Crisaborole Ointment Improves Quality of Life of Patients with Mild to Moderate Atopic Dermatitis and Their Families.

IntroductionThe impact of crisaborole ointment, a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD), on quality of life (QoL) was assessed in two identically designed phase 3 studies (AD-301: NCT02118766; AD-302: NCT02118792, both at http://www.clinicaltrials.gov ).MethodsIn both studies, patients aged ≥ 2 years with mild to moderate AD per the Investigator's Static Global Assessment were randomly assigned 2:1 to receive crisaborole or vehicle twice daily for 28 days. QoL was assessed using the Children's Dermatology Life Quality Index (CDLQI) (2-15 years), the Dermatology Life Quality Index (DLQI) (≥ 16 years), and the Dermatitis Family Impact Questionnaire (DFI) (parents/caregivers/family of patients aged 2-17 years). Established QoL score severity bands provided clinical context.ResultsGreater mean improvement in QoL was observed in crisaborole-treated patients than in vehicle-treated patients at day 29 [mean change from baseline (∆BL), CDLQI: - 4.6 vs. - 3.0; P < 0.001; DLQI: - 5.2 vs. - 3.5; P = 0.015]. At baseline, more than half the patients had a "moderate effect" or higher of AD on QoL. At day 29, there was a trend toward more crisaborole- than vehicle-treated patients having "small effect" to "no effect", The QoL of parents/caregivers/family improved more for crisaborole-treated than for vehicle-treated patients (∆BL, DFI: - 3.7 vs. - 2.7; P = 0.003).ConclusionCrisaborole treatment results in clinically meaningful improvement in QoL for patients and their parents/caregivers/families.Trial registrationAD-301: http://www.clinicaltrials.gov , NCT02118766; AD-302: http://www.clinicaltrials.gov , NCT02118792.FundingAnacor Pharmaceuticals, Inc., a wholly owned subsidiary of Pfizer Inc., New York, NY

Discovering the Undiscoverable: Patent Eligibility of DNA and the Future of Biotechnical Patent Claims Post-\u3ci\u3eMyriad\u3c/i\u3e

In June 2013 the Supreme Court held that naturally occurring human DNA cannot be patented, but synthetically created DNA is patent-eligible. Though a major victory for patients’ rights, the holding of Association for Molecular Pathology v. Myriad Genetics appears to be the latest in a series of restrictions on patents and the human body, much to the annoyance of biotechnology companies. However, this case should not be viewed as the final word in patenting “natural phenomena.” Patent claims of genetic material are still viable when the claim details a new and useful improvement on the naturally occurring product or an application of the product to a process. Furthermore, the Myriad Court noted that extending the natural products rule too far would be against public policy, giving litigators room to explore the contours of this rule. This Article examines the limits of the Supreme Court’s decision and the avenues that potential patent seekers still have for making eligible patent claims on naturally occurring products and phenomena, as well as the processes for identifying such products and phenomena. It highlights the areas where the courts are likely to take a hard stance against patent eligibility and where opportunities still exist to claim a valid patent in three areas. First, though discovery of a natural process in its naturally-occurring state is now un-patentable, the Myriad holding signals that a variation on this natural state, no matter how slight, could make the product eligible for a patent under the “new and useful improvements” rule. Second, the “application of new processes” rule is unchanged by this case. Third, a public policy argument on the importance of protecting medical and genetic discoveries may be more relevant in light of Myriad’s broad holding

Understanding economic evidence for the prevention and treatment of atopic eczema

Background Atopic eczema is an inflammatory skin condition, with a similar impact on health-related quality-of-life as other chronic diseases. Increasing pressures on resources within the NHS increase the importance of having good economic evidence to inform their allocation. This paper aims to educate dermatologists about economic methods with illustration to currently available economic evidence on eczema. Methods/design The type and role of different types of economic evidence is illustrated by evidence found in a systematic literature search conducted across 12 online databases published until 22nd May 2017. Primary empirical studies either reporting the results of a cost of illness study or evaluating the cost, utility or full economic evaluation of interventions for preventing or treating eczema were included. Two reviewers independently assessed studies for eligibility and performed data abstraction, with disagreements resolved by a third reviewer. Evidence tables of results were produced for narrative discussion. The reporting quality of economic evaluations was assessed. Results 78 studies (described in 80 papers) were deemed eligible. 33 (42%) were judged to be economic evaluations, 12 (15%) cost analyses, 6 (8%) utility analyses, 26 (34%) cost-of-illness studies and 1 feasibility study (1%). The calcineurin inhibitors: tacrolimus and pimecrolimus, as well as barrier creams had most economic evidence available. Partially hydrolysed infant formula was the most commonly evaluated prevention. Conclusions The current level of economic evidence for interventions aimed at preventing and treating eczema is limited compared to that available for clinical outcomes suggesting that greater collaboration between clinicians and economists might be beneficial

Genomic Profiling of Advanced-Stage, Metaplastic Breast Carcinoma by Next-Generation Sequencing Reveals Frequent, Targetable Genomic Abnormalities and Potential New Treatment Options

Context.— Metastatic metaplastic breast carcinoma (MPBC) is an uncommon, but aggressive, tumor resistant to conventional chemotherapy. Objective.— To learn whether next-generation sequencing could identify potential targets of therapy for patients with relapsed and metastatic MPBC. Design.— Hybridization capture of 3769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to a minimum of 50 ng of DNA extracted from 20 MPBC formalin-fixed, paraffin-embedded specimens and sequenced to high uniform coverage. Results.— The 20 patients with MPBC had a median age of 62 years (range, 42–86 years). There were 9 squamous (45%), 9 chondroid (45%), and 2 spindle cell (10%) MPBCs, all of which were high grade. Ninety-three genomic alterations were identified, (range, 1–11) with 19 of the 20 cases (95%) harboring an alteration that could potentially lead to a targeted treatment option. The most-common alterations were in TP53 (n = 69; 75%), PIK3CA (n = 37; 40%), MYC (n = 28; 30%), MLL2 (n = 28; 30%), PTEN (n = 23; 25%), CDKN2A/B (n = 19; 20%), CCND3 (n = 14; 15%), CCNE1 (n = 9; 10%), EGFR (n = 9; 10%), and KDM6A (n = 9; 10%); AKT3, CCND1, CCND2, CDK4, FBXW7, FGFR1, HRAS, NF1, PIK3R1, and SRC were each altered in a single case. All 16 MPBCs (100%) that were negative for ERBB2 (HER2) overexpression by immunohistochemistry and/or ERBB2 (HER2) amplification by fluorescence in situ hybridization were also uniformly (100%) negative for ERBB2 amplification by next-generation sequencing–based copy-number assessment. Conclusions.— Our results indicate that genomic profiling using next-generation sequencing can identify clinically meaningful alterations that have the potential to guide targeted treatment decisions in most patients with metastatic MPBC

Restoration Versus Retribution: Justice in Krzysztof Kieslowski's Dekalog

The topics of law and justice constantly manifest in Polish director Krzysztof Kieslowski&rsquo;s films. His 1988 television series, Dekalog, proves no exception. The ten-film series uses each segment to focus on one of the Ten Commandments, one of the most wellknown, early legal texts. While primarily dealing with the violations of these rules, the films also examine the consequences of such infringements and how wrongs may most effectively be amended. Through his portrayal of righting the violated commandment, Kieslowski reveals his interpretations of justice. Justice, however, never takes on an absolute definition in this series, as the director acknowledges the many different approaches to amending wrongs. Ultimately, Kieslowski depicts the concepts of restorative justice as being most effective in creating harmony after an offense. Restorative justice does not seek to punish the offender, but instead attempts to create a dialogue between the victim and the offender. In doing so, the offender can realize any wrongs and make amends, becoming a valuable member of society. Furthermore, the legal system is encouraged to understand the background of the offender so as to address the circumstances that could promote crime. Retributive justice provides the foil to this theory, with emphasis being placed on proportionate punishment, in the hopes of deterring future crime. For Kieslowski, understanding and emotional connections prove far more important that punishment. The more optimistic films in the series show the success of restorative justice, while the bleaker ones depict selfish quests for revenge. Analysis of Dekalog I, Dekalog V, Dekalog VII, Dekalog VIII, and Dekalog X reveals Kieslowski&rsquo;s vision of the moral benefits of restorative justice in handling violations of law over the selfish, shortsighted motivations behind retributive justice.</p

Atopic dermatitis and vitamin D: facts and controversies

Patients with atopic dermatitis have genetically determined risk factors that affect the barrier function of the skin and immune responses that interact with environmental factors. Clinically, this results in an intensely pruriginous and inflamed skin that allows the penetration of irritants and allergens and predisposes patients to colonization and infection by microorganisms. Among the various etiological factors responsible for the increased prevalence of atopic diseases over the past few decades, the role of vitamin D has been emphasized. As the pathogenesis of AD involves a complex interplay of epidermal barrier dysfunction and dysregulated immune response, and vitamin D is involved in both processes, it is reasonable to expect that vitamin D's status could be associated with atopic dermatitis' risk or severity. Such association is suggested by epidemiological and experimental data. in this review, we will discuss the evidence for and against this controversial relationship, emphasizing the possible etiopathogenic mechanisms involved.Univ Brasilia UNB, Brasilia, DF, BrazilFed Dist Hlth State Dept SES DF, Brasilia, DF, BrazilUniv Brasilia HUB UNB, Brasilia Univ Hosp, Brasilia, DF, BrazilSão Paulo Fed Univ UNIFESP, Brasilia, DF, BrazilSão Paulo Fed Univ UNIFESP, Brasilia, DF, BrazilWeb of Scienc

Antimicrobial Peptides and Skin: A Paradigm of Translational Medicine

Antimicrobial peptides (AMPs) are small, cationic, amphiphilic peptides with broad-spectrum microbicidal activity against both bacteria and fungi. In mammals, AMPs form the first line of host defense against infections and generally play an important role as effector agents of the innate immune system. The AMP era was born more than 6 decades ago when the first cationic cyclic peptide antibiotics, namely polymyxins and tyrothricin, found their way into clinical use. Due to the good clinical experience in the treatment of, for example, infections of mucus membranes as well as the subsequent understanding of mode of action, AMPs are now considered for treatment of inflammatory skin diseases and for improving healing of infected wounds. Based on the preclinical findings, including pathobiochemistry and molecular medicine, targeted therapy strategies are developed and first results indicate that AMPs influence processes of diseased skin. Importantly, in contrast to other antibiotics, AMPs do not seem to propagate the development of antibiotic-resistant micro-organisms. Therefore, AMPs should be tested in clinical trials for their efficacy and tolerability in inflammatory skin diseases and chronic wounds. Apart from possible fields of application, these peptides appear suited as an example of the paradigm of translational medicine for skin diseases which is today seen as a `two-way road' - from bench to bedside and backwards from bedside to bench. Copyright (c) 2012 S. Karger AG, Base

Molecular mechanisms in atopic eczema:insight gained from genetic studies

Atopic eczema (synonymous with atopic dermatitis and eczema) is a common heterogeneous phenotype with a wide spectrum of severity from mild transient disease to a severe chronic disorder with atopic and non-atopic co-morbidities. Eczema is a complex trait, resulting from the interaction of multiple genetic and environmental factors. The skin, as an organ that can be biopsied easily, provides opportunities for detailed molecular genetic analysis. Strategies applied to the investigation of atopic eczema include candidate gene and genome-wide studies, extreme phenotypes and comparative analysis of inflammatory skin diseases. Genetic studies have identified a central role for skin barrier impairment in eczema predisposition and perpetuation; this has brought about a paradigm shift in understanding atopic disease but specific molecular targets to improve skin barrier function remain elusive. The role of Th2-mediated immune dysfunction is also central to atopic inflammation and has proved to be a powerful target for biological therapy in atopic eczema. Advances in understanding eczema pathogenesis have provided opportunities for patient stratification, primary prevention and therapy development, but there remain considerable challenges in the application of this knowledge to optimise benefit for patients with atopic eczema in the era of personalised medicine