felt helpless (n = 5) due to the unpredictability of disease recurrence, and anxious (n = 19) about judgement from others. Many patients avoided social situations (n = 18), which impaired relationships and increased isolation. Coping strategies included concealment of hair loss through wigs or make-up, although fear of the displacement of these coverings also caused anxiety and the avoidance of activities that could result in scalp exposure (n = 22). Some patients became more accepting of AA over time, which lessened the emotional impact, though efficacious treatment was still desired. A conceptual framework was developed, and a conceptual model was created to depict the relationship between the physical signs/symptoms and the associated psychosocial effects of AA., Conclusion: AA impairs patients' emotional and psychological wellbeing, relationships and lifestyles. Greater disease awareness and effective treatments are needed.

Background: An Investigator Global Assessment (IGA) is recommended by health agencies for drug registration in atopic dermatitis (AD). Current IGA scales lack standardization., Objectives: To develop an IGA scale, training module, and clinical certification examination for use in AD trials; establish content validity; and assess reliability., Methods: Expert dermatologists participated in the development of the validated IGA for AD (vIGA-AD TM ). Reliability (interrater and intrarater) was assessed by 2 web-based surveys. Clinical certification for investigators consisted of a training module and examination., Results: Expert consensus was achieved around a 5-point IGA scale including morphologic descriptions, and content validity was established. Survey 1 showed strong interrater reliability (Kendall's coefficient of concordance W [Kendall's W], 0.809; intraclass correlation [ICC], 0.817) and excellent agreement (weighted kappa, 0.857). Survey 2, completed 5 months after training of dermatologists, showed improvements in scale reliability (Kendall's W, 0.819; ICC, 0.852; weighted kappa, 0.889). In this study, 627 investigators completed vIGA-AD training and certification., Limitations: Ratings were assessed on photographs., Conclusion: A validated IGA scale and training module were developed with the intent of harmonizing assessment of disease severity in AD trials. Strong reliability and excellent agreement between assessments were observed., (Copyright © 2020. Published by Elsevier Inc.)

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., (© 2020 British Association of Dermatologists.)

Environmental pollution in the form of particulate matter <2.5 μm (PM 2.5 ) is a major risk factor for diseases such as lung cancer, chronic respiratory infections, and major cardiovascular diseases. Our goal was to show that PM 2.5 eliciting a proinflammatory response activates the immune-pineal axis, reducing the pineal synthesis and increasing the extrapineal synthesis of melatonin. Herein, we report that the exposure of rats to polluted air for 6 hours reduced nocturnal plasma melatonin levels and increased lung melatonin levels. Melatonin synthesis in the lung reduced lipid peroxidation and increased PM 2.5 engulfment and cell viability by activating high-affinity melatonin receptors. Diesel exhaust particles (DEPs) promoted the synthesis of melatonin in a cultured cell line (RAW 264.7 cells) and rat alveolar macrophages via the expression of the gene encoding for AANAT through a mechanism dependent on activation of the NFκB pathway. Expression of the genes encoding AANAT, MT1, and MT2 was negatively correlated with cellular necroptosis, as disclosed by analysis of Gene Expression Omnibus (GEO) microarray data from the human alveolar macrophages of nonsmoking subjects. The enrichment score for antioxidant genes obtained from lung gene expression data (GTEx) was significantly correlated with the levels of AANAT and MT1 but not the MT2 melatonin receptor. Collectively, these data provide a systemic and mechanistic rationale for coordination of the pineal and extrapineal synthesis of melatonin by a standard damage-associated stimulus, which activates the immune-pineal axis and provides a new framework for understanding the effects of air pollution on lung diseases., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Baricitinib, an oral selective inhibitor of Janus kinase 1 and Janus kinase 2, modulates proinflammatory cytokine signaling., Objectives: The efficacy and safety of baricitinib were evaluated in patients with moderate-to-severe atopic dermatitis (AD)., Methods: In this phase 2, randomized, double-blind, placebo-controlled study, 124 patients with moderate-to-severe AD applied topical corticosteroids (TCSs) for 4 weeks before randomization to once-daily placebo, 2 mg of baricitinib, or 4 mg of baricitinib for 16 weeks. Use of TCSs was permitted during the study. The primary outcome was the proportion of patients achieving at least a 50% reduction in the Eczema Area and Severity Index (EASI-50) compared with placebo., Results: Significantly more patients who received baricitinib, 4 mg, achieved EASI-50 than did patients receiving placebo (61% vs 37% [P = .027]) at 16 weeks. The difference between the proportion of patients receiving baricitinib, 2 or 4 mg, who achieved EASI-50 and the proportion of patients receiving placebo and achieving EASI-50 was significant as early as week 4. Baricitinib also improved pruritus and sleep loss. Treatment-emergent adverse events were reported in 24 of the patients receiving placebo (49%), 17 of those receiving 2 mg of baricitinib (46%), and 27 of those receiving 4 mg of baricitinib (71%)., Limitations: A TCS standardization period before randomization reduced disease severity, limiting the ability to compare results with those of baricitinib monotherapy. Longer studies are required to confirm baricitinib's efficacy and safety in patients with AD., Conclusions: Baricitinib used with TCSs reduced inflammation and pruritus in patients with moderate-to-severe AD., (Copyright © 2018. Published by Elsevier Inc.)

Background: Inflammation signaled by Janus kinases (JAKs) promotes progression of diabetic kidney disease (DKD). Baricitinib is an oral, reversible, selective inhibitor of JAK1 and JAK2. This study tested the efficacy of baricitinib versus placebo on albuminuria in adults with Type 2 diabetes at high risk for progressive DKD., Methods: In this Phase 2, double-blind, dose-ranging study, participants were randomized 1:1:1:1:1 to receive placebo or baricitinib (0.75 mg daily; 0.75 mg twice daily; 1.5 mg daily; or 4 mg daily), for 24 weeks followed by 4-8 weeks of washout., Results: Participants (N = 129) were 63±9.1 (mean±standard deviation) years of age, 27.1% (35/129) women and 11.6% (15/129) African-American race. Baseline hemoglobin A1c (HbA1c) was 7.3±1% and estimated glomerular filtration rate was 45.0±12.1 mL/min/1.73 m2 with first morning urine albumin-creatinine ratio (UACR) of 820 (407-1632) (median; interquartile range) mg/g. Baricitinib, 4 mg daily, decreased morning UACR by 41% at Week 24 compared with placebo (ratio to baseline 0.59, 95% confidence interval 0.38-0.93, P = 0.022). UACR was decreased at Weeks 12 and 24 and after 4-8 weeks of washout. Baricitinib 4 mg decreased inflammatory biomarkers over 24 weeks (urine C-X-C motif chemokine 10 and urine C-C motif ligand 2, plasma soluble tumor necrosis factor receptors 1 and 2, intercellular adhesion molecule 1 and serum amyloid A). The only adverse event rate that differed between groups was anemia at 32.0% (8/25) for baricitinib 4 mg daily versus 3.7% (1/27) for placebo., Conclusions: Baricitinib decreased albuminuria in participants with Type 2 diabetes and DKD. Further research is required to determine if baricitinib reduces DKD progression.

This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12-14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon., (© 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Mutations in Janus kinase 2 (JAK2) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2 V617F mutation. The study had a standard 3+3 dose-escalation design to define the maximum-tolerated dose. Primary objectives were to determine safety, tolerability, and recommended oral daily dose of gandotinib for patients with JAK2 V617F -positive myelofibrosis, essential thrombocythemia, or polycythemia vera. Secondary objectives included estimating pharmacokinetic parameters and documenting evidence of efficacy by measuring clinical improvement. Thirty-eight patients were enrolled and treated (31 myelofibrosis, 6 polycythemia vera, 1 essential thrombocythemia). The maximum-tolerated dose of gandotinib was 120mg daily, based on dose-limiting toxicities of blood creatinine increase or hyperuricemia at higher doses. Maximum plasma concentration was reached 4h after single and multiple doses, and mean half-life on day 1 was approximately 6h. Most common treatment-emergent adverse events were diarrhea (55.3%) and nausea (42.1%), a majority of which were of grade 1 severity. Best response of clinical improvement was achieved by 29% of myelofibrosis patients. A ≥50% palpable spleen length reduction was observed at any time during therapy in 20/32 evaluable patients. Additionally, ≥50% reduction in the Total Symptom Myeloproliferative Neoplasm Symptom Assessment Form Score was seen in 11/21 (52%) and 6/14 patients (43%) receiving ≥120mg at 12 and 24 weeks respectively. Gandotinib demonstrated an acceptable safety and tolerability profile, and findings at the maximum-tolerated dose of 120mg supported further clinical testing. Clinicaltrials.gov identifier: NCT01134120., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Clinically validated biomarkers for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis (SWN) have not been identified to date. The biomarker working group's goals are to (1) define biomarker needs in NF1, NF2, and SWN; (2) summarize existing data on biomarkers in NF1, NF2, and SWN; (3) outline recommendations for sample collection and biomarker development; and (4) standardize sample collection and methodology protocols where possible to promote comparison between studies by publishing standard operating procedures (SOPs)., Methods: The biomarker group reviewed published data on biomarkers in NF1, NF2, and SWN and on biobanking efforts outside these diseases via literature search, defined the need for biomarkers in NF, and developed recommendations in a series of consensus meetings., Results: We describe existing biomarkers in NF and report consensus recommendations for SOP and a minimal clinical dataset to accompany samples derived from patients with NF1, NF2, and SWN in decentralized biobanks., Conclusions: These recommendations are intended to provide clinicians and researchers with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for NF1, NF2, and SWN., (© 2016 American Academy of Neurology.)

Background: Atrioventricular reentrant tachycardias account for approximately one third of cases referred for electrophysiological study (EPS). The anatomical substrate responsible for the reentry is an accessory pathway (AP) able to conduct the electrical stimulus in an anterograde, retrograde or bidirectional manner., Objective: To evaluate the correlation of AP location with the male and female genders and AP clinical presentation, whether manifest or concealed., Methods: Retrospective observational study including 942 consecutive patients, all diagnosed with EPS-confirmed AP from January 1994 to December 2008. APs were classified into eight anatomical groups: left lateral (LL), left posterior (LP), left posteroseptal (LPS), right posteroseptal (RPS), right midseptal (RMS), right anteroseptal (RAS), right lateral (RL), and right posterior (RP)., Results: Of the 942 patients, 52.6% were males. The mean age was 31.2±13.8years. As regards gender, APs were more prevalent among men. However, a statistically significant difference was observed only in the LPS (p=0.029) and RL (p=0.003) regions. In relation to the form of presentation of AP, the manifest form was more frequent than the concealed form in six of the eight regions studied, except for the LL and LPS regions., Conclusion: AP predominated in males and the manifest form was more frequent than the concealed form in most of the regions studied., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Capybaras (Hydrochoerus hydrochaeris) are the largest rodents found in South America. The aim of the present study was to investigate the occurrence of anti-Toxoplasma gondii and anti-Neospora caninum antibodies in 170 free-living capybaras in a residential park area in Itu Municipality, São Paulo State, Brazil. Serum samples were tested by indirect fluorescent antibody test (IFAT) for T. gondii (IFAT ≥ 1:16) and N. caninum (IFAT ≥ 1:50). Among the 170 samples analyzed, 10% (17/170) and 0% (0/170) were seropositive for T. gondii and N. caninum, respectively. This study confirms the widespread presence of T. gondii and reinforces the role of capybaras in the life cycle of this parasite. Capybaras may not be important as intermediate hosts of N. caninum in the studied environment.

Background/aims: Several studies have been performed to unravel the association between diabetes and increased susceptibility to infection. This study aimed to investigate the effect of insulin on the local environment after cecal ligation and puncture (CLP) in rats., Methods: Diabetic (alloxan, 42 mg/kg i.v., 10 days) and non-diabetic (control) male Wistar rats were subjected to a two-puncture CLP procedure and 6 h later, the following analyses were performed: (a) total and differential cell counts in peritoneal lavage (PeL) and bronchoalveolar lavage (BAL) fluids; (b) quantification of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL- 6, IL-10 and cytokine-induced neutrophil chemoattractant (CINC)-1 and CINC-2 in the PeL and BAL fluids by enzyme-linked immunosorbent assay (ELISA); (c) total leukocyte count using a veterinary hematology analyzer and differential leukocyte counts on stained slides; (d) biochemical parameters (urea, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) by colorimetric analyses); and (e) lung, kidney, and liver morphological analyses (hematoxylin and eosin staining)., Results: Relative to controls, non-diabetic and diabetic CLP rats exhibited an increased in the concentration of IL-1β, IL-6, IL-10, CINC-1, and CINC-2 and total and neutrophil in the PeL fluid. Treatment of these animals with neutral protamine Hagedorn insulin (NPH, 1IU and 4IU, respectively, s.c.), 2 hours before CLP procedure, induced an increase on these cells in the PeL fluid but it did not change cytokine levels. The levels of ALT, AST, ALP, and urea were higher in diabetic CLP rats than in non-diabetic CLP rats. ALP levels were higher in diabetic sham rats than in non-diabetic sham rats. Treatment of diabetic rats with insulin completely restored ALT, AST, and ALP levels., Conclusion: These results together suggest that insulin attenuates liver dysfunction during early two-puncture CLP-induced peritoneal inflammation in diabetic rats., (© 2015 S. Karger AG, Basel.)

Neoplasia is uncommon in Turner syndrome, although there is some evidence that brain tumors are more common in Turner syndrome patients than in the general population. We describe a woman with Turner syndrome (45,X) with a meningioma, in whom a second neoplasia, basal cell carcinomas of the scalp and nose, developed five years later in the absence of therapeutic radiation. Together with 7 cases of Turner syndrome with meningioma from a population-based survey in the United Kingdom, and 3 other isolated cases in the literature, we review this small number of patients for evidence of risk factors related to Turner syndrome, such as associated structural anomalies or prior treatment. We performed histological and fluorescent in situ hybridization (FISH) of 22q (NF2 locus) analyses of the meningeal tumor to search for possible molecular determinants. We are not able to prove causation between these two entities, but suggest that neoplasia may be a rare associated medical problem in Turner syndrome. Additional case reports and extension of population-based studies are needed., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background: Brazilian spotted fever (BSF), caused by the bacterium Rickettsia rickettsii, is the deadliest spotted fever of the world. In most of the BSF-endemic areas, capybaras (Hydrochoerus hydrochaeris) are the principal host for the tick Amblyomma cajennense, which is the main vector of BSF., Methods: In 2012, a BSF case was confirmed in a child that was bitten by ticks in a residential park area inhabited by A. cajennense-infested capybaras in Itú municipality, southeastern Brazil. Host questing A. cajennense adult ticks were collected in the residential park and brought alive to the laboratory, where they were macerated and intraperitoneally inoculated into guinea pigs. A tick-inoculated guinea pig that presented high fever was euthanized and its internal organs were macerated and inoculated into additional guinea pigs (guinea pig passage). Tissue samples from guinea pig passages were also used to inoculate Vero cells through the shell vial technique. Infected cells were used for molecular characterization of the rickettsial isolate through PCR and DNA sequencing of fragments of three rickettsial genes (gltA, ompA, and ompB). Blood serum samples were collected from 172 capybaras that inhabited the residential park. Sera were tested through the immunofluorescence assay using R. rickettsii antigen., Results: A tick-inoculated guinea pig presented high fever accompanied by scrotal reactions (edema and marked redness). These signs were reproduced by consecutive guinea pig passages. Rickettsia was successfully isolated in Vero cells that were inoculated with brain homogenate derived from a 3rd passage-febrile guinea pig. Molecular characterization of this rickettsial isolate (designated as strain ITU) yielded DNA sequences that were all 100% identical to corresponding sequences of R. rickettsii in Genbank. A total of 83 (48.3%) out of 172 capybaras were seroreactive to R. rickettsii, with endpoint titers ranging from 64 to 8192., Conclusions: A viable isolate of R. rickettsii was obtained from the tick A. cajennense, comprising the first viable R. rickettsi isolate from this tick species during the last 60 years. Nearly half of the capybara population of the residential park was seroreactive to R. rickettsii, corroborating the findings that the local A. cajennense population was infected by R. rickettsii.

Background/aims: Diabetes mellitus (DM) is characterized by hyperglycemia, associated to a lack or inefficiency of the insulin to regulate glucose metabolism. DM is also marked by alterations in a diversity of cellular processes that need to be further unraveled. In this study, we examined the autophagy pathway in diabetic rat macrophages before and after treatment with insulin., Methods: Bone marrow-derived macrophages (BMM), bronchoalveolar lavage (BAL) and splenic tissue of diabetic male Wistar rats (alloxan, 42 mg/kg, i.v., 10 days) and control rats (physiological saline, i.v.). Some diabetic rats were given neutral protamine Hagedorn insulin (4 IU, s.c.) 8 h before experiments. For characterization of the model and evaluation of the effect of insulin on the autophagic process, the following analyzes were performed: (a) concentrations of cytokines: interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, IL-4, IL-10, cytokine-induced neutrophil chemoattractant (CINC)-1 and CINC-2 in the BAL supernatant was measured by ELISA; (b) characterization of alveolar macrophage (AM) of the BAL as surface antigens (MHCII, pan-macrophage KiM2R, CD11b) and autophagic markers (protein microtubule-associated light chain (LC)3, autophagy protein (Atg)12 by flow cytometry and confocal microscopy (c) study of macrophages differentiated from the bone marrow by flow cytometry and confocal microscopy (d) histology of the spleen by immunohistochemistry associated with confocal microscopy., Results: Interestingly, insulin exerted antagonistic effects on macrophages from different tissues. Macrophages from bronchoalveolar lavage (BAL) enhanced their LC3 autophagosome bound content after treatment with insulin whereas splenic macrophages from red pulp in diabetic rats failed to enhance their Atg 12 levels compared to control animals. Insulin treatment in diabetic rats did not change LC3 content in bone marrow derived macrophages (BMM). M1 and M2 macrophages behaved accordingly to the host they were derived from. Diabetic M1 BMM had their LC3 vesicle-bound content diminished and M2 BMM enhanced their LC3 levels and insulin treatment failed to rescue autophagy to control levels. Insulin normalizes CINC-2 level but does not modulate autophagy markers., Conclusion: Taking these results together, diabetic macrophages derived from different compartments show different levels of autophagy markers compared to healthy animals, therefore, they suffer distinctively in the absence of insulin.

Objective and Design: Antithrombin is known as the most important natural coagulation inhibitor and has been shown to have anti-inflammatory properties. The present study aimed to investigate the effects of Bothrops jararaca antithrombin on acute inflammation induced by carrageenan in mice., Methods: We evaluated the anti-inflammatory activity of antithrombin on models of paw edema formation, cell migration and leukocyte-endothelium interaction in mice (Swiss; n = 5). Acute inflammation was induced by the administration of carrageenan (15 mg kg⁻¹)., Results: Treatment with B. jararaca antithrombin (1 mg kg⁻¹) 1 h before or after carrageenan administration significantly inhibited paw edema formation, reduced cell influx to the peritoneal cavity due to reduction in the migration of polymorphonuclear cells, and attenuated leukocyte rolling in the microcirculation of the cremaster muscle.The effects of antithrombin on vascular and cellular events of inflammation were completely abolished by treatment with the cyclo-oxygenase inhibitor indomethacin (4 mg kg⁻¹), suggesting the involvement of prostacyclin in the mechanism of inflammation inhibition by B. jararaca antithrombin., Conclusion: This work showed for the first time the anti-inflammatory properties of B. jararaca antithrombin on vascular and cellular events of inflammation. These findings suggest that antithrombin is effective in preventing paw edema formation, cell migration and leukocyte rolling induced by carrageenan in mice.

Bevacizumab treatment can result in tumor shrinkage of progressive vestibular schwannomas in some neurofibromatosis 2 (NF2) patients but its effect on meningiomas has not been defined. To determine the clinical activity of bevacizumab against NF2-related meningiomas, we measured changes in volume of meningiomas in NF2 patients who received bevacizumab for treatment of progressive vestibular schwannomas. A radiographic response was defined as a 20% decrease in tumor size by volumetric MRI analysis. In addition, we determined the expression pattern of growth factors associated with tumor angiogenesis in paraffin-embedded tissues from 26 unrelated meningiomas. A total of 48 meningiomas in 15 NF2 patients were included in this study with a median follow up time of 18 months. A volumetric radiographic response was seen in 29% of the meningiomas (14/48). Tumor shrinkage was not durable: the median duration of response was 3.7 months and the median time to progression was 15 months. There was no significant correlation between pre-treatment growth rate and meningioma response in regression models. Tissue analysis showed no correlation between tumor microvascular density and expression of VEGF pathway components. This data suggests that, in contrast to schwannomas, activation of VEGF pathway is not the primary driver of angiogenesis in meningiomas. Our results suggest that a minority of NF2-associated meningiomas shrink during bevacizumab therapy and that these responses were of short duration. These results are comparable to previous studies of bevacizumab in sporadic meningiomas.

The environmental changes resulting from the construction of hydroelectric dams may affect the fauna of insect vectors and consequently the epidemiology of the diseases they transmit. This work examined the mosquito and sand fly fauna in the area of the Aimorés hydroelectric power plant, analyzing the seasonal distribution and the degree of species synanthropy in different ecotopes. Between November, 2008 and September, 2009, entomological captures were performed with the help of HP light traps in the rural, urban, and forest areas of Aimorés, Ituêta, Resplendor, and Baixo Guandu counties. The fauna proved to be quite diversified. Twenty-two species of mosquitoes and 11 species of sand flies were found. Culex quinquefasciatus was predominant among mosquitoes (76.7%), while Lutzomyia intermedia prevailed among sand flies (34.5%). Some of the captured species have medical interest. Supported by the high degree of synanthropy, those species reinforce the need for epidemiological surveillance., (© 2012 The Society for Vector Ecology.)

Object: The aim of this paper was to define the clinical characteristics of spinal ependymomas associated with neurofibromatosis Type 2 (NF2)., Methods: The authors retrospectively reviewed the clinical records of patients with NF2 who had imaging findings consistent with ependymomas and were seen at Massachusetts General Hospital between 1994 and 2007. Clinical characteristics of these patients were obtained from hospital records, imaging studies, surgical reports, and pathology reports. Mutational analysis of the NF2 gene was performed in 37 of 44 unrelated patients., Results: Fifty-five patients met inclusion criteria for the study. The median age at diagnosis of NF2 was 21 years; the median time after diagnosis until identification of ependymomas was 5 years. Multiple ependymomas were present in 58% of patients. The most common site of involvement was the cervical cord or cervicomedullary junction (86% of imaging studies), followed by the thoracic and lumbar cords (62% and 8%, respectively). The majority of patients had no symptoms related to their tumors (42 patients [76%]). After a median follow-up of 50 months, surgery was performed in 11 patients (20%) for symptomatic progression (indications for surgery). Mutational analysis of the NF2 gene detected alterations in 28 (76%) of 37 unrelated patients, with nonsense and frameshift mutations accounting for 64% of detected mutations. The high rate of truncating mutations may help explain the high tumor burden in these patients., Conclusions: Neurofibromatosis Type 2-related ependymomas exhibit an indolent growth pattern with tumor progression limited to a minority of patients. The authors believe that surveillance is reasonable for asymptomatic ependymomas, including those with cystic areas that expand the cord. For symptomatic tumors, resection may be warranted depending on age, overall clinical status, and ease of resectability.

In the present study, it was investigated which components are responsible for the anti-inflammatory properties of Crotalus durissus terrificus venom (CdtV). The effect of crotoxin, as well as of other CdtV components was evaluated on edema, cell migration and alterations in leukocyte-endothelium interactions induced by carrageenan. Crotoxin (40 microg kg(-1)) was injected at different time periods before or after the injection of carrageenan (15 mg kg(-1)) into the mouse hind paw, peritoneum or scrotum. Results showed that crotoxin, but not other CdtV components, significantly inhibited inflammatory edema and cell migration when administered before or after carrageenan injection in mice. This toxin also prevented the occurrence of alterations in leukocyte-endothelium interactions induced by carrageenan injection, such as the increase in adhered cells. In animals pretreated with Boc2 (a selective antagonist of formyl peptide receptors), crotoxin showed neither inhibitory effects on edema and cell migration, nor prevented alterations in leukocyte-endothelium interactions induced by carrageenan. These findings demonstrate that crotoxin is the component responsible for the long-lasting anti-inflammatory activity of crude C. durissus terrificus venom, and activation of formyl peptide receptors seems to play a major role in this effect., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Atrial fibrillation (AF) is an arrhythmia frequently seen in the postoperative period of cardiac surgery. In this context, it is associated with the presence of comorbidities, longer length of hospital stay, and higher costs related to surgery. The mechanisms involved in the genesis of AF in the postoperative period of cardiac surgery (AFPO) are different from those causing paroxysmal AF. Knowledge of these mechanisms permits the use of efficient measures to reduce the incidence of this arrhythmia. According to recommendations of the literature, treatment is efficient and safe, because the rates of reversion to sinus rhythm are high and complications are reduced, and it is not associated with a high frequency of side effects.

The neurofibromatosis 2 locus (NF2) is inactivated through mutation and loss of heterozygosity (LOH) in 40-65% of all sporadic meningiomas, while the role of the p53 tumor suppression pathway in meningioma initiation and progression is still unclear. This study aims to determine if a p53 codon 72 arginine-to-proline polymorphism, found to be correlated with cancer development and cancer patient survival in other tumors, is associated with sporadic meningioma initiation or progression. We investigated Pro72 incidence in a cohort of 92 sporadic meningiomas and analyzed its association with histological grade (WHO classification) and with NF2 LOH (determined using polymorphic microsatellite markers on 22q). The Pro72 allele was not found to be selected for in the cohort. However, in the subgroup of meningiomas with NF2 LOH and carrying Pro72, 50.0% had high grade tumors (WHO grades II and III) compared to only 14.3% of those without NF2 LOH (OR = 6.0, CI = 1.56-23.11, P = 0.012). The significant association occurred only when considering subgroups of meningiomas with or without NF2 LOH, suggesting that not including NF2 status when analyzing study cohorts may explain the variability seen in the literature where all meningiomas were grouped together. Our data suggests a role for the p53 pathway in the progression of meningiomas in which NF2 is inactivated, and highlights the importance of accounting for NF2 LOH in future studies of meningiomas and the p53 pathway.

Neurofibromatosis type 1 (NF1) or von Recklinghausen disease is a genetic disorder affecting the growth of cells in nervous system. One of the most remarkable characteristics of this disease is the development of benign tumors of the nervous system (neurofibromas).The purpose of this study was to test tissue samples taken from neurofibromas and plexiform neurofibromas of NF1 patients for the presence of estrogen and progesterone receptors. We used previously collected samples from patients registered in the database of the Centro Nacional de Neurofibromatose (CNNF-Brazil). Samples from twenty-five patients in the database presenting plexiform neurofibromas (N1 group) and 25 samples from the same database from patients presenting neurofibromas (N2 group) were tested.We observed positive staining for progesterone receptors in 13 of the neurofibroma samples and 19 of the plexiform neurofibroma samples. Among the neurofibroma samples, we observed one sample with positive estrogen receptor staining, but none of the plexiform neurofibroma samples showed positive staining. We suggest further studies to investigate in greater depth possible hormonal influences on the development and growth of neurofibromas and plexiform neurofibromas in NF1.

Objective and Design: The present study investigates the supposed advantage of using an association of anti-inflammatory drugs and serum therapy to treat mouse paw edema induced by injection of Bothrops jararaca snake venom (BjV)., Material and Methods: Edema was induced by injecting BjV (2 microg) into the footpad of male Swiss mice (20-25 g) and measured by plethysmography. Groups of mice were treated 15, 30 or 45 min after BjV injection with Bothrops antivenom or anti-inflammatory drugs (dexamethasone, indomethacin or zileuton), or with the association of antivenom and each one of these drugs., Results: Antivenom, dexamethasone and indomethacin were effective in reducing the paw edema when used up to 30 min after BjV injection. Zileuton had the same effect, but only if used up to 15 min after BjV injection. The association of antivenom and dexamethasone showed the greatest inhibitory effect when used up to 45 min after BjV injection. At this time, antivenom or anti-inflammatory drugs administered alone were ineffective., Conclusion: Results suggest that dexamethasone combination with serum therapy can be beneficial for treatment of inflammatory edema caused by B. jararaca envenomation.

In the present study, we investigated the effects of Crotalus durissus terrificus venom (CdtV) on vascular and cellular events of inflammation induced by carrageenan (cg) in mice. To evaluate edema, CdtV (75 microg kg(-1)) was administered subcutaneously before (1h, 7 or 14 days) or after (1, 4 or 48 h) subplantar injection of cg (15 mg kg(-1)) into the mouse right hind paw; to analyze leukocyte influx, cg (200 microL) was injected i.p. in mice. The inhibitory action of CdtV on edema, either before or after cg injection, was prolonged, lasting even 72 h after administration. Besides, CdtV significantly inhibited migration of polymorphonuclear cells to peritoneal cavity when administered before or after cg. Such inhibitory effects of CdtV on edema and cell migration were also compared with well-known anti-inflammatory drugs. The results demonstrated that CdtV, when injected either 7 or 14 days or 1h before cg, induced a more effective and long-lasting anti-inflammatory effect than that observed with classical anti-inflammatory drugs. The association of CdtV with different drugs did not potentialize their actions on cell migration. These results demonstrate that CdtV exhibits long-lasting anti-inflammatory effects.

Objective: To evaluate CAD prevalence in patients with aortic aneurysm, as well as differences related to aneurysm topographies. To describe the primary risk factors for CAD related to this association and their occasional differences according to AA topographies., Methods: This was an open, prospective, nonrandomized study that evaluated 95 patients (66 men and 33 women, mean age 63 +/- 11.8). All patients, asymptomatic for CAD, had undergone aortic CT and coronary angiography. According to the AA topography, they were classified into three groups: 1) patients with thoracic aortic aneurysm (TAA); 2) thoracoabdominal aortic aneurysm (TAAA); and 3) abdominal aortic aneurysm (AAA). A database was created to store information from clinical data and complementary examinations. Statistical analysis was performed using the Students t test or analysis of variance (ANOVA) for continuous variables and chi-square test for categorical variables. P values < 0.05 were considered statistically significant., Results: CAD prevalence was 63.1%, and AAA was more prevalent than TAA and TAAA (76% vs. 70% vs. 30%, p = 0.001). The comparative analysis of CAD risk factors based on the aortic aneurysm topography revealed that smoking and dyslipidemia were more prevalent among AAA patients (74.5% vs. 42.3% vs. 60%, p = 0.01 and (54.2% vs. 19.9% vs. 60%, p = 0.007, respectively). As for coronary lesion severity in the population of AA patients, 12 (20%) had at least one lesion > or = 70% and 19 (31.6%), > or = 50%. Fifteen patients (25%) had single-vessel disease, 11 (18%) had two-vessel disease, and 34 (57%) had three-vessel disease., Conclusion: Asymptomatic CAD is highly prevalent in AA patients, particularly among those with AAA. Study results suggest the need for diagnostic stratification for CAD in patients with AA, especially those with AAA.

The NF2 tumor suppressor gene on chromosome 22 is a member of the protein 4.1 family of cytoskeletal elements. A number of single- and multiple-tumor phenotypes have been linked to alterations of NF2 since its characterization in 1993. We present a meta-analysis of 967 constitutional and somatic NF2 alterations from 93 published reports, along with 59 additional unpublished events identified in our laboratory and 115 alterations identified in clinical samples submitted to the Massachusetts General Hospital (MGH) Neurogenetics DNA Diagnostic Laboratory. In total, these sources defined 1,070 small genetic changes detected primarily by exon scanning, 42 intragenic changes of one whole exon or larger, and 29 whole gene deletions and gross chromosomal rearrangements. Constitutional single-exon events (N=422) were significantly more likely to be nonsense or splice site changes than somatic events (N=533), which favored frameshift changes (chi(2) test; P<0.001). Somatic events also differed markedly between tumors of different pathology, most significantly in the tendency of somatic events in meningiomas to lie within the 5' FERM domain of the transcript (Fisher's exact test; P<0.01 in comparison to schwannomas) with a complete absence of mutations in exons 14 and 15. There was no statistically significant difference in mutation type or exon distribution between published constitutional events and those found by the clinical laboratory. Less than 10% of all published and unpublished small alterations are nontruncating (N=63) and these changes are clustered in exons 2 and 3, suggesting that this region may be especially crucial to tumor suppressor activity in the protein., (Published 2006 Wiley-Liss, Inc.)

A descriptive case study was performed on 75 patients with NF1 (neurofibromatosis type 1) from the CNNF (Brazil) database. Serum IgE levels were determined using the IgE radioimmunosorbent test, with the reference values of 75-502 IU mL(-1). The patients were divided into groups, with 25 patients presenting plexiform neurofibromas, 25 presenting neurofibromas and 25 presenting no neurofibromas. The purposes of this study were to determine the serum IgE levels of patients with NF1 presenting plexiform neurofibromas, neurofibromas and no neurofibromas, as well as to determine possible correlations between serum IgE levels and the size of the plexiform neurofibromas and neurofibromas presented by these patients. Elevated serum IgE levels were observed in all the patient groups. We did not observe a correlation between IgE levels and age in these patients; however, we did observe correlations between IgE levels and neurofibroma and plexiform neurofibroma size. We suggest further studies to confirm these results and to investigate in greater depth the possible role of IgE in the development and growth of neurofibromas and plexiform neurofibromas in NF1.

Objective: This study was undertaken to evaluate the efficacy and safety of intravaginal administration of glyceryl trinitrate plus dinoprostone versus dinoprostone, for cervical ripening and induction of labor., Study Design: A prospective, double-blind, placebo-controlled, randomized clinical trial was conducted among 196 singleton low-risk nullipara women with term pregnancies and unfavorable cervices who were randomly assigned to receive intravaginal glyceryl trinitrate plus dinoprostone or placebo plus dinoprostone. The main outcome variables were time from application to active phase of labor and to delivery. Secondary outcomes were change in Bishop score, fetal and maternal morbidity, and incidence of cesarean deliveries., Results: The interval from application of the initial dose to the beginning of active phase of labor was 868 +/- 582 and 1136 +/- 692 minutes (P = .004) and from initial dose to delivery was 1339 +/- 826 and 1620 +/- 975 minutes (P = .03) for the glyceryl trinitrate and placebo groups, respectively. There were no significant differences in Bishop score change, cesarean section rate, and in the incidence of hypersystole and hyperstimulation. The incidence of tachysystole was significantly lower in the glyceryl trinitrate group (4% vs 15%, P < or = .02). No maternal and neonatal adverse effects were noted., Conclusion: The association of glyceryl trinitrate with dinoprostone is more effective than dinoprostone alone for labor induction in low-risk patients at term with unfavorable cervices.

In the present article, regarding a clinical case of Thrombasthenia of Glanzmann with severe anaemia by menometrorrhagia, the authors propose the vaginal hysterectomy and the administration of the recombinant factor VIIa on the immediate pre and postoperative as effective therapeutical alternatives.